Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients

Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients | 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 Primary research Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients Hong Qu, Yongfang Chen, Wenjing Zeng, Xiaohua Huang, Shuqin Cheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-35124/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Present study was to explore the association between gene polymorphisms in Fc gamma receptor IIa ( FCGR2A ) and Iib ( FCGR2B ) and factor VIII (FVIII) inhibitor development in patients with hemophili A (HA) in a Chinese Han population. Methods: FCGR2A (131H/R) and FCGR2B (232I/T) polymorphsims were genotyped using PCR and direct sequencing method in 108 HA patients, including 23 cases with inhibitors and 85 without inhibitors. Chi-square (c 2 ) test was applied to compare the genotype and allele frequencies between two groups. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated to indicate the relative susceptibility of HA. Results: FCGR2A 131RH genotype frequency had a significantly increased trend in inhibitor group compared with the non-inhibitor group, suggesting a momentous role of 131H/R polymorphism for inhibitor development in HA patients. Individuals carrying 131RH genotype showed higher risk to be attacked by the inhibitor development in HA patients (OR=4.929; 95%CI=1.029-23.605). However, there were no significant differences of FCGR2B (232I/T) polymorphism genotype and allele frequencies between inhibitor and non-inhibitor groups. Conclusion: FCGR2A (131H/R) was in relation to the susceptibility of FVIII inhibitors development in HA patients. Cancer Biology Hemophilia A FCGR2A FCGR2B FVIII inhibitors polymorphisms Background Hemophilia A (HA) is an X-linked recessive bleeding disorder resulting from a quantitative or qualitative deficiency in the factor VIII (FVIII) protein [1-5]. Manifestation of neutralizing antibodies (inhibitors) against infused FVIII protein is the most burdensome complication of HA patients [6]. In China, overall prevalence of FVIII inhibitors in severe HA patients is showed to reach 4.3% [7], which is much lower than the value reported in other ethnic groups. As a typical multifactorial trait, there are several risk factors identified for inhibitor formation in HA patients, which divided into two groups as follows: environmental factors and genetic factors [8-10]. Main genetic predisposition for inhibitor development in HA patients is the causative FVIII genotype, but it also includes a group of auxiliary risk factors that are weaker than the FVIII genotype, including a family history of inhibitors, ethnicity, human leucocyte antigen haplotype, and polymorphisms of immune system-related genes, such as interleukin ( IL )-1, IL-2 , IL-10 , tumor necrosis factor ( TNF )-ɑ and cytotoxic T lymphocyte-associated protein ( CTLA )-4 [11-14]. Receptors of the Fc region of IgG (FcγR) are glycoproteins that are usually detected at hematopoietic system. These receptors have a pivotal relevance of cellular with humoral immunity via binding to the Fc domain of the IgG sub-types ( IgG1-4 ). Low-affinity FcγRs (FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa and FcγIIIb) modulate both pro- and anti-inflammatory response, and vary in their affinity with the antibody Fc-fragment and in the signaling pathways induced. They are encoded by the FCGR genes ( FCGR2A , FCGR2B , FCGR2C , FCGR3A and FCGR3B ) clustered on chromosome 1q23-24 [15]. Recently, FCGR gene polymorphisms are demonstrated to be associated with autoimmune diseases. But few is known about the FCGR2A and FCGR2B gene polymorphisms and the inhibitor development of HA. The current study was aimed at evaluating whether FCGR2A 131H/R (rs1801274) and FCGR2B 232I/T (rs1050501) polymorphisms influence the risk of inhibitors development in 108 patients with HA in Chinese Han population. Methods Patients Among 108 unrelated HA patients, 23 patients had been diagnosed as having FVIII inhibitors, and 85 patients had no inhibitors. All patients received on-demand treatment with plasma-derived FVIII. All non-inhibitors patients had more than 5 exposure months. Nijmegen-modified Bethesda assay was used for quantification of the FVIII inhibitor titre. Inhibitor titres ≧0.6BU/mL at any time were considered to be inhibitor positive [ 16 ]. Antibody titers <5BU/mL was defined as low-response inhibitors, while inhibitor titres persistently ≧5BU/mL were defined as high-response inhibitors [ 17 ]. Severity of haemophilia was classified according to the criteria of White et al. [ 18 ]. The study was permitted by the medical ethics committee of PanYu Central Hospital Hospital. Subjects were signed the written informed consent. Detection of polymorphisms Genomic DNA was extracted from the peripheral blood of every individual using vacuum vessel collection tube. TIANGEN biochemical blood genome DNA extraction Kit (TIANGEN, BEIJING) was used to extract the genomic DNA based on the manufacturer’s specification. Primers of FCGR2A 131H/R and FCGR2B 