Polymorphisms rs693421 and rs2499601 at locus 1q43 and their haplotypes are not associated with primary open-angle glaucoma: a case-control study

Polymorphisms rs693421 and rs2499601 at locus 1q43 and their haplotypes are not associated with primary open-angle glaucoma: a case-control study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research note Polymorphisms rs693421 and rs2499601 at locus 1q43 and their haplotypes are not associated with primary open-angle glaucoma: a case-control study Altaf A Kondkar, Taif A. Azad, Tahira Sultan, Faisal A. Al-Mobarak, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.10703/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jul, 2019 Read the published version in BMC Research Notes → Version 2 posted 4 You are reading this latest preprint version Show more versions Abstract Objective: The genetic spectrum of primary open-angle glaucoma (POAG) in middle-eastern Saudi's is still elusive. To this end, we investigated an association between rs693421, rs2499601 and their haplotypes at chromosome 1q43 locus with POAG and its clinical phenotypes. Genotyping was performed with TaqMan® assays. Haplotypes and their interaction analysis were carried out by SHEsis and SNPStats online tools. Results: The minor “T” allele frequency of rs693421 was 0.48 in controls and 0.52 in cases (odds ratio (OR)=1.15, 95% confidence interval (CI)=0.85–1.54, p=0.368). Similarly, for rs2499601, the minor “C” allele frequency was 0.49 in controls as compared to 0.53 in cases (OR=1.19, 95% CI=0.89–1.60, p=0.236). Besides, genotype distribution for both these polymorphisms was also not significant in additive, dominant and recessive models. rs693421 and rs2499601, showed significant linkage disequilibrium (D’ statistics = 0.69, p<0.001) but haplotype association was non-significant (p=0.698). The significance did not vary after adjustment to age and sex. No significant genotype association was observed with intraocular pressure, cup/disc ratio and number of anti-glaucoma medication in POAG group. Furthermore, age, sex and genotypes did not contribute any significant risk of POAG in regression analysis. We report no association between rs693421, rs2499601 and their haplotypes with POAG and related phenotypes. Epidemiology Ophthalmology chromosome 1q43 genetic association glaucoma haplotype rs693421 rs2499601 Saudi INTRODUCTION Epidemiological studies in the past suggest that primary open-angle glaucoma (POAG), at least in part, can be caused by heritable factors [ 1–3 ], with five to 10-fold increased risk in the first-degree relatives and an estimated heritability of 0.81 [ 4 ]. However, given the polygenic nature of POAG, its exact genetic etiology still remains elusive. Genetic studies are a critical tool to identify genes and molecular pathways in complex human diseases. Likewise, using a similar approach, population-based genome-wide and candidate gene studies have reported a number of polymorphic variations or loci that have been associated with POAG and/or its quantitative endophenotyes [ 5 , 6 ]. In an initial study, using a 2-stage genome-wide approach in a group of Japanese POAG patients, Nakano et al reported 3 genetic loci, harboring six single nucleotide polymorphisms (SNPs), of having significant association with the disease [ 7 ]. Of these, 4 intergenic polymorphisms such as rs540782, rs540784, rs693421 and rs2499601 are located on chromosome 1q43. The genes flanking the locus 1q43 include Zona Pellucida glycoprotein 4 ( ZP4) and Ryanodine Receptor 2 ( RYR2). . ZP4 plays a role in fertilization and preimplantation development; and genetic variations in ZP4 are reported to be associated with ovarian disease [ 8 ] and glaucoma [ 7 ]. Ryanodine receptors (RyRs) are ubiquitous intracellular calcium (Ca 2+ ) release channels localized in the plasma membrane of endoplasmic or sarcoplasmic reticulum of many organs, including retina [ 9 ]. Given the important physiological role of RyR channel, defect(s) in RyR function, either due to oxidative stress or genetic mutations can render these channels leaky to Ca 2+ influx. These may thereby produce disease-causing signals and contribute to severe pathologies as those observed in heart failure, muscular dystrophy, diabetes, or neurodegenerative diseases [ 10 , 11 ]. Also, considering the potential role of calcium channel blockers in treatment of glaucoma [ 12 ], RYR2 may be a potential candidate in POAG. Replication of case-control association studies in various ethnicities has genetic epidemiological importance, so as to enable future utilization of these genetic biomarkers in evaluation of the disease risk. Association studies using candidate gene approach are a useful tool to identify the genetic contribution of SNPs/loci, each of which may exhibit a relatively small risk but have a significant impact in a population. The genetic spectrum of POAG, especially in middle-eastern Saudi POAG patients, is still unclear. We have previously reported a lack of association between SNPs rs540782 and rs540784 with POAG in a small group of Saudi patients [ 13 , 14 ]. The present study investigated an association between rs693421, rs2499601 and their haplotypes with POAG or its clinical indices in a much larger and different set of sample cohort of Saudi origin. Besides, there are no other published reports of association of these SNPs (rs693421 and rs2499601) in this population. METHODS Study design and participants: We conducted a retrospective case-control genetic association study. The study followed the principles of the Declaration of Helsinki and had an institutional review board ethics committee approval (# 08–657). Patients (n = 185) and controls (n = 171) were recruited at King Abdul-Aziz University Hospital in Riyadh, Saudi Arabia. The inclusion-exclusion criteria for patients and controls have been detailed elsewhere [ 15 ]. Briefly, POAG patients showed (i) optic disk or retinal nerve fiber layer changes; (ii) visual field abnormalities; (iii) bilateral open anterior chamber angles; and (iv) adult onset. Secondary forms of glaucoma and history of steroid usage or ocular trauma were excluded. Controls were >20 years of age with normal IOP, normal optic disk, open anterior chamber angles and no history of ocular disease(s) or eye surgeries. Subjects refusing to participate were also excluded. Genotyping of rs693421 and rs2499601 at Chr.1q43: DNA samples were genotyped for rs693421 and rs2499601using the TaqMan® genotyping assays C_80796_20 and C__26180887_10, respectively (Applied Biosystems Inc., Foster City, CA, USA; Cat#: 4351379) as described previously [ 13 ]. Statistical Analysis: SPSS version 22 (IBM Inc. Chicago, IIinois, USA) was used to perform statistical tests as indicated. Linkage disequilibrium analysis was conducted using SHEsis online software ( http://analysis. bio-x.cn/myAnalysis.php). . SNPStats online software ( http:// bioinfo.iconcologia.net/snpstats/start.htm) was used to construct haplotypes and analyze the interactions with related factors. p<0.05 (2-sided) was considered statistically significant. RESULTS Demographic and clinical characteristics: Except for family history of glaucoma ( p = 0.019), there was no significant difference in age, gender, systemic co-morbidities and smoking habit between POAG cases and controls (Supplementary Table 1). Genotype and allele frequency: rs693421 and rs2499601 did not deviate significantly from the HWE (p>0.05). For rs693421, the minor “T” allele frequency was 0.48 in controls and 0.52 in cases, but non-significant (OR = 1.15, 95% CI = 0.85—1.54, p = 0.368). Besides, genotype distribution was also not significant in additive (Chi 2 = 1.74, df = 2, p = 0.417), dominant (p = 0.860) and recessive (p = 0.190) models ( Table 1). . Similarly, for rs2499601, the minor “C” allele frequency was 0.49 in controls as compared to 0.53 in cases (OR = 1.19, 95% CI = 0.89—1.60, p = 0.236) with no significant genotype effect in additive (Chi 2 = 1.69, df = 2, p = 0.429), dominant (p = 0.512) and recessive (p = 0.195) models. In addition, for both the SNPs, the genotype/ allele distribution between POAG cases and controls was also non-significant after adjustment for age and sex. There was no significant interaction with sex for rs693421 (p = 0.83) and rs2499601 (p = 0.83); and the significance did not vary after adjustment for age. Linkage disequilibrium and haplotype association: rs693421 and rs2499601 showed significant linkage disequilibrium as reflected by D’ value (D’ statistics = 0.69, p<0.001) ( Supplementary Fig ure 1). . No significant haplotype association was observed (p = 0.698) ( Table 2). . The significance did not vary after adjustment to age and sex (p = 0.750). Genotype effect on demographic and clinical phenotypes in POAG: Age and gender distribution was not significant for both rs693241 and rs2499601 genotypes. In addition, phenotypes such as intraocular pressure (IOP), cup/disc ratio and number of antiglaucoma medication showed no significant