Disc degenerative disease in South Africa: A case-control analysis of selected gene variants

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Liebenberg, Mongi Benjeddou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4241025/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Sep, 2024 Read the published version in Molecular Biology Reports → Version 1 posted 8 You are reading this latest preprint version Abstract Background Disc degenerative disease is a multifactorial disease for which genetics plays an integral role. Several genes, and their variants, associated with the development and progression of disc degenerative disease have been identified. While several studies have investigated these genes in Asian and European populations, no available evidence exists for the South African population. Therefore, this study aimed to investigate these parameters. Methods and results Biological samples were collected in the form of buccal swabs from patients. DNA extraction was carried out according to established methods. All genotyping was performed using the MassARRAY®System IPLEX extension reaction. or associations between variants and the presence of disc degenerative disease, odds ratios, confidence intervals, chi-squared analysis and logistic regression was calculated. This study found statistically significant associations for five of the evaluated single nucleotide polymorphisms (SNPs) with disc degenerative disease, namely IL-1α rs1304037 and rs1800587, GDF-5 rs143383, ADAMTs-5 rs162509, and MMP-3 rs632478. Conclusion To the best of our knowledge, this study represents the first of its kind to investigate the association of gene variants associated with disc degenerative disease within the South African population. This study has shown that 5 of these gene variants were significantly associated with the presence of disc degenerative disease, reflecting their integral roles in development and possible progression of the disease. Disc degenerative disease single nucleotide polymorphism genotype allele South Africa Introduction Disc degenerative disease and related back pain are either acute or chronic forms of disease that may be caused by various factors [ 1 ]. Globally, these conditions represent a significant cause of diminished quality of life, morbidity, and mortality. Lower back pain (LBP), in particular, is a common debilitating musculoskeletal condition and affects approximately 637 million people, globally–with a lifetime prevalence of approximately 80% [ 2 , 3 ]. In South Africa, the prevalence of diagnosed spinal degenerative disease in the urban population is estimated to range from 48-78.2% [ 4 ]. Many causes for LBP exist, but disc degeneration has been found to be a more common diagnosis among individuals who suffer from LBP than those who do not. Back pain may not always be a symptom of disc degeneration, although it is often an early sign of degenerative spine pathologies. The intervertebral disc (IVD) is among the most pivotal biological structures of the human body [ 5 , 6 ]. Progressive degradation of IVD structures that leads to disruption of the homeostasis of the spine is clinically known as disc degeneration and is often associated with severe pain [ 6 ]. IVDs are composed of fibrocartilaginous tissue that assists in maintaining stability and flexibility of the entire spine [ 7 ]. The primary role of the IVD is to connect two adjacent vertebral bodies while acting as a cushion that carries weight and pressure attributed to mechanical load. An intact and healthy IVD is comprised of three main structures: the central nucleus pulposus, the external annulus fibrosus, and endplates [ 8 ]. These structures provide the IVD with high compressive and tensile strength, support axial compression of the spine, and allow multiaxial flexibility [ 9 ]. Disc degenerative disease is a multifactorial disease often emerging due to several factors causing tissue weakening which ultimately results in pathological changes in the IVD—particularly the production of inflammatory mediators, increased apoptosis, and