232I/T single nucleotide polymorphisms (SNPs) were designed and synthesized by Sangon Biotech (Shanghai) Co., Ltd. Genotyping of the FCGR2A and FCGR2B was conducted by PCR amplification and direct sequencing method on an ABI PRISM Sequence Detection System 7500 (Applied Biosystems Foster City. CA. USA) by DNA sequencing. Statistical analysis All the data were analyzed by SPSS software 18.0 (SPSS Inc., Chicago, IL, USA). Allele and genotype frequencies were calculated using directing counting. Data in with or without inhibitors groups were compared by c 2 test. Hardy-Weinberg euilibrium (HWE) was detected in these two groups. Odd ratio (OR) and 95% confidence interval (95%CI) were calculated using Chi-square test. P value less than 0.05 was regarded to be statistical significant. Results Basic information of patients A total of 108 HA patients were enrolled in this study, including 82 cases with severe disease, 21 cases with moderate disease and 5 cases with mild disease. 23 patients had inhibitors, 85 patients did not have inhibitors. HWE test Genotypes of FCGR2A 131H/R and FCGR2B 232I/T polymorphisms in HA patients with and without inhibitors did not deviated from HWE test, revealing the reliability of the study samples. Relationship of FCGR2A (131H/R) and FCGR2B (232I/T) gene polymorphsims with HA susceptibility FCGR2A ( 131H/R ) exhibited significant differences between the inhibitor and non-inhibitor groups. Frequency of 131RH genotype was higher in inhibitor group than in non-inhibitor group ( P =0.032). When the 131RR genotype was taken as a reference, the 131RH genotype was associated with an increased risk of FVIII inhibitor development (OR=4.929, 95%CI=1.029-23.605). Although 131HH genotype had higher frequency in non-inhibitor group than in inhibitor group, the difference was not significant. 131H allele was also had no signoficant associantion with the development of FVIII inhibitor. 232II, 232IT, and 232TT genotype frequencies of FCGR2B 232I/T SNP were 75.29%, 22.35%, and 2.35% in non-inhibitor group and 69.57%, 21.74%, 8.70% in inhibitor group, respectively ( Table 1 ). Besides, the allele 232I and 232T frequencies were 86.47% and 13.53% in non-inhibitor and 80.43%, 19.57% in inhibitor group. But all differences of genotype and allele distributions did not reach a significant level ( P >0.05). It suggested that 232I/T might not be in relation to the susceptibility of the FVIII inhibitor development in HA patients. Discussion As is known to all, cytokines are more or less directly in relation to the antibody-modulated immune responses [19, 20]. In autoimmune diseases, polymorphisms in the immune response genes were reported to be related to the formation of antibody. In addition, SNPs in the regulatory regions of cytokine genes are crucial components in the pathogenesis of various diseases, including HA [21, 22]. Individual immune response traits might influence a patient’s reaction to exogenous factor VIII. The development of FVIII inhibitor is the main complication of replacement therapy in HA patients. Therefore, it is necessary to recognize indicators which could induce the inhibitors formation for applying appropriate treatments and avoiding the inhibitor response. FcγR give a link between antigen-specific antibody and non-sepcific cellular responses of the native immune system. These reports are mainly detected at haemopoietic cells, and have important roles for activating and modulating immune responses. In human autoimmune diseases, published studies have demonstrated that genetic variants in FcγRs, particularly FCGR2A 131H/R, FCGR2B 232I/T, were showed to be in relation to rheumatoid arthritis, systemic lupus erythematosus [23, 24]. In the autoimmune disorders above mentioned, FCGR2A 131H/R polymorphism influences FcγRIIa affinity to IgG2, phagocytosis, and immune complexes clearance. Nevertheless, to date, no examination was performed about the association of FcγR polymorphisms with the inhibitor development in HA patients. In present study, association of FCGR2A and FCGR2B SNPs with inhibitors development was detected in HA patients in a Chinese Han Population. When the allelic and genotypic frequencies of FCGR2A 131R/H were compared, 131RH genotype frequency showed remarkable increase trend in inhibitor group, and 131RH genotype carriers had higher risk to be attacked by inhibitors development. It was suggested that FCGR2A 131R/H displayed significant association with positive inhibitor development in HA patients. In recent years, increasing studies have reported that there are significant differences between SNPs of the FCGR genes and their association with the inhibitors development of HA patients in different ethnic groups. In a Caucasian population, the polymorphism 131R>H of FCGR2A gene was in relation to an increased risk of inhibitor development [25]. Our study results were in accordance with the previous evidences. Meanwhile, FCGR2A has also been largely researched in other human diseases. For instance, Schneider et al. reported that FCGR2A 131R/H polymorphism is correlated with impaired