genotype effect (Supplementary Table 2). Besides, logistic regression showed that age, sex, rs693241 and rs2496601 could not significantly explain the likelihood of having POAG ( Supplementary Table 3). . DISCUSSION POAG is the second most common type of glaucoma in Saudi Arabia [ 16 ]. Despite its high prevalence, the role of genetic factors contributing to the progression and/or development of POAG are largely unknown and thus warrants genetic investigation(s) to identify these factors that may plausibly be associated or contribute to POAG pathogenesis. To this end, evaluation of an association between rs693421, rs2496601 and their haplotypes in a Saudi POAG cohort in this study did not yield any significant relationship with the disease. Nakano and colleagues have previously reported a moderate association of polymorphisms rs693241 (OR = 1.48, 95% CI = 1.20—1.83, p = 0.00029) and rs2499601 (OR = 1.45, 95% CI = 1.17—1.79, p = 0.000589) at locus 1q43 in 1,575 Japanese POAG patients. The findings were successfully replicated in stage–2 GWA study [ 7 ]. However, except for rs693421 (OR = 1.4 (1.1–1.7), p = 0.0082) in Korean subjects, subsequent studies in a South Indian [ 17 ], Afro-Caribbean [ 18 ], Japanese [ 19 ], the Hong Kong cohort [ 20 ], Korean (for SNP rs2499601) [ 21 ] and very recently in the Han Chinese population [ 22 ] have failed to replicate this association between rs693241, rs2499601 and POAG. Besides, the functional significance of these SNPs or locus to POAG development remains unknown. In contrast to the findings of Nakano et al [ 7 ] and consistent with the findings reported in other population [ 17 , 19–21 ], no significant genotype/allelic effect of these SNPs in POAG was observed in our study. These conflicting results can be ascribed to factors such as differences in sample size, lack of adequate statistical power or differences in the phenotypes of the sample population included in the study. A comparison of minor allele frequencies of these SNPs in different ethnic groups is shown in Table 3. The minor allele frequencies observed for these variants in the Saudi population (controls) was comparable to the Oriental population’s [ 7 , 19–21 ], but higher than that reported among the Indian [ 17 ] and Afro-Caribbean ethnic groups [ 18 ]. The genotypes of adjacent polymorphisms are often highly correlated, referred to as being in linkage disequilibrium, and could be inherited as haplotypes. Haplotypes display an interaction of these polymorphisms and can serve as a maker of disease susceptibility [ 23 ]. In complex multifactorial diseases, such as POAG, multiple polymorphisms/loci in the form of haplotypes can be more informative as compared to single allele polymorphism analysis. Hence, to gain additional information we performed association between 1q43 locus haplotypes (for polymorphisms rs693421 and rs2499601) and POAG. The four SNPs (rs540782, rs540784, rs693421 and rs2499601) at chromosome 1q43 have been reported to exhibit strong linkage disequilibrium (D’ = 0.90–1.0) [ 7 , 17 ], but data on haplotypes with these did not indicate any association with POAG among Indians [ 17 ] as opposed to significant association (p<0.05) among Han Chinese POAG subjects [ 22 ]. In our study, significant linkage disequilibrium between rs693421 and rs2499601 was found (D’ = 0.69) but analysis of distribution differences of the four haplotypes in the POAG cases and controls did not show any significant association with the disease. Unfortunately, genotype data for two other SNPs rs540782 and rs540784 at 1q43 were not available for all the subjects included in this study to assess their linkage and/or haplotype association. Association analysis for any genotype effect of rs693421 and rs2499601 on clinical phenotypes did not provide any significant link. Age and gender showed no significant distribution and clinical phenotypes for glaucoma such as IOP, cup/disc ratio and number of anti-glaucoma medication that serves as markers of disease severity also showed no significant genotype effects in the POAG group. Similar to Nakano et al study in 2009, many other recent GWA-studies have reported numerous SNPs in multiple loci/genes in association with POAG and its endophenotypes among European, African and Asian ethnic groups (as reviewed elsewhere [ 5 , 6 ]). In another recent large-scale study by Shiga et al [ 24 ] in the Japanese population, variants near cyclin-dependent kinase inhibitor 2B-antisense 1 ( CDKN2B-AS1, rs2157719), SIX Homeobox 6 ( SIX6, rs33912345) and growth arrest-specific 7 ( GAS7, rs9913911) were found to be associated with POAG. In contrast, with the exception of variant rs10483727 in ( SIX1/ SIX6) gene locus [ 25 ], our previous studies to identify genetic polymorphisms associated with Saudi POAG patients in genes including caveolin 1/caveolin 2 ( CAV1/CAV2) [ 26 ], atonal homolog 7 ( ATOH7) [ 27 ], ( CDKN2B) [ 28 ], transmembrane and coiled-coil domain 1( TMCO1) [ 29 ], ( GAS7) [ 30 ] and ZP4 [ 13 , 14 ], have yielded negative results indicating that the plausible causal genetic defect(s) in POAG cases of Saudi origin may be different than those from European, African and Asian descents, including the Japanese population. There can be several potential reasons for differences in association findings. The differences could reflect an ethnic-specific genetic etiology of POAG. Furthermore, the differences could be attributed to variations in environmental exposures, clinical variability observed in patients with POAG, variations in the endophenotypic traits related to POAG or other epistatic interactions. Nonetheless, based on our findings and that of reported in other ethnic groups, it appears that polymorphisms rs693421 and rs2499601 at chromosome 1q43 (near ZP4/ RYR2 genes), may not have a significant role in POAG pathogenesis and hence, cannot serve as genetic markers to assess the disease risk. LIMITATIONS Our study could not replicate the previously observed association of rs693421 and rs2499601 in POAG. The results suggest that these SNPs and their haplotypes at locus 1q43, independently or in relation to other clinical phenotypes, are not associated with POAG and hence may not pose a significant risk of POAG in individuals of Saudi origin. However, the lack of association needs cautious interpretation since the study is limited by its sample size, performed in specific ethnicity and their interaction with other genetic or non-genetic factors cannot be ruled out. Nonetheless, based on the minor allele frequency from 1000 Genomes database or that observed in our current study, the sample size used, showed an estimated power of 90% with a detectable odds per allele of 1.60 (2-sided test) and 1.53 (one-sided test). However, assuming an OR of 1.45 as observed in the Japanese POAG patients [ 7 ], our study had only 70% and 71% powers (2-sided test) to detect any significant associations between POAG and rs693421 and rs2499601 polymorphisms, respectively. As in most genetic association studies, in order to detect an odds of ≤1.5-fold a much larger sample size would be needed. ABBREVIATIONS ATOH7: atonal homolog 7; CAV1/CAV2: caveolin 1/ caveolin 2; CDKN2B: cyclin-dependent kinase inhibitor 2B; CI: confidence interval; GWAS: genome-wide association study; GAS7: growth arrest-specific 7; HWE: Hardy-Weinberg Equilibrium; IOP: intraocular pressure; OR: odds ratio; POAG: primary open angle glaucoma; RYR2: ryanodine receptor 2; SNP: single nucleotide polymorphism; SIX1/ SIX6: SIX Homeobox 1/ SIX Homeobox 6; TMCO1: transmembrane and coiled-coil domain 1; ZP4: zona pellucida glycoprotein 4 DECLARATIONS Ethics approval and consent to participate The study adhered to the tenets of the Declaration of Helsinki and had received approval from the Institutional Review Board and Research Ethics Committee of College of Medicine, King Saud University, Riyadh, Saudi Arabia (approval number # 08–657). Written, informed consent was obtained from all participants prior to their inclusion in this study. Consent for publication Not applicable. Availability of data The data supporting the conclusions of this article are all presented within the article. Competing interests Authors have no conflict of interests. Funding: This work was supported by King Saud University through Vice Deanship of Scientific Research Chair, Glaucoma Research Chair in Ophthalmology but had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Authors’ contributions AAK: study design, analysis, interpretations, manuscript preparation; TAA, TS: sample preparation, genotyping; FAM, HK: subject recruitment, clinical diagnosis, clinical data. SAA: study design, recruitment, clinical diagnosis and data. All the authors have approved the final version of the manuscript. Acknowledgments: The authors would like to thank the Vice Deanship of Scientific Research Chair, Glaucoma Research Chair in Ophthalmology at the King Saud University for supporting this study. 