extracellular matrix loss [ 9 ]. These include endplate damage, nutritional deficiency, abnormal load, smoking, ageing, and genetics [ 9 ]. Genetic factors in particular have been estimated to contribute an estimated 75% to IVD degenerative disease aetiology [ 10 , 11 ]. Genetic variation associated with the genes involved in processes that are related to degradation of the extracellular matrix components, apoptosis, and inflammation, have been associated with structural and functional changes within the IVD, which leads to disruption of the disc’s metabolic activities and mechanical properties [ 7 ]. To date, several genes, and their variants, associated with the development and progression of disc degenerative disease have been identified, including COL1A1 and COL11A1, GDF-5, CASP-3 and CASP-9, IL-1α and IL-6, ADAMTS-5, KIAA, CILP, COMT, MMP-3, and MMP-6 [ 6 , 7 , 12 , 13 ]. Notably, associated gene variants have been extensively investigated in Asian and European populations, for which risk genotypes and alleles have been identified. It is essential to note, however, that South Africa is home to several genetically diverse population groups representing unique genetic profiles which include novel and rare variants regarding pharmaco-genetically relevant genes [ 14 – 16 ]. Moreover, this genomic diversity is a largely understudied domain, as compared to European populations, and within the context of disc degenerative diseases is non-existent in the available literature. It is therefore unclear how previously identified genetic associations to disc degenerative disease relate to the South African population and the unique genetic diversity represented therein. Therefore, this study aimed to investigate selected gene variants with the greatest level of evidence for association with disc degenerative disease within the South African population. Materials and methods Patient and study design All participants were briefed about the project and a consent form was completed and submitted by each participant before the experiment was conducted. Ethics clearance for this study was obtained from the Senate Research Committee of the University of the Western Cape [Ethics clearance number BM 22/4/7]. Data collection Biological samples were collected in the form of buccal swabs from patients visiting the Health Collective, Panorama Healthcare Building, Cape Town, South Africa. All patients included in this study were confirmed to have disc degenerative disease by magnetic resonance imaging (MRI) and/or radionuclide scans and were confirmed to not have evidence of active cancer(s), a record of spinal trauma, or trauma to the surrounding spinal structures. Convenience sampling was employed for samples collected from healthy volunteers. An ethnically mixed population was utilised for the study cohort, and ethnicities of participants were determined by self-report. Single Nucleotide Polymorphism selection and genotyping The 20 relevant genetic variants selected for this study were chosen based upon previous publications, where association was made between single nucleotide polymorphisms (SNPs) and the presence of disc degenerative disease. The Ensembl data-base was also used for cross-referencing the selected SNPs ( http://www.ensembl.org ) [ 17 ]. Genomic DNA was isolated from buccal swabs using a standard salt-lysis protocol [ 18 ]. Samples were stored at − 20°C. DNA was quantified using a NanoDrop™2000/ 2000c UV/VIS Spectrophotometer (Thermo Scientific, Waltham, MA, USA). The SNPs were genotyped using the MassARRAY®System IPLEX extension reaction (Agena Bioscience, San Diego, CA, USA). Genotypes of the selected SNP variants were determined for all the study participants (Table 3 and Table 4 ). Statistical Analysis Statistical analysis for Hardy-Weinberg equilibrium (HWE), genotype frequencies, and allele frequencies were performed using GenALEx version 6.5 [ 19 , 20 ]. For HWE, P < 0.05 was considered significant and thus a departure from HWE. For associations between variants and disc degenerative disease, odds ratios, confidence intervals, chi-squared