endothelium-dependent vasodilatation [26]. However, genotype and allele distributions of FCGR2B 232I/T polymorphism had no significant difference between inhibitor and non-inhibitor groups. It suggested that FCGR2B 232I/T polymorphism had no significant correlation with FVIII inhibitor development in HA patients. Conclusion Taken together, FCGR2A 131R/H polymorphism was closely correlated with FVIII inhibitor development of HA patients in the Chinese Han Population, while no association was found between FCGR2B 232I/T polymorphism and FVIII inhibitor development. Even so, some shortages remains to be stated in the present study. Firstly, the sample size might be not large enough for the correlation analysis. Secondly, the OR value was not corrected by clinical data, which may reduce the statistical power for the determination of differences between two groups. In additional, functional study would also be necessary to identify the molecular mechanisms underlying the association. Further researches should be performed to explore whether the FCGR2A and FCGR2B gene polymorphisms were in relation to the inhibitor development of HA patients in other ethnic groups. Abbreviations Fc gamma receptor IIa (FCGR2A) Fc gamma receptor Iib (FCGR2B) Factor VIII (FVIII) Hemophili A (HA) Odds ratio (OR) 95% confidence interval (95%CI) Tumor necrosis factor (TNF) Cytotoxic T lymphocyte-associated protein (CTLA) Fc region of IgG (FcγR) IgG sub-types (IgG1-4) single nucleotide polymorphisms (SNPs) Hardy-Weinberg euilibrium (HWE) Declarations Ethics approval and consent to participate This study was supported by the Ethics Committee of PanYu Central Hospital and also has been carried out in accordance with the World Medical Association Declaration of Helsinki. Consent for publication The subjects had been informed the objective. Certainly, written consents were signed by every subject in this study. Data availability b)All data generated or analysed during this study are included in this published article Funding No funding was received Competing interest The authors declare that they have no competing interests. Authors’ contributions H.Q. design of the work; Y.C. the acquisition, analysis, W.Z. interpretation of data; X.H. the creation of new software used in the work; S.C. have drafted the work or substantively revised it. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Zhang AH, Skupsky J, Scott DW: Factor VIII inhibitors: risk factors and methods for prevention and immune modulation. Clinical reviews in allergy & immunology 2009, 37(2):114-124. Witmer C, Young G: Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Therapeutic advances in hematology 2013, 4(1):59-72. Di Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A: Cost of care of haemophilia with inhibitors. Haemophilia : the official journal of the World Federation of Hemophilia 2010, 16(1):e190-201. Mannucci PM, Shi Q, Bonanad S, Klamroth R: Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development. Haemophilia : the official journal of the World Federation of Hemophilia 2014, 20 Suppl 6:2-16. Lieuw K: Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches? Journal of blood medicine 2017, 8:67-73. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM: Acquired hemophilia A: Updated review of evidence and treatment guidance. American journal of hematology 2017, 92(7):695-705. Wang XF, Zhao YQ, Yang RC, Wu JS, Sun J, Zhang XS, Ding QL, Ge HL, Wang HL: The prevalence of factor VIII inhibitors and genetic aspects of inhibitor development in Chinese patients with haemophilia A. Haemophilia : the official journal of the World Federation of Hemophilia 2010, 16(4):632-639. Garagiola I, Palla R, Peyvandi F: Risk factors for inhibitor development in severe hemophilia a. Thrombosis research 2018, 168:20-27. Hu Q, Zhang A, Liu AG, Wang SM, Wang YQ, Zhang LQ: A Retrospective Analysis of Intracranial Hemorrhage in Children with Hemophilia A. Current medical science 2018, 38(5):875-879. Lillicrap D, Fijnvandraat K, Santagostino E: Inhibitors - genetic and environmental factors. Haemophilia : the official journal of the World Federation of Hemophilia 2014, 20 Suppl 4:87-93. Pinto P, Ghosh K, Shetty S: Immune regulatory gene polymorphisms as predisposing risk factors for the development of factor VIII inhibitors in Indian severe haemophilia A patients. Haemophilia : the official journal of the World Federation of Hemophilia 2012, 18(5):794-797. Yingying L, Jiangrong W, Jing L: Characteristics of the cellular immune response in HIV/HCV patients with hemophilia during peginterferon/ribavirin therapy in southern China. Diagnostic microbiology and infectious disease 2014, 78(1):45-48. Soori S, Dadashizadeh G, Dorgalaleh A, Tabibian S, Keramati MR, Alizadeh S, Hosseini MS, Zaker F, Shams M: Relationship Between Single-Nucleotide Polymorphisms of Tumor Necrosis Factor Alpha, Interleukin-10, Factor II and Factor V with Risk of Inhibitor Development in Patients with Severe Hemophilia A. Cardiovascular & hematological disorders drug targets 2019, 19(3):228-232. Pavlova A, Diaz-Lacava A, Zeitler H, Satoguina