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Tables Table 1 Association analysis of allele frequency and genotype distribution between POAG cases and controls SNP locus Gene type Controls (%) POAG (%) OR (95% CI) p value a Rs693421 GG 43 (25.10 45 (24.3) 1.00 Reference GT 91 (53.2) 89 (48.1) 0.93 (0.56 – 1.56) 0.791 TT 37 (21.6) 51 (27.6) 1.32 (0.73 – 2.39) 0.362 Additive - - - 0.417 Dominant - - 1.05 (0.65 –1.69) 0.860 Recessive - - 1.38 (0.85 – 2.24) 0.190 G 177 (52.0) 179 (48.0) 1.00 Reference T 165 (48.0) 191 (52.0) 1.15 (0.85 – 1.54) 0.368 HWE P 0.390 0.616 - - Rs2499601 TT 48 (28.1) 47 (25.4) 1.00 Reference TC 80 (46.7) 80 (43.2) 1.02 (0.61 – 1.70) 0.920 CC 43 (25.1) 58 (31.4) 1.38 (0.78 – 2.42) 0.265 Additive - - - 0.429 Dominant - - 1.18 (0.72 – 1.92) 0.512 Recessive - - 1.36 (0.85 – 2.16) 0.195 T 176 (51.0) 174 (47.0) 1.00 Reference C 166 (49.0) 196 (53.0) 1.19 (0.89 – 1.60) 0.236 HWE P 0.406 0.072 a Pearson Chi 2 test, OR (95% CI) – odds ratio (95% confidence interval), HWE P – Hardy-Weinberg equilibrium p value Table 2 Haplotype frequencies and association with POAG Haplotype* Frequency Controls Frequency POAG Odds ratio (95% confidence interval) p value GC 0.079 0.087 1.10 (0.64 – 1.87) 0.726 GT 0.438 0.397 0.84 (0.62 – 1.13) 0.267 TC 0.406 0.443 1.16 (0.86 – 1.56) 0.317 TT 0.076 0.073 0.95 (0.54 – 1.66) 0.865 *Haplotypes were sorted in the order of rs 693421 and rs 2499601 Global haplotype association X 2 =1.43, df=3, p=0.698 (Pearson’s) Table 3 Comparison of rs693421 and rs2499601 minor allele frequency distribution among different ethnic group Population SNP Minor allele frequency* p value References Controls POAG Japan rs693421 0.450 0.550 0.00029 [ 7 ] rs2499601 0.460 0.550 0.00058 India rs693421 0.357 0.405 0.616 [ 17 ] rs2499601 0.413 0.482 0.286 Afro-Caribbean rs693421 0.291 0.313 0.733 [ 18 ] rs2499601 0.295 0.271 0.528 Korea rs693421 0.476 0.548 0.030 [ 21 ] rs2499601 0.480 0.533 0.120 Japan rs693421 0.498 0.528 0.246 [ 19 ] rs2499601 0.497 0.530 0.208 China rs693421 0.465 0.459 0.98 [ 20 ] rs2499601 ns ns - Saudi rs693421 0.482 0.516 0.368 This Study rs2499601 0.485 0.530 0.236 * rs693421[T] and rs2499601[C]; ns – not studied Supplementary Files supplement1.doc Cite Share Download PDF Status: Published Journal Publication published 23 Jul, 2019 Read the published version in BMC Research Notes → Version 2 posted Editorial decision: Accept 16 Jul, 2019 Editor assigned by journal 15 Jul, 2019 Submission checks completed at journal 14 Jul, 2019 Editor invited by journal 14 Jul, 2019 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1654","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research note","associatedPublications":[],"authors":[{"id":111734,"identity":"df67fd0b-664f-4d8f-9488-e8294ffa4a4e","order_by":1,"name":"Altaf A Kondkar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYDACHhA+wMDAD+IkFJCiRbIBpMWAFC0GB0A8YrTw9xw+9uDNGbt84/OrEz88MGCQ5xc7gF+LxNm2dMM5N5Itt914u1kC6DDDmbMTCFhznsdMmucDs4HZjbMbQFoSDG4T0CIP0VJvYDzj7OYfRGkxONsD1HLjsIEBf+824mwxPHMsTXLOmeMGEjd4t1kkGEgQ9ovcmeRjEm+OVRvw95/dfPNHhY08vzQBLQggAVYpQaxyEOA/QIrqUTAKRsEoGEkAAL8LRZlmOhNxAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5516-6951","institution":"King Saud University","correspondingAuthor":true,"prefix":"","firstName":"Altaf","middleName":"A","lastName":"Kondkar","suffix":""},{"id":111735,"identity":"31f0c78b-719d-40b6-89e7-5f392e1f1f98","order_by":2,"name":"Taif A. Azad","email":"","orcid":"","institution":"King Saud University","correspondingAuthor":false,"prefix":"","firstName":"Taif","middleName":"A.","lastName":"Azad","suffix":""},{"id":111736,"identity":"e2590d47-935d-42d8-9105-320326c9bb9a","order_by":3,"name":"Tahira Sultan","email":"","orcid":"","institution":"King Saud University","correspondingAuthor":false,"prefix":"","firstName":"Tahira","middleName":"","lastName":"Sultan","suffix":""},{"id":111737,"identity":"d4a59b47-5a38-425b-998f-0984ddaf998c","order_by":4,"name":"Faisal A. Al-Mobarak","email":"","orcid":"","institution":"King Saud University","correspondingAuthor":false,"prefix":"","firstName":"Faisal","middleName":"A.","lastName":"Al-Mobarak","suffix":""},{"id":111738,"identity":"52660612-0962-4efd-bbf7-8aa2cd903abc","order_by":5,"name":"Hatem Kalantan","email":"","orcid":"","institution":"King Saud University","correspondingAuthor":false,"prefix":"","firstName":"Hatem","middleName":"","lastName":"Kalantan","suffix":""},{"id":111739,"identity":"d78c2915-edb0-4480-9eed-09053aaaf2cd","order_by":6,"name":"Saleh A. Al-Obeidan","email":"","orcid":"","institution":"King Saud University","correspondingAuthor":false,"prefix":"","firstName":"Saleh","middleName":"A.","lastName":"Al-Obeidan","suffix":""}],"badges":[],"createdAt":"2019-06-25 14:19:27","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.10703/v2","doiUrl":"https://doi.org/10.21203/rs.2.10703/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13104-019-4491-x","type":"published","date":"2019-07-23T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":13469591,"identity":"16be5807-c428-4b77-b8f7-264686128cbd","added_by":"auto","created_at":"2021-09-16 21:02:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":266429,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1654/v2/05651f69-b02a-4b43-9fd4-76e49fef7065.pdf"},{"id":2615616,"identity":"aeed36f9-a9dd-4a55-ad80-aeac0c2f0a10","added_by":"399a65fa-c8d4-440b-992c-2804352e6ac3","created_at":"2020-09-25 20:55:02","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":79360,"visible":true,"origin":"","legend":"","description":"","filename":"supplement1.doc","url":"https://assets-eu.researchsquare.com/files/rs-1654/v2/supplement_1.doc"}],"financialInterests":"","formattedTitle":"Polymorphisms rs693421 and rs2499601 at locus 1q43 and their haplotypes are not associated with primary open-angle glaucoma: a case-control study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eEpidemiological studies in the past suggest that primary open-angle glaucoma (POAG), at least in part, can be caused by heritable factors [\u003ca href=\"#_ENREF_1\"\u003e1–3\u003c/a\u003e], with five to 10-fold increased risk in the first-degree relatives and an estimated heritability of 0.81 [\u003ca href=\"#_ENREF_4\"\u003e4\u003c/a\u003e]. However, given the polygenic nature of POAG, its exact genetic etiology still remains elusive. Genetic studies are a critical tool to identify genes and molecular pathways in complex human diseases. Likewise, using a similar approach, population-based genome-wide and candidate gene studies have reported a number of polymorphic variations or loci that have been associated with POAG and/or its quantitative endophenotyes [\u003ca href=\"#_ENREF_5\"\u003e5\u003c/a\u003e, \u003ca href=\"#_ENREF_6\"\u003e6\u003c/a\u003e].\u003c/p\u003e\n\u003cp\u003eIn an initial study, using a 2-stage genome-wide approach in a group of Japanese POAG patients, Nakano et al reported 3 genetic loci, harboring six single nucleotide polymorphisms (SNPs), of having significant association with the disease [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e]. Of these, 4 intergenic polymorphisms such as rs540782, rs540784, rs693421 and rs2499601 are located on chromosome 1q43. The genes flanking the locus 1q43 include Zona Pellucida glycoprotein 4 (\u003cem\u003eZP4)\u003c/em\u003e and Ryanodine Receptor 2 (\u003cem\u003eRYR2).\u003c/em\u003e. \u003cem\u003eZP4\u003c/em\u003e plays a role in fertilization and preimplantation development; and genetic variations in \u003cem\u003eZP4\u003c/em\u003e are reported to be associated with ovarian disease [\u003ca href=\"#_ENREF_8\"\u003e8\u003c/a\u003e] and glaucoma [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e]. Ryanodine receptors (RyRs) are ubiquitous intracellular calcium (Ca\u003csup\u003e2+\u003c/sup\u003e) release channels localized in the plasma membrane of endoplasmic or sarcoplasmic reticulum of many organs, including retina [\u003ca href=\"#_ENREF_9\"\u003e9\u003c/a\u003e]. Given the important physiological role of RyR channel, defect(s) in RyR function, either due to oxidative stress or genetic mutations can render these channels leaky to Ca\u003csup\u003e2+\u003c/sup\u003e influx. These may thereby produce disease-causing signals and contribute to severe pathologies as those observed in heart failure, muscular dystrophy, diabetes, or neurodegenerative diseases [\u003ca href=\"#_ENREF_10\"\u003e10\u003c/a\u003e, \u003ca href=\"#_ENREF_11\"\u003e11\u003c/a\u003e]. Also, considering the potential role of calcium channel blockers in treatment of glaucoma [\u003ca href=\"#_ENREF_12\"\u003e12\u003c/a\u003e], \u003cem\u003eRYR2\u003c/em\u003e may be a potential candidate in POAG.