analysis and logistic regression was calculated using IBM Statistical Package for Social Sciences (SPSS) version 26. A significance threshold of 0.05 was employed for association studies. Results Study population demographic data are shown in Table 1 , and age sex and smoking were evaluated as possible covariates. Following analysis, only age (P = 0.0056) and sex, i.e. female (P = 0.0019), were determined to be covariates within the study population (Table 1 ). The identified covariates were subsequently utilised in logistic regression. Genotype and allele distribution of the 20 SNPs were determined in the study participants (Table 3 and Table 4 ). All SNPs analysed within the study population were found to be within Hardy-Weinberg equilibrium (HWE), with p-values ranging between 0.1007–0.9835 (Table 2 ). Among the SNPs selected for this study, five displayed a significant association between disc degenerative disease and genotype or allele prior to adjustment (Table 4 ). All non-significant SNPs are displayed in Table 3 . The five significantly associated genes/SNPs are: IL-1α rs1304037 and rs1800587, GDF-5 rs143383, ADAMTS-5 rs162509, and MMP-3 rs632478. Prior to adjustment, the heterozygous genotype CT, and the minor allele C of rs1304037 demonstrated significant associations with diagnosis of disc degenerative disease [P = 0.0456, (OR: 2.22, 95% CI: 1.01–4.91) and P = 0.0476 (OR:1.77, 95% CI: 1.00-3.15) respectively] (Table 4 ). For rs1800587, the heterozygous genotype GA, and the minor allele A demonstrated significant associations with diagnosis of disc degenerative disease [P = 0.0249, (OR: 2.50, 95% CI: 1.11–5.62) and P = 0.0434 (OR:1.78, 95% CI: 1.01–3.14) respectively] (Table 4 ). When analysed, the heterozygous genotype GA, and the minor allele A of rs143383 demonstrated significant associations with diagnosis of disc degenerative disease [P = 0.0299, (OR: 0.37, 95% CI: 0.15–0.90) and P = 0.0474 (OR:0.58, 95% CI: 0.34–0.99) respectively] (Table 4 ). Next, the homozygous minor genotype CC and the minor allele C of rs162509 demonstrated significant associations with diagnosis of disc degenerative disease [P = 0.0152, (OR: 3.71, 95% CI: 1.29–10.68) and P = 0.0112 (OR: 1.99, 95% CI: 1.16–3.40) respectively] (Table 4 ). Finally, the heterozygous genotype GT of rs632478 demonstrated significant associations with diagnosis of disc degenerative disease [P = 0.0249, (OR: 2.70, 95% CI: 1.13–6.44)] (Table 4 ). Following adjustment, only the C allele of rs1304037 remained significantly associated [P = 0.0459 (OR:1.99, 95% CI: 1.01–3.93) respectively] (Table 4 ). For rs1800587, the heterozygous genotype GA, and the minor allele A remained significantly associated following adjustment [P = 0.0249, (OR: 2.55, 95% CI: 1.00-6.49) and P = 0.0434 (OR:2.14 95% CI: 1.10–4.18) respectively] (Table 4 ). The homozygous minor genotype CC and the minor allele C of rs162509 remained significantly associated with disc degenerative disease following adjustment [P = 0.0105, (OR: 6.47, 95% CI: 1.54–27.07) and P = 0.0040 (OR: 2.59, 95% CI: 1.35–4.96) respectively] (Table 4 ). Once adjusted, only the heterozygous genotype i.e. GT of rs632478 demonstrated a significant association with diagnosis of disc degenerative disease [P = 0.0057, (OR: 5.17, 95% CI: 1.61–16.61) (Table 4 ). Lastly, after Bonferroni correction, significance was maintained for the A allele of rs1800587 (P = 0.0498), the homozygous minor genotype CC, and the minor allele C of rs162509 (P = 0.0210 and P = 0.0080), along with the heterozygous GT genotype of rs632478 (P = 0.0114) (Table 4 ). Discussion In this study, the genetic association of 20 possible biomarkers for the presence of disc degenerative disease was determined. All SNPs tested were found to be within HWE and showed p-values ranging between 0.1007–0.9835 within the study population (Table 2 ). Genotype and allele distribution of the 20 SNPs were determined in study cohort (Tables 3 and Table 4 ). Among the SNPs analysed, 15 of the selected SNPs exhibited no statistically significant association with disc degenerative