J, Niemann B, Krause M, Scharrer I, Hoerauf A, Wienker T, Oldenburg J: Increased frequency of the CTLA-4 49 A/G polymorphism in patients with acquired haemophilia A compared to healthy controls. Haemophilia : the official journal of the World Federation of Hemophilia 2008, 14(2):355-360. Bournazos S, Ravetch JV: Fcgamma Receptor Function and the Design of Vaccination Strategies. Immunity 2017, 47(2):224-233. Krudysz-Amblo J, Parhami-Seren B, Butenas S, Brummel-Ziedins KE, Gomperts ED, Rivard GE, Mann KG: Quantitation of anti-factor VIII antibodies in human plasma. Blood 2009, 113(11):2587-2594. Naderi N, Ebrahimzadeh F, Jazebi M, Namvar A, Hashemi M, Bolhassani A: Polymorphisms in the TGF-beta1 (rs1982037) and IL-2 (rs2069762, rs4833248) genes are not associated with inhibitor development in Iranian patients with hemophilia A. Hematology 2018, 23(10):839-843. White GC, 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J: Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thrombosis and haemostasis 2001, 85(3):560. Furman D, Davis MM: New approaches to understanding the immune response to vaccination and infection. Vaccine 2015, 33(40):5271-5281. Seledtsova GV, Ivanova IP, Shishkov AA, Seledtsov VI: Immune responses to polyclonal T-cell vaccination in patients with progressive multiple sclerosis. Journal of immunotoxicology 2016, 13(6):879-884. Abdulqader AMR, Mohammed AI, Rachid S: Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A. The Journal of international medical research 2019, 47(10):4981-4992. Zhao M, Zhang Y, Liu Y, Sun G, Tian H, Hong L: Polymorphisms in MAPK9 (rs4147385) and CSF1R (rs17725712) are associated with the development of inhibitors in patients with haemophilia A in North China. International journal of laboratory hematology 2019, 41(4):572-577. Gorski MM, Blighe K, Lotta LA, Pappalardo E, Garagiola I, Mancini I, Mancuso ME, Fasulo MR, Santagostino E, Peyvandi F: Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients. Blood 2016, 127(23):2924-2933. Li R, Peng H, Chen GM, Feng CC, Zhang YJ, Wen PF, Qiu LJ, Leng RX, Pan HF, Ye DQ: Association of FCGR2A-R/H131 polymorphism with susceptibility to systemic lupus erythematosus among Asian population: a meta-analysis of 20 studies. Archives of dermatological research 2014, 306(9):781-791. Eckhardt CL, Astermark J, Nagelkerke SQ, Geissler J, Tanck MW, Peters M, Fijnvandraat K, Kuijpers TW: The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A. Journal of thrombosis and haemostasis : JTH 2014, 12(8):1294-1301. Schneider MP, Leusen JH, Herrmann M, Garlichs CD, Amann K, John S, Schmieder RE: The Fcgamma receptor IIA R131H gene polymorphism is associated with endothelial function in patients with hypercholesterolaemia. Atherosclerosis 2011, 218(2):411-415. Tables Table 1. Genotype and allele distributions of FCGR2A 131H/R and FCGR2B 232I/T polymorphisms in non-inhibitor and inhibitor patients. Genotype/allele Non-inhibitor n=85 (%) Inhibitor n=23 (%) P value OR (95%CI) 131H/R 131RR 23 (27.06) 2 (8.70) - - 131RH 35 (41.18) 15 (65.22) 0.032 4.929 (1.029-23.605) 131HH 27 (31.76) 6 (26.09) 0.265 2.556 (0.470-13.908) 131R 81 (47.65) 19 (41.30) - - 131H 89 (52.35) 27 (58.70) 0.184 0.640 (0.331-1.239) P HWE 0.107 0.182 232I/T 232II 64 (75.29) 16 (69.57) - - 232IT 19 (22.35) 5 (21.74) 0.929 1.053 (0.341-3.249) 232TT 2 (2.35) 2 (8.70) 0.154 4.000 (0.523-30.612) 232I 147 (86.47) 37 (80.43) - - 232T 23 (13.53) 9 (19.57) 0.307 1.555 (0.664-3.640) P HWE 0.681 0.138 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-35124","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Primary research","associatedPublications":[],"authors":[{"id":666951,"identity":"12f5f142-532c-4c10-9e88-db3115c93007","order_by":0,"name":"Hong Qu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACCQbGBxI8DDY8/OwNRGthNgBqSZOR7DlAmpbDNgY3HIjUIjkjmfHG2z3neRhuMDB++JhDhBZpiWRmyznPbvMwzm5glpy5jQgtchL5x6R5DtzmYZY5wMbMS5yWZDaglnM8bBIJRGqRhmg5wMNDtBbJnsdAvxxI5pHgOdhMnF8kjgND7M0BO3v7480HP3wkRguDQAKMxdhAjHog4D9ApMJRMApGwSgYuQAAOR4x0kH09SIAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-0728-2744","institution":"PanYu Central Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Qu","suffix":""},{"id":666952,"identity":"aa04eb74-3c1d-457b-9772-2227a4bc1346","order_by":1,"name":"Yongfang Chen","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yongfang","middleName":"","lastName":"Chen","suffix":""},{"id":666953,"identity":"71f8b6a9-d01b-4662-b9f3-66d8ce972e96","order_by":2,"name":"Wenjing Zeng","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wenjing","middleName":"","lastName":"Zeng","suffix":""},{"id":666954,"identity":"9f8da537-5708-422c-9c50-1db30ebbab20","order_by":3,"name":"Xiaohua Huang","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaohua","middleName":"","lastName":"Huang","suffix":""},{"id":666955,"identity":"74f1e72e-d5cb-457a-a3c9-be915d91cda9","order_by":4,"name":"Shuqin Cheng","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shuqin","middleName":"","lastName":"Cheng","suffix":""}],"badges":[],"createdAt":"2020-06-12 04:39:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-35124/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-35124/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":15667568,"identity":"91281b3b-a3f3-4e21-b88c-d9156071dcd8","added_by":"auto","created_at":"2021-11-18 13:42:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":232461,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-35124/v1/44c1415f-4284-4028-bb98-c91b088d0e24.