\u003c/p\u003e\n\u003cp\u003eReplication of case-control association studies in various ethnicities has genetic epidemiological importance, so as to enable future utilization of these genetic biomarkers in evaluation of the disease risk. Association studies using candidate gene approach are a useful tool to identify the genetic contribution of SNPs/loci, each of which may exhibit a relatively small risk but have a significant impact in a population. The genetic spectrum of POAG, especially in middle-eastern Saudi POAG patients, is still unclear. We have previously reported a lack of association between SNPs rs540782 and rs540784 with POAG in a small group of Saudi patients [\u003ca href=\"#_ENREF_13\"\u003e13\u003c/a\u003e, \u003ca href=\"#_ENREF_14\"\u003e14\u003c/a\u003e]. The present study investigated an association between rs693421, rs2499601 and their haplotypes with POAG or its clinical indices in a much larger and different set of sample cohort of Saudi origin. Besides, there are no other published reports of association of these SNPs (rs693421 and rs2499601) in this population.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cem\u003eStudy design and participants:\u003c/em\u003e We conducted a retrospective case-control genetic association study. The study followed the principles of the Declaration of Helsinki and had an institutional review board ethics committee approval (# 08–657). Patients (n = 185) and controls (n = 171) were recruited at King Abdul-Aziz University Hospital in Riyadh, Saudi Arabia. The inclusion-exclusion criteria for patients and controls have been detailed elsewhere [\u003ca href=\"#_ENREF_15\"\u003e15\u003c/a\u003e]. Briefly, POAG patients showed (i) optic disk or retinal nerve fiber layer changes; (ii) visual field abnormalities; (iii) bilateral open anterior chamber angles; and (iv) adult onset. Secondary forms of glaucoma and history of steroid usage or ocular trauma were excluded. Controls were \u0026gt;20 years of age with normal IOP, normal optic disk, open anterior chamber angles and no history of ocular disease(s) or eye surgeries. Subjects refusing to participate were also excluded.\u003c/p\u003e\n\u003cp\u003eGenotyping of rs693421 and rs2499601 at Chr.1q43: \u003c/em\u003eDNA samples were genotyped for rs693421 and rs2499601using the TaqMan® genotyping assays C_80796_20 and C__26180887_10, respectively (Applied Biosystems Inc., Foster City, CA, USA; Cat#: 4351379) as described previously [\u003ca href=\"#_ENREF_13\"\u003e13\u003c/a\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Analysis:\u003c/em\u003e SPSS version 22 (IBM Inc. Chicago, IIinois, USA) was used to perform statistical tests as indicated. Linkage disequilibrium analysis was conducted using SHEsis online software (\u003cem\u003ehttp://analysis. \u003ca href=\"http://bio-x.cn/myAnalysis.php\"\u003ebio-x.cn/myAnalysis.php).\u003c/a\u003e\u003c/em\u003e. SNPStats online software (\u003cem\u003ehttp:// \u003ca href=\"http://bioinfo.iconcologia.net/snpstats/start.htm\"\u003ebioinfo.iconcologia.net/snpstats/start.htm)\u003c/a\u003e\u003c/em\u003e was used to construct haplotypes and analyze the interactions with related factors. p\u0026lt;0.05 (2-sided) was considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cem\u003eDemographic and clinical characteristics:\u003c/em\u003e Except for family history of glaucoma (\u003cem\u003ep\u003c/em\u003e = 0.019), there was no significant difference in age, gender, systemic co-morbidities and smoking habit between POAG cases and controls\u003cem\u003e (Supplementary\u003c/em\u003e \u003cem\u003eTable 1).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGenotype and allele frequency:\u003c/em\u003e rs693421 and rs2499601 did not deviate significantly from the HWE (p\u0026gt;0.05). For rs693421, the minor “T” allele frequency was 0.48 in controls and 0.52 in cases, but non-significant (OR = 1.15, 95% CI = 0.85—1.54, p = 0.368). Besides, genotype distribution was also not significant in additive (Chi\u003csup\u003e2\u003c/sup\u003e = 1.74, df = 2, p = 0.417), dominant (p = 0.860) and recessive (p = 0.190) models (\u003cem\u003eTable 1).\u003c/em\u003e. Similarly, for rs2499601, the minor “C” allele frequency was 0.49 in controls as compared to 0.53 in cases (OR = 1.19, 95% CI = 0.89—1.60, p = 0.236) with no significant genotype effect in additive (Chi\u003csup\u003e2\u003c/sup\u003e = 1.69, df = 2, p = 0.429), dominant (p = 0.512) and recessive (p = 0.195) models. In addition, for both the SNPs, the genotype/ allele distribution between POAG cases and controls was also non-significant after adjustment for age and sex. There was no significant interaction with sex for rs693421 (p = 0.83) and rs2499601 (p = 0.83); and the significance did not vary after adjustment for age.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLinkage disequilibrium and haplotype association:\u003c/em\u003e rs693421 and rs2499601 showed significant linkage disequilibrium as reflected by D’ value (D’ statistics = 0.69, p\u0026lt;0.001) (\u003cem\u003eSupplementary\u003c/em\u003e \u003cem\u003eFig\u003c/em\u003e\u003cem\u003eure 1).\u003c/em\u003e. No significant haplotype association was observed (p = 0.698) (\u003cem\u003eTable 2).\u003c/em\u003e. The significance did not vary after adjustment to age and sex (p = 0.750).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGenotype effect on demographic and clinical phenotypes in POAG:\u003c/em\u003e Age and gender distribution was not significant for both rs693241 and rs2499601 genotypes. In addition, phenotypes such as intraocular pressure (IOP), cup/disc ratio and number of antiglaucoma medication showed no significant genotype effect\u003cem\u003e (Supplementary\u003c/em\u003e \u003cem\u003eTable 2).\u003c/em\u003e Besides, logistic regression showed that age, sex, rs693241 and rs2496601 could not significantly explain the likelihood of having POAG (\u003cem\u003eSupplementary\u003c/em\u003e \u003cem\u003eTable 3).\u003c/em\u003e.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePOAG is the second most common type of glaucoma in Saudi Arabia [\u003ca href=\"#_ENREF_16\"\u003e16\u003c/a\u003e]. Despite its high prevalence, the role of genetic factors contributing to the progression and/or development of POAG are largely unknown and thus warrants genetic investigation(s) to identify these factors that may plausibly be associated or contribute to POAG pathogenesis. To this end, evaluation of an association between rs693421, rs2496601 and their haplotypes in a Saudi POAG cohort in this study did not yield any significant relationship with the disease.\u003c/p\u003e\n\u003cp\u003eNakano and colleagues have previously reported a moderate association of polymorphisms rs693241 (OR = 1.48, 95% CI = 1.20—1.83, p = 0.00029) and rs2499601 (OR = 1.45, 95% CI = 1.17—1.79, p = 0.000589) at locus 1q43 in 1,575 Japanese POAG patients. The findings were successfully replicated in stage–2 GWA study [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e]. However, except for rs693421 (OR = 1.4 (1.1–1.7), p = 0.0082) in Korean subjects, subsequent studies in a South Indian [\u003ca href=\"#_ENREF_17\"\u003e17\u003c/a\u003e], Afro-Caribbean [\u003ca href=\"#_ENREF_18\"\u003e18\u003c/a\u003e], Japanese [\u003ca href=\"#_ENREF_19\"\u003e19\u003c/a\u003e], the Hong Kong cohort [\u003ca href=\"#_ENREF_20\"\u003e20\u003c/a\u003e], Korean (for SNP rs2499601) [\u003ca href=\"#_ENREF_21\"\u003e21\u003c/a\u003e] and very recently in the Han Chinese population [\u003ca href=\"#_ENREF_22\"\u003e22\u003c/a\u003e] have failed to replicate this association between rs693241, rs2499601 and POAG. Besides, the functional significance of these SNPs or locus to POAG development remains unknown. In contrast to the findings of Nakano et al [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e] and consistent with the findings reported in other population [\u003ca href=\"#_ENREF_17\"\u003e17\u003c/a\u003e, \u003ca href=\"#_ENREF_19\"\u003e19–21\u003c/a\u003e], no significant genotype/allelic effect of these SNPs in POAG was observed in our study. These conflicting results can be ascribed to factors such as differences in sample size, lack of adequate statistical power or differences in the phenotypes of the sample population included in the study. A comparison of minor allele frequencies of these SNPs in different ethnic groups is shown in \u003cem\u003eTable 3.\u003c/em\u003e The minor allele frequencies observed for these variants in the Saudi population (controls) was comparable to the Oriental population’s [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e, \u003ca href=\"#_ENREF_19\"\u003e19–21\u003c/a\u003e], but higher than that reported among the Indian [\u003ca href=\"#_ENREF_17\"\u003e17\u003c/a\u003e] and Afro-Caribbean ethnic groups [\u003ca href=\"#_ENREF_18\"\u003e18\u003c/a\u003e].