disease within the study cohort (Table 3 ). The respective genotypes and alleles of the remaining 5 SNPs i.e. rs1304037 (CT P = 0.0456; C P = 0.0476), rs1800587 (GG P = 0.0249; A P = 0.0434), rs162509 (GG P = 0.0152; C P = 0.0112), rs632478 (GT P = 0.0249), and rs143383 (GA P = 0.0299; A P = 0.0474), however demonstrated significant associations between variant and disc degenerative disease, prior to adjustment (Table 4 ). From our analysis, SNPs rs1304037, rs1800587, rs162509, rs632478 demonstrated increased odds of a positive diagnosis for disc degenerative disease. Conversely, decreased odds of disc degenerative disease were seen for rs143383. Interleukin-1 (IL-1) is an inflammatory cytokine expressed in the IVD that is tied to the degradation of extracellular matrix components through the production of degradative enzymes, inhibition of proteoglycan resynthesis, cytokine upregulation, and through inhibition of extracellular matrix component production [ 6 , 10 , 21 ]. The IL-1α gene in particular is linked to an increased risk of disc degenerative disease [ 6 ]. Hypersensitivity to IL-1α in disc cells has been described as a significant motivator for degeneration, playing a key role in extracellular matrix metabolism and modic changes—an MRI trait associated with disc degenerative disease [ 22 ]. To date, several IL-1α polymorphisms have been shown to be associated with IVD severity and modic changes, including the rs1800587 and rs1304037 variants [ 21 ]. The C allele of the IL-1α rs1304037 variant was reported to be associated with increased severity of disc degenerative disease and the accompanying modic changes [ 21 ]. In this study, we have similarly shown a significant association between the rs1304037 variant and disc degenerative disease (Table 4 ), particularly for the CT genotype and C allele prior to adjustment. Following adjustment, the C allele remained significantly associated with disc degenerative disease within the study cohort. Thus, the findings presented here for rs1304037 are in accordance with those reported by Parera et al [ 21 ]. With regard to the rs1800587 variant, the TT genotype, as compared to the CC genotype, has previously been shown to be associated with and increased risk of disc degenerative disease in several studies [ 22 – 26 ]. Particularly, this association was demonstrated in a Caucasian population [ 22 , 23 ], a Chinese Han population [ 24 ], and a Finnish population in studies investigating middle-aged men [ 25 ] and young girls aged 12–14 [ 26 ]. Thus, from the available literature, the C and T allele combination is the most reported, however, a G and A combination has also been described. To date, two studies have demonstrated an association with disc degenerative disease for the G and A allelic combination for the variant in a Spanish population [ 27 ], as well as a Sri Lankan population [ 21 ]. In their studies, the A allele was shown to be associated with reduced severity of disc degenerative disease and the accompanying modic changes [ 21 , 27 ]. Presently, we similarly report the G and A allelic combination for rs1800587 within the study cohort. Unlike previous studies, however, our analysis revealed a significantly increased likelihood of disc degenerative disease for the GA genotype and A allele (Table 4 ). These findings are contradictory to previous reports and thus merit further investigation within a larger study cohort. Nevertheless, the findings presented here reiterate the importance of the interleukins in disc degenerative disease and its progression. ADAMTS form a group of metalloproteinases possessing several important biological functions, such as extracellular matrix remodelling, procollagen processing, cell migration, and inflammatory processes [ 28 , 29 ]. The binding of ADAMTS to extracellular matrix components is modulated via a thrombospondin structural domain which may lead to proteolysis [ 29 ]. ADAMTS-5 (aggrecanase-2) in particular has been identified as an important risk factor in the development of disc degenerative disease [ 28 ]. Several studies have shown