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003ePolymorphisms in \u003cem\u003eFCGR2A\u003c/em\u003e (131H/R) and \u003cem\u003eFCGR2B\u003c/em\u003e (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eHemophilia A (HA) is an X-linked recessive bleeding disorder resulting from a quantitative or qualitative deficiency in the factor VIII (FVIII) protein [1-5]. Manifestation of neutralizing antibodies (inhibitors) against infused FVIII protein is the most burdensome complication of HA patients [6]. In China, overall prevalence of FVIII inhibitors in severe HA patients is showed to reach 4.3% [7], which is much lower than the value reported in other ethnic groups. As a typical multifactorial trait, there are several risk factors identified for inhibitor formation in HA patients, which divided into two groups as follows: environmental factors and genetic factors [8-10]. Main genetic predisposition for inhibitor development in HA patients is the causative FVIII genotype, but it also includes a group of auxiliary risk factors that are weaker than the FVIII genotype, including a family history of inhibitors, ethnicity, human leucocyte antigen haplotype, and polymorphisms of immune system-related genes, such as interleukin (\u003cem\u003eIL\u003c/em\u003e)-1, \u003cem\u003eIL-2\u003c/em\u003e, \u003cem\u003eIL-10\u003c/em\u003e, tumor necrosis factor (\u003cem\u003eTNF\u003c/em\u003e)-ɑ and cytotoxic T lymphocyte-associated protein (\u003cem\u003eCTLA\u003c/em\u003e)-4 [11-14].\u003c/p\u003e\n\u003cp\u003eReceptors of the Fc region of IgG (Fc\u0026gamma;R) are glycoproteins that are usually detected at hematopoietic system. These receptors have a pivotal relevance of cellular with humoral immunity via binding to the Fc domain of the IgG sub-types (\u003cem\u003eIgG1-4\u003c/em\u003e). Low-affinity Fc\u0026gamma;Rs (Fc\u0026gamma;RIIa, Fc\u0026gamma;RIIb, Fc\u0026gamma;RIIc, Fc\u0026gamma;RIIIa and Fc\u0026gamma;IIIb) modulate both pro- and anti-inflammatory response, and vary in their affinity with the antibody Fc-fragment and in the signaling pathways induced. They are encoded by the FCGR genes (\u003cem\u003eFCGR2A\u003c/em\u003e, \u003cem\u003eFCGR2B\u003c/em\u003e, \u003cem\u003eFCGR2C\u003c/em\u003e, \u003cem\u003eFCGR3A\u003c/em\u003e and \u003cem\u003eFCGR3B\u003c/em\u003e) clustered on chromosome 1q23-24 [15]. Recently, \u003cem\u003eFCGR\u003c/em\u003e gene polymorphisms are demonstrated to be associated with autoimmune diseases. But few is known about the \u003cem\u003eFCGR2A\u003c/em\u003e and \u003cem\u003eFCGR2B\u003c/em\u003e gene polymorphisms and the inhibitor development of HA.\u003c/p\u003e\n\u003cp\u003eThe current study was aimed at evaluating whether \u003cem\u003eFCGR2A\u003c/em\u003e 131H/R (rs1801274) and \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T (rs1050501) polymorphisms influence the risk of inhibitors development in 108 patients with HA in Chinese Han population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong 108 unrelated HA patients, 23 patients had been diagnosed as having FVIII inhibitors, and 85 patients had no inhibitors. All patients received on-demand treatment with plasma-derived FVIII. All non-inhibitors patients had more than 5 exposure months. Nijmegen-modified Bethesda assay was used for quantification of the FVIII inhibitor titre. Inhibitor titres ≧0.6BU/mL at any time were considered to be inhibitor positive [\u003ca href=\"#_ENREF_16\"\u003e16\u003c/a\u003e]. Antibody titers \u0026lt;5BU/mL was defined as low-response inhibitors, while inhibitor titres persistently ≧5BU/mL were defined as high-response inhibitors [\u003ca href=\"#_ENREF_17\"\u003e17\u003c/a\u003e]. Severity of haemophilia was classified according to the criteria of White et al. [\u003ca href=\"#_ENREF_18\"\u003e18\u003c/a\u003e]. The study was permitted by the medical ethics committee of PanYu Central Hospital Hospital. Subjects were signed the written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDetection of polymorphisms\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eGenomic DNA was extracted from the peripheral blood of every individual using vacuum vessel collection tube. TIANGEN biochemical blood genome DNA extraction Kit (TIANGEN, BEIJING) was used to extract the genomic DNA based on the manufacturer\u0026rsquo;s specification. Primers of FCGR2A 131H/R and FCGR2B 232I/T single nucleotide polymorphisms (SNPs) were designed and synthesized by Sangon Biotech (Shanghai) Co., Ltd. Genotyping of the FCGR2A and FCGR2B was conducted by PCR amplification and direct sequencing method on an ABI PRISM Sequence Detection System 7500 (Applied Biosystems Foster City. CA. USA) by DNA sequencing.