\u003c/p\u003e\n\u003cp\u003eThe genotypes of adjacent polymorphisms are often highly correlated, referred to as being in linkage disequilibrium, and could be inherited as haplotypes. Haplotypes display an interaction of these polymorphisms and can serve as a maker of disease susceptibility [\u003ca href=\"#_ENREF_23\"\u003e23\u003c/a\u003e]. In complex multifactorial diseases, such as POAG, multiple polymorphisms/loci in the form of haplotypes can be more informative as compared to single allele polymorphism analysis. Hence, to gain additional information we performed association between 1q43 locus haplotypes (for polymorphisms rs693421 and rs2499601) and POAG. The four SNPs (rs540782, rs540784, rs693421 and rs2499601) at chromosome 1q43 have been reported to exhibit strong linkage disequilibrium (D’ = 0.90–1.0) [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e, \u003ca href=\"#_ENREF_17\"\u003e17\u003c/a\u003e], but data on haplotypes with these did not indicate any association with POAG among Indians [\u003ca href=\"#_ENREF_17\"\u003e17\u003c/a\u003e] as opposed to significant association (p\u0026lt;0.05) among Han Chinese POAG subjects [\u003ca href=\"#_ENREF_22\"\u003e22\u003c/a\u003e]. In our study, significant linkage disequilibrium between rs693421 and rs2499601 was found (D’ = 0.69) but analysis of distribution differences of the four haplotypes in the POAG cases and controls did not show any significant association with the disease. Unfortunately, genotype data for two other SNPs rs540782 and rs540784 at 1q43 were not available for all the subjects included in this study to assess their linkage and/or haplotype association. \u003c/p\u003e\n\u003cp\u003eAssociation analysis for any genotype effect of rs693421 and rs2499601 on clinical phenotypes did not provide any significant link. Age and gender showed no significant distribution and clinical phenotypes for glaucoma such as IOP, cup/disc ratio and number of anti-glaucoma medication that serves as markers of disease severity also showed no significant genotype effects in the POAG group.\u003c/p\u003e\n\u003cp\u003eSimilar to Nakano et al study in 2009, many other recent GWA-studies have reported numerous SNPs in multiple loci/genes in association with POAG and its endophenotypes among European, African and Asian ethnic groups (as reviewed elsewhere [\u003ca href=\"#_ENREF_5\"\u003e5\u003c/a\u003e, \u003ca href=\"#_ENREF_6\"\u003e6\u003c/a\u003e]). In another recent large-scale study by Shiga et al [\u003ca href=\"#_ENREF_24\"\u003e24\u003c/a\u003e] in the Japanese population, variants near cyclin-dependent kinase inhibitor 2B-antisense 1 (\u003cem\u003eCDKN2B-AS1,\u003c/em\u003e rs2157719), SIX Homeobox 6 (\u003cem\u003eSIX6, \u003c/em\u003ers33912345) and growth arrest-specific 7 (\u003cem\u003eGAS7,\u003c/em\u003e rs9913911) were found to be associated with POAG. In contrast, with the exception of variant rs10483727 in (\u003cem\u003eSIX1/\u003c/em\u003e\u003cem\u003eSIX6)\u003c/em\u003e gene locus [\u003ca href=\"#_ENREF_25\"\u003e25\u003c/a\u003e], our previous studies to identify genetic polymorphisms associated with Saudi POAG patients in genes including caveolin 1/caveolin 2 (\u003cem\u003eCAV1/CAV2)\u003c/em\u003e [\u003ca href=\"#_ENREF_26\"\u003e26\u003c/a\u003e], atonal homolog 7 (\u003cem\u003eATOH7)\u003c/em\u003e [\u003ca href=\"#_ENREF_27\"\u003e27\u003c/a\u003e], (\u003cem\u003eCDKN2B)\u003c/em\u003e [\u003ca href=\"#_ENREF_28\"\u003e28\u003c/a\u003e], transmembrane and coiled-coil domain 1(\u003cem\u003eTMCO1)\u003c/em\u003e [\u003ca href=\"#_ENREF_29\"\u003e29\u003c/a\u003e], (\u003cem\u003eGAS7)\u003c/em\u003e [\u003ca href=\"#_ENREF_30\"\u003e30\u003c/a\u003e] and \u003cem\u003eZP4\u003c/em\u003e [\u003ca href=\"#_ENREF_13\"\u003e13\u003c/a\u003e, \u003ca href=\"#_ENREF_14\"\u003e14\u003c/a\u003e], have yielded negative results indicating that the plausible causal genetic defect(s) in POAG cases of Saudi origin may be different than those from European, African and Asian descents, including the Japanese population. There can be several potential reasons for differences in association findings. The differences could reflect an ethnic-specific genetic etiology of POAG. Furthermore, the differences could be attributed to variations in environmental exposures, clinical variability observed in patients with POAG, variations in the endophenotypic traits related to POAG or other epistatic interactions. Nonetheless, based on our findings and that of reported in other ethnic groups, it appears that polymorphisms rs693421 and rs2499601 at chromosome 1q43 (near \u003cem\u003eZP4/\u003c/em\u003e\u003cem\u003eRYR2\u003c/em\u003e genes), may not have a significant role in POAG pathogenesis and hence, cannot serve as genetic markers to assess the disease risk.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLIMITATIONS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOur study could not replicate the previously observed association of rs693421 and rs2499601 in POAG. The results suggest that these SNPs and their haplotypes at locus 1q43, independently or in relation to other clinical phenotypes, are not associated with POAG and hence may not pose a significant risk of POAG in individuals of Saudi origin. However, the lack of association needs cautious interpretation since the study is limited by its sample size, performed in specific ethnicity and their interaction with other genetic or non-genetic factors cannot be ruled out. Nonetheless, based on the minor allele frequency from 1000 Genomes database or that observed in our current study, the sample size used, showed an estimated power of 90% with a detectable odds per allele of 1.60 (2-sided test) and 1.53 (one-sided test). However, assuming an OR of 1.45 as observed in the Japanese POAG patients [\u003ca href=\"#_ENREF_7\"\u003e7\u003c/a\u003e], our study had only 70% and 71% powers (2-sided test) to detect any significant associations between POAG and rs693421 and rs2499601 polymorphisms, respectively. As in most genetic association studies, in order to detect an odds of ≤1.5-fold a much larger sample size would be needed.\u003c/p\u003e\n"},{"header":"ABBREVIATIONS","content":"\u003cp\u003e\u003cem\u003eATOH7:\u003c/em\u003e atonal homolog 7; \u003cem\u003eCAV1/CAV2:\u003c/em\u003e caveolin 1/ caveolin 2; \u003cem\u003eCDKN2B:\u003c/em\u003e cyclin-dependent kinase inhibitor 2B; CI: confidence interval; GWAS: genome-wide association study; \u003cem\u003eGAS7:\u003c/em\u003e growth arrest-specific 7; HWE: Hardy-Weinberg Equilibrium; IOP: intraocular pressure; OR: odds ratio; POAG: primary open angle glaucoma; \u003cem\u003eRYR2:\u003c/em\u003e ryanodine receptor 2; SNP: single nucleotide polymorphism; \u003cem\u003eSIX1/\u003c/em\u003e\u003cem\u003eSIX6:\u003c/em\u003e SIX Homeobox 1/ SIX Homeobox 6; \u003cem\u003eTMCO1:\u003c/em\u003e transmembrane and coiled-coil domain 1; \u003cem\u003eZP4:\u003c/em\u003e zona pellucida glycoprotein 4\u003c/p\u003e"},{"header":"DECLARATIONS ","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to the tenets of the Declaration of Helsinki and had received approval from the Institutional Review Board and Research Ethics Committee of College of Medicine, King Saud University, Riyadh, Saudi Arabia (approval number # 08–657). Written, informed consent was obtained from all participants prior to their inclusion in this study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the conclusions of this article are all presented within the article.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAuthors have no conflict of interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding: \u003c/em\u003eThis work was supported by King Saud University through Vice Deanship of Scientific Research Chair, Glaucoma Research Chair in Ophthalmology but had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors’ contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAAK: study design, analysis, interpretations, manuscript preparation; TAA, TS: sample preparation, genotyping; FAM, HK: subject recruitment, clinical diagnosis, clinical data. SAA: study design, recruitment, clinical diagnosis and data. All the authors have approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgments: \u003c/em\u003eThe authors would like to thank the Vice Deanship of Scientific Research Chair, Glaucoma Research Chair in Ophthalmology at the King Saud University for supporting this study.\u003c/p\u003e"},{"header":"REFERENCES","content":"\u003cp\u003e1.Weih LM, Nanjan M, McCarty CA, Taylor HR: \u003cem\u003ePrevalence and predictors of open-angle glaucoma: results from the visual impairment project.\u003c/em\u003e \u003cem\u003eOphthalmology \u003c/em\u003e2001, \u003cem\u003e108(\u003c/em\u003e11):1966–1972.\u003c/p\u003e\n\u003cp\u003e2.Carbonaro F, Andrew T, Mackey DA, Spector TD, Hammond CJ: \u003cem\u003eHeritability of intraocular pressure: a classical twin study.\u003c/em\u003e \u003cem\u003eBr J Ophthalmol \u003c/em\u003e2008, \u003cem\u003e92(\u003c/em\u003e8):1125–1128.\u003c/p\u003e\n\u003cp\u003e3.Healey P, Carbonaro F, Taylor B, Spector TD, 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Angle Glaucoma in a Saudi Cohort.\u003c/em\u003e \u003cem\u003eGenet Res Int \u003c/em\u003e2018, \u003cem\u003e2018:\u003c/em\u003e2148056.\u003c/p\u003e\n\u003cp\u003e16.Al Obeidan SA, Dewedar A, Osman EA, Mousa A: \u003cem\u003eThe profile of glaucoma in a Tertiary Ophthalmic University Center in Riyadh, Saudi Arabia.