an association between the ADAMTS-5 rs162509 variant and disc degenerative disease [ 30 – 32 ]. Early studies of the ADAMTS-5 rs162509 variant in the Chinese Han population reported the C and G allele combination and further showed no statistically significant association with disc degenerative disease [ 33 ]. Interestingly, however, a later study of the same population reported a G and A allelic combination and further reported the G allele to be significantly higher in patients with disc degenerative disease, as compared to healthy individuals [ 32 ]. Similarly, a study by Rajasekaran et al also reported a significant association between rs165209 and the severity of disc degenerative disease in an Indian population [ 31 ]. The present analysis demonstrated the C and G allele combination within the study cohort, and further that the CC genotype and C allele were significantly associated with the presence of disc degenerative disease following adjustment and Bonferroni correction (Table 4 ). These findings are contradictory to those reported by Wu et al , however, and may indicate that the ADAMTS-5 rs165209 variant plays an integral role in the presence of disc degenerative disease within the South African population. Based on this, further, more rigorous investigation of this variant within a larger cohort is essential Matrix metalloproteinases (MMPs) are the principal catabolic enzymes of the IVD and are the main mediators of extracellular matrix degradation that allow for normal remodelling and the abolishment of pathological tissues [ 13 ]. Degradation of the IVD’s extracellular matrix by MMP enzymes is important in the pathogenesis of IVD degeneration [ 7 ]. MMP-3 is reportedly one of the most significant proteoglycan-degrading enzymes [ 7 , 13 ]. Specific conditions such as inflammation and mechanical loading can trigger the expression of the MMP-3 gene and the resulting IVD degeneration from this expression may, hereby, increase with time [ 13 ]. While available literature is limited, the MMP-3 rs63248 variant has been shown to play an integral role toward spinal bone mineral density and degenerative disease [ 34 , 35 ]. Investigations into the role of MMP-3 rs63248 variant in disc degenerative disease by Saberi et al demonstrated a significant association within an Iranian population [ 35 ]. More specifically, they showed that the CC genotype was associated with a significantly increased risk of disc degenerative disease, relative to the AA genotype, and was further suggested to be a contributing factor toward increased susceptibility within the studied population [ 35 ]. Presently, the alternate G and T allele combination was detected within the SA study cohort, for which our analysis revealed a significant association for the GT genotype (Table 4 ). Furthermore, the GT genotype remained significantly associated with the presence of disc degenerative disease following adjustment and Bonferroni correction (Table 4 ). Accordingly, these findings add a valuable contribution to the limited body of literature associating this variant to the presence of disc degenerative disease, and further highlight the importance of MMP-3 in the aetiology of this disease. Furthermore, these findings may be indicative of an integral role of the variant for disc degenerative disease within the South African population. However, considering the limited size of the studied cohort, further analysis in a larger population is crucial. Members of the growth differentiation factor (GDF) family are the most significant signalling molecules that maintain the homeostasis of the IVD, and its upregulation increases the expression of healthy cell marker genes [ 36 ]. Growth differentiation factor-5 (GDF-5), which is present in both normal and degenerated IVDs, has the capacity to regulate the composition of the extracellular matrix and plays an important role in the formation of soft tissues and the development of bones, cartilage, and ligaments [ 36 ]. The polymorphism on rs143383 is located in the 5’ non-coding region of GDF-5 gene and is thought to