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll the data were analyzed by SPSS software 18.0 (SPSS Inc., Chicago, IL, USA). Allele and genotype frequencies were calculated using directing counting. Data in with or without inhibitors groups were compared by c\u003csup\u003e2\u003c/sup\u003e test. Hardy-Weinberg euilibrium (HWE) was detected in these two groups. Odd ratio (OR) and 95% confidence interval (95%CI) were calculated using Chi-square test. \u003cem\u003eP\u003c/em\u003e value less than 0.05 was regarded to be statistical significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eBasic information of patients\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 108 HA patients were enrolled in this study, including 82 cases with severe disease, 21 cases with moderate disease and 5 cases with mild disease. 23 patients had inhibitors, 85 patients did not have inhibitors.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHWE test\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eGenotypes of \u003cem\u003eFCGR2A\u003c/em\u003e 131H/R and \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T polymorphisms in HA patients with and without inhibitors did not deviated from HWE test, revealing the reliability of the study samples.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRelationship of FCGR2A (131H/R) and FCGR2B (232I/T) gene polymorphsims with HA susceptibility\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFCGR2A\u003c/em\u003e (\u003cem\u003e131H/R\u003c/em\u003e) exhibited significant differences between the inhibitor and non-inhibitor groups. Frequency of 131RH genotype was higher in inhibitor group than in non-inhibitor group (\u003cem\u003eP\u003c/em\u003e=0.032). When the 131RR genotype was taken as a reference, the 131RH genotype was associated with an increased risk of FVIII inhibitor development (OR=4.929, 95%CI=1.029-23.605). Although 131HH genotype had higher frequency in non-inhibitor group than in inhibitor group, the difference was not significant. 131H allele was also had no signoficant associantion with the development of FVIII inhibitor.\u003c/p\u003e\n\u003cp\u003e232II, 232IT, and 232TT genotype frequencies of \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T SNP were 75.29%, 22.35%, and 2.35% in non-inhibitor group and 69.57%, 21.74%, 8.70% in inhibitor group, respectively (\u003cstrong\u003eTable 1\u003c/strong\u003e). Besides, the allele 232I and 232T frequencies were 86.47% and 13.53% in non-inhibitor and 80.43%, 19.57% in inhibitor group. But all differences of genotype and allele distributions did not reach a significant level (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). It suggested that 232I/T might not be in relation to the susceptibility of the FVIII inhibitor development in HA patients.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs is known to all, cytokines are more or less directly in relation to the antibody-modulated immune responses [19, 20]. In autoimmune diseases, polymorphisms in the immune response genes were reported to be related to the formation of antibody. In addition, SNPs in the regulatory regions of cytokine genes are crucial components in the pathogenesis of various diseases, including HA [21, 22]. Individual immune response traits might influence a patient\u0026rsquo;s reaction to exogenous factor VIII. The development of FVIII inhibitor is the main complication of replacement therapy in HA patients. Therefore, it is necessary to recognize indicators which could induce the inhibitors formation\u0026nbsp; for applying appropriate treatments and avoiding the inhibitor response.\u003c/p\u003e\n\u003cp\u003eFc\u0026gamma;R give a link between antigen-specific antibody and non-sepcific cellular responses of the native immune system. These reports are mainly detected at haemopoietic cells, and have important roles for activating and modulating immune responses. In human autoimmune diseases, published studies have demonstrated that genetic variants in Fc\u0026gamma;Rs, particularly \u003cem\u003eFCGR2A\u003c/em\u003e 131H/R, \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T, were showed to be in relation to rheumatoid arthritis, systemic lupus erythematosus [23, 24]. In the autoimmune disorders above mentioned, \u003cem\u003eFCGR2A\u003c/em\u003e 131H/R polymorphism influences Fc\u0026gamma;RIIa affinity to IgG2, phagocytosis, and immune complexes clearance. Nevertheless, to date, no examination was performed about the association of Fc\u0026gamma;R polymorphisms with the inhibitor development in HA patients.