\u003c/em\u003e \u003cem\u003eSaudi J Ophthalmol \u003c/em\u003e2011, \u003cem\u003e25(\u003c/em\u003e4):373–379.\u003c/p\u003e\n\u003cp\u003e17.Rao KN, Kaur I, Chakrabarti S: \u003cem\u003eLack of association of three primary open-angle glaucoma-susceptible loci with primary glaucomas in an Indian population.\u003c/em\u003e \u003cem\u003eProc Natl Acad Sci U S A \u003c/em\u003e2009, \u003cem\u003e106(\u003c/em\u003e44):E125–126; author reply E127.\u003c/p\u003e\n\u003cp\u003e18.Cao D, Jiao X, Liu X, Hennis A, Leske MC, Nemesure B, Hejtmancik JF: \u003cem\u003eCDKN2B polymorphism is associated with primary open-angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies.\u003c/em\u003e \u003cem\u003ePLoS One \u003c/em\u003e2012, \u003cem\u003e7(\u003c/em\u003e6):e39278.\u003c/p\u003e\n\u003cp\u003e19.Takamoto M, Kaburaki T, Mabuchi A, Araie M, Amano S, Aihara M, Tomidokoro A, Iwase A, Mabuchi F, Kashiwagi K\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eCommon variants on chromosome 9p21 are associated with normal tension glaucoma.\u003c/em\u003e \u003cem\u003ePLoS One \u003c/em\u003e2012, \u003cem\u003e7(\u003c/em\u003e7):e40107.\u003c/p\u003e\n\u003cp\u003e20.Chen LJ, Tam PO, Leung DY, Fan AH, Zhang M, Tham CC, Chiang SW, Fan BJ, Wang N, Pang CP: \u003cem\u003eSNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma.\u003c/em\u003e \u003cem\u003eMol Vis \u003c/em\u003e2012, \u003cem\u003e18:\u003c/em\u003e1629–1639.\u003c/p\u003e\n\u003cp\u003e21.Kim K, Heo DW, Kim S, Kim JS, Kim CS, Kang C: \u003cem\u003eExpansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31.\u003c/em\u003e \u003cem\u003eEur J Hum Genet \u003c/em\u003e2014, \u003cem\u003e22(\u003c/em\u003e3):409–413.\u003c/p\u003e\n\u003cp\u003e22.Tan Y, Zhang D, Gong B, Zhang X, Jiang L, Lin Y: \u003cem\u003e[Association of ZP4 gene polymorphism with primary open-angle glaucoma in an ethnic Chinese population from Sichuan province].\u003c/em\u003e \u003cem\u003eZhonghua Yi Xue Yi Chuan Xue Za Zhi \u003c/em\u003e2018, \u003cem\u003e35(\u003c/em\u003e5):737–740.\u003c/p\u003e\n\u003cp\u003e23.Zintzaras E, Lau J: \u003cem\u003eSynthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches.\u003c/em\u003e \u003cem\u003eJ Clin Epidemiol \u003c/em\u003e2008, \u003cem\u003e61(\u003c/em\u003e7):634–645.\u003c/p\u003e\n\u003cp\u003e24.Shiga Y, Nishiguchi KM, Kawai Y, Kojima K, Sato K, Fujita K, Takahashi M, Omodaka K, Araie M, Kashiwagi K\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eGenetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7.\u003c/em\u003e \u003cem\u003ePLoS One \u003c/em\u003e2017, \u003cem\u003e12(\u003c/em\u003e12):e0186678.\u003c/p\u003e\n\u003cp\u003e25.Kondkar AA, Azad TA, Almobarak FA, Kalantan H, Sultan T, Alsabaani NA, Al-Obeidan SA, Abu-Amero KK: \u003cem\u003ePolymorphism rs10483727 in the SIX1/SIX6 Gene Locus Is a Risk Factor for Primary Open Angle Glaucoma in a Saudi Cohort.\u003c/em\u003e \u003cem\u003eGenet Test Mol Biomarkers \u003c/em\u003e2018, \u003cem\u003e22(\u003c/em\u003e1):74–78.\u003c/p\u003e\n\u003cp\u003e26.Abu-Amero KK, Kondkar AA, Mousa A, Osman EA, Al-Obeidan SA: \u003cem\u003eLack of association of SNP rs4236601 near CAV1 and CAV2 with POAG in a Saudi cohort.\u003c/em\u003e \u003cem\u003eMol Vis \u003c/em\u003e2012, \u003cem\u003e18:\u003c/em\u003e1960–1965.\u003c/p\u003e\n\u003cp\u003e27.Kondkar AA, Mousa A, Azad TA, 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a Saudi cohort.\u003c/em\u003e \u003cem\u003eJ Negat Results Biomed \u003c/em\u003e2016, \u003cem\u003e15(\u003c/em\u003e1):17.\u003c/p\u003e\n\u003cp\u003e30.Kondkar AA, Azad TA, Almobarak FA, Kalantan H, Sultan T, Al-Obeidan SA, Abu-Amero KK: \u003cem\u003ePolymorphism rs11656696 in GAS7 Is Not Associated with Primary Open Angle Glaucoma in a Saudi Cohort.\u003c/em\u003e \u003cem\u003eGenet Test Mol Biomarkers \u003c/em\u003e2017, \u003cem\u003e21(\u003c/em\u003e12):754–758.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eTable 1 \u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eAssociation analysis of \u003c/span\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eallele frequency and genotype distribution between POAG cases and controls \u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable style=\"width: 512.7pt; border-collapse: collapse;\" width=\"684\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eSNP locus\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eGene type\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.3pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"112\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eControls (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ePOAG (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eOR (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ep value\u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 25.6pt;\"\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 25.6pt;\" rowspan=\"9\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eRs693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 25.6pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eGG\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 25.6pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e43 (25.10\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 25.6pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e45 (24.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 25.6pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 25.6pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eReference\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eGT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e91 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windowtext;\"\u003e0.791\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eTT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e37 (21.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 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5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eAdditive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.417\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eDominant\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.05 (0.65 \u0026ndash;1.69)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.860\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eRecessive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.38 (0.85 \u0026ndash; 2.24)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.190\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eG \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e177 (52.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e179 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windowtext;\"\u003e1.15 (0.85 \u0026ndash; 1.54)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.368\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 22.5pt;\"\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eHWE P\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.390\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.616\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"9\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eRs2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eTT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e48 (28.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e47 (25.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" 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windowtext;\"\u003eTC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e80 (46.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e80 (43.2)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.02 (0.61 \u0026ndash; 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font-family: 'Arial',sans-serif; color: windowtext;\"\u003e43 (25.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e58 (31.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.38 (0.78 \u0026ndash; 2.42)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: 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font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.18 (0.72 \u0026ndash; 1.92)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.512\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eRecessive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.36 (0.85 \u0026ndash; 2.16)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.195\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e176 (51.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e174 (47.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e1.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eReference\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e166 (49.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e196 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width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eHWE P\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.406\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.072\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 109.2pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"146\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 79.