yield downregulation of GDF-5 gene expression, ultimately yielding an increased onset risk of disc degenerative disease [ 37 , 38 ]. The rs143883 variant has, accordingly, been shown to have a strong association with the development of hip dysplasia, osteoarthritis, and lumbar-related disease in several populations [ 38 – 42 ]. A study by Williams et al linked the rs143383 variant with disc degenerative disease, reporting a significantly increased risk of disc-space narrowing and osteophyte formation in Northern European women expressing the T allele [ 38 ]. Subsequent meta-analysis has similarly shown an association between the rs143383 variant and susceptibility to disc degenerative disease, with the T allele conferring risk and the C allele protection [ 41 ]. A more recent meta-analysis has shown the CC genotype to confer an increased incidence of disc degenerative disease in the Chinese Han population [ 42 ]. Present analysis of the rs143383 variant in the South African cohort reveals a G and A allelic combination for the rs143383 variant, along with a significant association with the presence of disc degenerative disease prior to adjustment (Table 4 ). In particular, low odds ratios for the GA genotype (OR: 0.38) and A allele (OR: 0.57) were observed. These findings may be indicative of a potential protective function toward GDF-5 gene dysfunction in those expressing the G/A allelic combination, and further that GDF-5 may ultimately not be involved in the presence of disc degenerative disease within the South African population. While interesting, adjusting for age and sex diminished the statistical significance of these observations—an occurrence likely due to the limited sample size used in this study. It is therefore imperative that the relationship of the rs143383 GDF-5 variant within the SA population be evaluated within a larger cohort. Moreover, determining if this potential protective function is unique to any specific racial group within the SA population would be beneficial. Conclusion To the best of our knowledge, this study represents the first of its kind to investigate the association of gene variants with disc degenerative disease within the South African population. This study has shown that 5 of these gene variants were significantly associated with the presence of disc degenerative disease, reflecting their integral roles in the development and possible progression of the disease. Declarations Acknowledgements The authors would like to express their immense gratitude to the Health Collective for their expertise, access to patient samples and records, and for their continued research support. Keenau Pearce was partially supported as a Post-Doctoral Fellow by funding from the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development under the Research Capacity Development Initiative (RCDI) Programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders. Data availability All data is available from the author upon reasonable request. Funding This study was made possible through funding by the South African Medical Research Counsil through its Division of Research Capacity Development under funding received from the South African National Treasury (Cape Town, Western Cape, South Africa). Competing interests The authors declare no competing interests. Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Keenau Pearce and Stephanie Less. The first draft of the manuscript was written by Keenau Pearce, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics approval This study was approved by the Senate Research Ethics Committee of the University of the Western Cape, South Africa [Ethics clearance number BM 22/4/7]. 