\u003c/p\u003e\n\u003cp\u003eIn present study, association of \u003cem\u003eFCGR2A\u003c/em\u003e and \u003cem\u003eFCGR2B\u003c/em\u003e SNPs with inhibitors development was detected in HA patients in a Chinese Han Population. When the allelic and genotypic frequencies of \u003cem\u003eFCGR2A\u003c/em\u003e 131R/H were compared, 131RH genotype frequency showed remarkable increase trend in inhibitor group, and 131RH genotype carriers had higher risk to be attacked by inhibitors development. It was suggested that \u003cem\u003eFCGR2A\u003c/em\u003e 131R/H displayed significant association with positive inhibitor development in HA patients. In recent years, increasing studies have reported that there are significant differences between SNPs of the \u003cem\u003eFCGR\u003c/em\u003e genes and their association with the inhibitors development of HA patients in different ethnic groups. In a Caucasian population, the polymorphism 131R\u0026gt;H of \u003cem\u003eFCGR2A\u003c/em\u003e gene was in relation to an increased risk of inhibitor development [25]. Our study results were in accordance with the previous evidences. Meanwhile, \u003cem\u003eFCGR2A\u003c/em\u003e has also been largely researched in other human diseases. For instance, Schneider et al. reported that \u003cem\u003eFCGR2A\u003c/em\u003e 131R/H polymorphism is correlated with impaired endothelium-dependent vasodilatation [26]. However, genotype and allele distributions of \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T polymorphism had no significant difference between inhibitor and non-inhibitor groups. It suggested that \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T polymorphism had no significant correlation with FVIII inhibitor development in HA patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTaken together, \u003cem\u003eFCGR2A\u003c/em\u003e 131R/H polymorphism was closely correlated with FVIII inhibitor development of HA patients in the Chinese Han Population, while no association was found between \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T polymorphism and FVIII inhibitor development.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEven so, some shortages remains to be stated in the present study. Firstly, the sample size might be not large enough for the correlation analysis. Secondly, the OR value was not corrected by clinical data, which may reduce the statistical power for the determination of differences between two groups. In additional, functional study would also be necessary to identify the molecular mechanisms underlying the association. Further researches should be performed to explore whether the \u003cem\u003eFCGR2A\u003c/em\u003e and \u003cem\u003eFCGR2B\u003c/em\u003e gene polymorphisms were in relation to the inhibitor development of HA patients in other ethnic groups.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eFc gamma receptor IIa (FCGR2A)\u003c/p\u003e\n\u003cp\u003eFc gamma receptor Iib (FCGR2B)\u003c/p\u003e\n\u003cp\u003eFactor VIII (FVIII)\u003c/p\u003e\n\u003cp\u003eHemophili A (HA)\u003c/p\u003e\n\u003cp\u003eOdds ratio (OR)\u003c/p\u003e\n\u003cp\u003e95% confidence interval (95%CI)\u003c/p\u003e\n\u003cp\u003eTumor necrosis factor (TNF)\u003c/p\u003e\n\u003cp\u003eCytotoxic T lymphocyte-associated protein (CTLA)\u003c/p\u003e\n\u003cp\u003eFc region of IgG (Fc\u0026gamma;R)\u003c/p\u003e\n\u003cp\u003eIgG sub-types (IgG1-4)\u003c/p\u003e\n\u003cp\u003esingle nucleotide polymorphisms (SNPs)\u003c/p\u003e\n\u003cp\u003eHardy-Weinberg euilibrium (HWE)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Ethics Committee of PanYu Central Hospital and also has been carried out in accordance with the World Medical Association Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe subjects had been informed the objective. Certainly, written consents were signed by every subject in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eb)All data generated or analysed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.Q. design of the work; Y.C. the acquisition, analysis, W.Z. interpretation of data; X.H. the creation of new software used in the work; S.C. have drafted the work or substantively revised it. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhang AH, Skupsky J, Scott DW: Factor VIII inhibitors: risk factors and methods for prevention and immune modulation. \u003cem\u003eClinical reviews in allergy \u0026amp; immunology \u003c/em\u003e2009, 37(2):114-124.\u003c/li\u003e\n\u003cli\u003eWitmer C, Young G: Factor VIII inhibitors in hemophilia A: rationale and latest evidence. \u003cem\u003eTherapeutic advances in hematology \u003c/em\u003e2013, 4(1):59-72.\u003c/li\u003e\n\u003cli\u003eDi Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A: Cost of care of haemophilia with inhibitors. \u003cem\u003eHaemophilia : the official journal of the World Federation of Hemophilia \u003c/em\u003e2010, 16(1):e190-201.\u003c/li\u003e\n\u003cli\u003eMannucci PM, Shi Q, Bonanad S, Klamroth R: Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development. \u003cem\u003eHaemophilia : the official journal of the World Federation of Hemophilia \u003c/em\u003e2014, 20 Suppl 6:2-16.\u003c/li\u003e\n\u003cli\u003eLieuw K: Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches? 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\u003c/em\u003e2019, 47(10):4981-4992.\u003c/li\u003e\n\u003cli\u003eZhao M, Zhang Y, Liu Y, Sun G, Tian H, Hong L: Polymorphisms in MAPK9 (rs4147385) and CSF1R (rs17725712) are associated with the development of inhibitors in patients with haemophilia A in North China. \u003cem\u003eInternational journal of laboratory hematology \u003c/em\u003e2019, 41(4):572-577.