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"106\"\u003e\n\u003cp style=\"border: none;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: none; padding: 0in 0in 0in 0in;\" width=\"6\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: none;\" width=\"106\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"106\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"106\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"100\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"140\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"100\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"margin-bottom: .0001pt;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ea\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ePearson Chi\u003csup\u003e2\u003c/sup\u003e test, OR (95% CI) \u0026ndash; odds ratio (95% confidence interval), HWE P \u0026ndash; Hardy-Weinberg equilibrium p value\u003c/span\u003e\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003eTable 2\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e Haplotype frequencies and association with POAG\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 437.4pt; border-collapse: collapse; border: none;\" width=\"583\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 95.75pt; border: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"128\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eHaplotype*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.15pt; border: solid black 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"102\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eFrequency Controls\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.0in; border: solid black 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eFrequency POAG\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.75in; border: solid black 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"168\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eOdds ratio (95% confidence interval)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 67.5pt; border: solid black 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"90\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003ep value\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 95.75pt; border: solid black 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"128\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eGC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.15pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"102\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.079\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.0in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.087\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.75in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"168\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e1.10 (0.64 \u0026ndash; 1.87)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 67.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"90\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.726\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 95.75pt; border: solid black 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"128\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eGT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.15pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"102\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.438\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.0in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.397\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.75in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"168\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.84 (0.62 \u0026ndash; 1.13)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 67.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"90\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.267\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 95.75pt; border: solid black 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"128\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eTC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.15pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"102\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.406\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.0in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.443\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.75in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"168\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e1.16 (0.86 \u0026ndash; 1.56)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 67.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"90\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.317\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 95.75pt; border: solid black 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"128\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eTT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.15pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"102\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.076\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.0in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.073\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 1.75in; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"168\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.95 (0.54 \u0026ndash; 1.66)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 67.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"90\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e0.865\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e*Haplotypes were sorted in the order of rs\u003c/span\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e693421 and\u003c/span\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e rs\u003c/span\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e2499601\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003eGlobal haplotype association \u003cem\u003eX\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e=1.43, df=3, p=0.698 (Pearson\u0026rsquo;s)\u003c/span\u003e\u003c/p\u003e\n\n\u003cp style=\"line-height: 115%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003eTable 3\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 115%; font-family: 'Arial',sans-serif;\"\u003e Comparison of rs693421 and rs2499601 minor allele frequency distribution among different ethnic group\u003c/span\u003e\u003c/p\u003e\n\n\u003ctable style=\"margin-left: 1.4pt; background: #CED7E7; border-collapse: collapse; border: none;\" width=\"692\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ePopulation\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-left: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eSNP\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 181.8pt; border: solid black 1.0pt; border-left: none; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" colspan=\"2\" width=\"242\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eMinor allele frequency*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border: solid black 1.0pt; border-left: none; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e value\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border: solid black 1.0pt; border-left: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eReferences\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eControls\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ePOAG\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eJapan\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.450\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.550\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.00029\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e[\u003ca href=\"#_ENREF_7\"\u003e\u003cspan style=\"color: windowtext; text-decoration: none; text-underline: none;\"\u003e7\u003c/span\u003e\u003c/a\u003e]\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.460\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.550\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.00058\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eIndia\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.357\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.405\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.616\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e[\u003ca href=\"#_ENREF_17\"\u003e\u003cspan style=\"color: windowtext; text-decoration: none; text-underline: none;\"\u003e17\u003c/span\u003e\u003c/a\u003e]\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.413\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.482\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.286\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eAfro-Caribbean\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.291\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.313\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.733\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e[\u003ca