\u003c/li\u003e\n\u003cli\u003eGorski MM, Blighe K, Lotta LA, Pappalardo E, Garagiola I, Mancini I, Mancuso ME, Fasulo MR, Santagostino E, Peyvandi F: Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients. \u003cem\u003eBlood \u003c/em\u003e2016, 127(23):2924-2933.\u003c/li\u003e\n\u003cli\u003eLi R, Peng H, Chen GM, Feng CC, Zhang YJ, Wen PF, Qiu LJ, Leng RX, Pan HF, Ye DQ: Association of FCGR2A-R/H131 polymorphism with susceptibility to systemic lupus erythematosus among Asian population: a meta-analysis of 20 studies. \u003cem\u003eArchives of dermatological research \u003c/em\u003e2014, 306(9):781-791.\u003c/li\u003e\n\u003cli\u003eEckhardt CL, Astermark J, Nagelkerke SQ, Geissler J, Tanck MW, Peters M, Fijnvandraat K, Kuijpers TW: The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A. \u003cem\u003eJournal of thrombosis and haemostasis : JTH \u003c/em\u003e2014, 12(8):1294-1301.\u003c/li\u003e\n\u003cli\u003eSchneider MP, Leusen JH, Herrmann M, Garlichs CD, Amann K, John S, Schmieder RE: The Fcgamma receptor IIA R131H gene polymorphism is associated with endothelial function in patients with hypercholesterolaemia. \u003cem\u003eAtherosclerosis \u003c/em\u003e2011, 218(2):411-415.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Genotype and allele distributions of \u003cem\u003eFCGR2A\u003c/em\u003e 131H/R and \u003cem\u003eFCGR2B\u003c/em\u003e 232I/T polymorphisms in non-inhibitor and inhibitor patients.\u003c/p\u003e\n\u003ctable\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003eGenotype/allele\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003eNon-inhibitor\u003c/p\u003e\n\u003cp\u003en=85 (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003eInhibitor\u003c/p\u003e\n\u003cp\u003en=23 (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27%\"\u003e\n\u003cp\u003eOR (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e131H/R\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e131RR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e23 (27.06)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e2 (8.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e131RH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e35 (41.18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e15 (65.22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.032\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"27%\"\u003e\n\u003cp\u003e\u003cstrong\u003e4.929 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width=\"27%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hemophilia A, FCGR2A, FCGR2B, FVIII inhibitors, polymorphisms","lastPublishedDoi":"10.21203/rs.3.rs-35124/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-35124/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Present study was to explore the association between gene polymorphisms in Fc gamma receptor IIa (\u003cem\u003eFCGR2A\u003c/em\u003e) and Iib (\u003cem\u003eFCGR2B\u003c/em\u003e) and factor VIII (FVIII) inhibitor development in patients with hemophili A (HA) in a Chinese Han population.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e \u003cem\u003eFCGR2A\u003c/em\u003e (131H/R) and \u003cem\u003eFCGR2B\u003c/em\u003e (232I/T) polymorphsims were genotyped using PCR and direct sequencing method in 108 HA patients, including 23 cases with inhibitors and 85 without inhibitors. Chi-square (c\u003csup\u003e2\u003c/sup\u003e) test was applied to compare the genotype and allele frequencies between two groups. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated to indicate the relative susceptibility of HA.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e \u003cem\u003eFCGR2A\u003c/em\u003e 131RH genotype frequency had a significantly increased trend in inhibitor group compared with the non-inhibitor group, suggesting a momentous role of 131H/R polymorphism for inhibitor development in HA patients. Individuals carrying 131RH genotype showed higher risk to be attacked by the inhibitor development in HA patients (OR=4.929; 95%CI=1.029-23.605). However, there were no significant differences of \u003cem\u003eFCGR2B\u003c/em\u003e (232I/T) polymorphism genotype and allele frequencies between inhibitor and non-inhibitor groups.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e \u003cem\u003eFCGR2A\u003c/em\u003e (131H/R) was in relation to the susceptibility of\u0026nbsp;FVIII inhibitors development in HA patients.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-06-15 21:14:56","doi":"10.21203/rs.3.rs-35124/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"74827653-bb50-4bee-aa5a-be53eca09c24","owner":[],"postedDate":"June 15th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":120126,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2020-06-30T19:09:52+00:00","versionOfRecord":[],"versionCreatedAt":"2020-06-15 21:14:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-35124","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-35124","identity":"rs-35124","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}