href=\"#_ENREF_18\"\u003e\u003cspan style=\"color: windowtext; text-decoration: none; text-underline: none;\"\u003e18\u003c/span\u003e\u003c/a\u003e]\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.295\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.271\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003e0.528\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eKorea\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.476\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.548\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.030\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e[\u003ca href=\"#_ENREF_21\"\u003e\u003cspan style=\"color: black; text-decoration: none; text-underline: none;\"\u003e21\u003c/span\u003e\u003c/a\u003e]\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.480\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.533\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.120\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eJapan\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.498\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.528\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.246\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e[\u003ca href=\"#_ENREF_19\"\u003e\u003cspan style=\"color: black; text-decoration: none; text-underline: none;\"\u003e19\u003c/span\u003e\u003c/a\u003e]\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.497\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.530\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.208\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eChina\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.465\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.459\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.98\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e[\u003ca href=\"#_ENREF_20\"\u003e\u003cspan style=\"color: black; text-decoration: none; text-underline: none;\"\u003e20\u003c/span\u003e\u003c/a\u003e]\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt !msorm;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none !msorm; border-left: none !msorm; border-bottom: solid black 1.0pt !msorm; border-right: solid black 1.0pt !msorm; background: transparent; padding: 0in 5.4pt 0in 5.4pt !msorm; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none !msorm; border-left: none !msorm; border-bottom: solid black 1.0pt !msorm; border-right: solid black 1.0pt !msorm; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt !msorm; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003ens\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none !msorm; border-left: none !msorm; border-bottom: solid black 1.0pt !msorm; border-right: solid black 1.0pt !msorm; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt !msorm; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003ens\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none !msorm; border-left: none !msorm; border-bottom: solid black 1.0pt !msorm; border-right: solid black 1.0pt !msorm; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt !msorm; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border: solid black 1.0pt; border-top: none; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003eSaudi\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers693421\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.482\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.516\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.368\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" rowspan=\"2\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003eThis Study\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 14.1pt;\"\u003e\n\u003ctd style=\"width: 92.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 0in 5.4pt 0in 5.4pt; height: 14.1pt;\" width=\"123\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; text-align: center; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: windowtext;\"\u003ers2499601\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 96.3pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"128\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.485\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"114\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.530\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.5pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; background: transparent; padding: 4.0pt 4.0pt 4.0pt 4.0pt; height: 14.1pt;\" width=\"102\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 12.0pt; font-family: 'Arial',sans-serif; color: black;\"\u003e0.236\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"font-family: 'Arial',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-family: 'Arial',sans-serif;\"\u003e* rs693421[T] and rs2499601[C]; ns \u0026ndash; not studied\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"chromosome 1q43, genetic association, glaucoma, haplotype, rs693421, rs2499601, Saudi ","lastPublishedDoi":"10.21203/rs.2.10703/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.10703/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Objective: The genetic spectrum of primary open-angle glaucoma (POAG) in middle-eastern Saudi's is still elusive. To this end, we investigated an association between rs693421, rs2499601 and their haplotypes at chromosome 1q43 locus with POAG and its clinical phenotypes. Genotyping was performed with TaqMan® assays. Haplotypes and their interaction analysis were carried out by SHEsis and SNPStats online tools.\nResults: The minor “T” allele frequency of rs693421 was 0.48 in controls and 0.52 in cases (odds ratio (OR)=1.15, 95% confidence interval (CI)=0.85–1.54, p=0.368). Similarly, for rs2499601, the minor “C” allele frequency was 0.49 in controls as compared to 0.53 in cases (OR=1.19, 95% CI=0.89–1.60, p=0.236). Besides, genotype distribution for both these polymorphisms was also not significant in additive, dominant and recessive models. rs693421 and rs2499601, showed significant linkage disequilibrium (D’ statistics = 0.69, p\u003c0.001) but haplotype association was non-significant (p=0.698). The significance did not vary after adjustment to age and sex. No significant genotype association was observed with intraocular pressure, cup/disc ratio and number of anti-glaucoma medication in POAG group. Furthermore, age, sex and genotypes did not contribute any significant risk of POAG in regression analysis. We report no association between rs693421, rs2499601 and their haplotypes with POAG and related phenotypes.","manuscriptTitle":"Polymorphisms rs693421 and rs2499601 at locus 1q43 and their haplotypes are not associated with primary open-angle glaucoma: a case-control study","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2019-08-02 18:29:07","doi":"10.21203/rs.2.10703/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2019-07-16T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-07-15T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-07-14T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2019-07-14T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-06-28 23:10:51","doi":"10.21203/rs.2.10703/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2019-07-08T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-06-26T12:00:00+00:00","index":1,"fulltext":"Form responses:\n---\n* Does the work include the necessary controls?\nIf not, please specify which controls are required in your comments to the authors.\tYes: **Are the conclusions drawn adequately supported by the data shown?\nIf not, please explain in your comments to the authors.\tYes**\n"},{"type":"checksComplete","content":"","date":"2019-06-24T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2019-06-24T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-06-24T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvited","content":"","date":"2019-06-14T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-06-14T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-06-13T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ed491166-5823-473d-befa-46a8f84adc0d","owner":[],"postedDate":"August 2nd, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":14903,"name":"Epidemiology"},{"id":14904,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2020-05-14T08:36:04+00:00","versionOfRecord":{"articleIdentity":"rs-1654","link":"https://doi.org/10.1186/s13104-019-4491-x","journal":{"identity":"bmc-research-notes","isVorOnly":false,"title":"BMC Research Notes"},"publishedOn":"2019-07-23 12:00:00","publishedOnDateReadable":"July 23rd, 2019"},"versionCreatedAt":"2019-08-02 18:29:07","video":"","vorDoi":"10.1186/s13104-019-4491-x","vorDoiUrl":"https://doi.org/10.1186/s13104-019-4491-x","workflowStages":[]},"version":"v2","identity":"rs-1654","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-1654","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}