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Zhonghua Wai Ke Za Zhi 52:739–744 Gologorsky Y, Chi J (2014) Genetic Predisposition to Lumbar Disc Degeneration. Neurosurgery 74:N10–N11. https://doi.org/10.1227/NEU.0000000000000275 Jiang L, Wang Y, Zhu X et al (2017) A Single Nucleotide Polymorphism in the GDF5 Gene (rs143383) may contribute to the Increased Risk of Osteoarthritis and Lumbar Disc Degeneration: an Updated Meta-Analysis. J Bone Res 05. https://doi.org/10.4172/2572-4916.1000183 Wang Z, Li Y, Wang Y et al (2018) Association between GDF5 single nucleotide polymorphism rs143383 and lumbar disc degeneration. Exp Ther Med 16:1900–1904. https://doi.org/10.3892/etm.2018.6382 Tables Table 1 Study population demographic data. Parameter Total patients (n = 117) Diagnosed disc degenerative disease (n = 67) No disc degenerative disease (n = 50) p-value Age (years; mean ± SD) Combined 50.5 ± 18.6 58.9 ± 13.2 39.2 ± 19.0 P = 0.0056 Sex Male Female 47 70 23 44 24 26 P = 0.1390 P = 0.0019 Smoking 37 15 22 P = 0.2498 Table 2 HWE and SNP information. SNP Gene Chromosomal position Location Allele change HWE p-value rs1052576 CASP-9 1:15506048 Missense C > T 0.9260 rs1304037 IL-1α 2:112774659 3’ UTR T > C 0.6098 rs1420100 IL-18 2:102420542 Intron A > C 0.2543 rs143383 GDF-5 20:35438203 5’ UTR G > A 0.9010 rs162509 ADAMTS-5 21:26953456 Intron G > C 0.3239 rs1676486 COL11A1 1:102888582 Missense G > A 0.1379 rs16924573 KIAA1217 10:24315964 Intron G > A 0.6592 rs16944 IL-1β 2:112837290 Intergenic A > G 0.1048 rs17561 IL-1α 2:112779646 Missense C > A 0.9750 rs17576 MMP-9 20:46011586 Missense A > G 0.9835 rs1800012 COL1A1 17:50200388 Intron C > A 0.3443 rs1800587 IL-1α 2:112785383 Intergenic G > A 0.7842 rs1800795 IL-6 7:22727026 Intron G > C 0.2240 rs20575 DR4 8:23201811 Missense G > C 0.3416 rs2073711 CILP 15:65201874 Missense A > G 0.2693 rs2076311 COL11A2 6:33177592 Intron C > A 0.8490 rs2228564 COL9A2 1:40307477 Missense C > T 0.1320 rs2856836 IL-1α 2:112774506 3’ UTR A > G 0.7926 rs4633 COMT 22:19962712 Synonymous C > T 0.1007 rs632478 MMP-3 11:102844950 Intergenic G > T 0.1721 Table 3 Genotype and allele frequencies of 20 SNPs demonstrating no significant association to disc degenerative disease for 15 SNPs. SNP Genotype/ Allele Case n (%) Control n (%) OR (95% CI) p-value rs1052576 CC CT TT C T 29 (43.9) 27 (40.9) 10 (15.1) 85 (64.4) 47 (35.6) 13 (27) 27 (56.2) 8 (16.6) 53 (55.2) 43 (44.8) Reference 2.23 (0.96–5.19) 1.78 (0.57–5.56) Reference 1.46 (0.86–2.51) P = 0.0625 P = 0.3180 P = 0.1620 rs1420100 AA AC CC A C 14 (21.2) 29 (43.9) 23 (34.8) 57 (43.1) 75 (56.8) 13 (26.5) 22 (44.8) 14 (28.5) 48 (48.9) 50 (51) Reference 0.81 (0.32–2.08) 0.66 (0.24–1.79) Reference 0.78 (0.46–1.33) P = 0.6722 P = 0.4104 P = 0.3830 rs1676486 GG GA AA G A 40 (61.5) 24 (36.9) 1 (1.5) 104 (80) 26 (20) 29 (61.7) 17 (36.1) 1 (2.1) 75 (79.7) 19 (20.2) Reference 0.98 (0.45–2.14) 1.38 (0.08–22.97) Reference 1.01 (0.52–1.96) P = 0.9536 P = 0.8227 P = 0.9687 rs16924573 GG AG G A 61 (93.8) 4 (6.1) 126 (96.9) 4 (3) 43 (89.5) 5 (10.4) 91 (94.7) 5 (5.2) Reference 1.77 (0.45–6.99) Reference 1.73 (0.45–6.62) P = 0.4130 P = 0.4231 rs16944 AA GA GG A G 13 (19.6) 25 (37.8) 28 (42.4) 51 (38.6) 81 (61.3) 11 (22.9) 22 (45.8) 15 (31.2) 44 (45.8) 52 (54.1) Reference 1.04 (0.39–2.79) 0.63 (0.23–1.75) Reference 0.74 (0.43–1.26) P = 0.9379 P = 0.3792 P = 0.2770 rs17561 CC CA AA C A 40 (61.5) 22 (33.8) 3 (4.6) 102 (78.4) 28 (21.5) 24 (50) 20 (41.6) 4 (8.3) 68 (70.8) 28 (29.1) Reference 1.51 (0.69–3.34) 2.22 (0.46–10.79) Reference 1.5 (0.81–2.75) P = 0.3021 P = 0.3220 P = 0.1905 rs17576 AA AG GG A G 17 (26.1) 32 (49.2) 16 (24.6) 66 (50.7) 64 (49.2) 14 (28.5) 25 (51) 10 (20) 53 (54) 45 (45.9) Reference 0.95 (0.39–2.29) 0.76 (0.26–2.19) Reference 0.87 (0.51–1.48) P = 0.9065 P = 0.6102 P = 0.6202 rs1800012 CC CA AA C A 43 (70.4) 17 (27.8) 1 (1.6) 103 (84.4) 19 (15.5) 36 (75) 12 (25) 0 (0) 84 (87.5) 12 (12.5) Reference 0.84 (0.36–1.99) 0.39 (0.02–10.05) Reference 0.74 (0.35–1.68) P = 0.6979 P = 0.5754 P = 0.5196 rs1800795 GG CG CC G C 32 (48.4) 28 (42.4) 6 (9) 92 (69.6) 40 (30.3) 31 (64.5) 12 (25) 5 (10.4) 74 (77) 22 (22.9) Reference 0.44 (0.19–1.02) 0.86 (0.24–3.11) Reference 0.68 (0.37–1.25) P = 0.0563 P = 0.8184 P = 0.2171 rs20575 GG GC CC G C 12 (18.1) 39 (59) 15 (22.7) 63 (47.7) 69 (52.2) 16 (33.3) 23 (47.9) 9 (18.7) 55 (57.2) 41 (42.7) Reference 0.44 (0.18–1.09) 0.45 (0.15–1.37) Reference 0.68 (0.40–1.15) P = 0.0785 P = 0.1604 P = 0.1543 rs2073711 AA AG GG A G 14 (22.2) 28 (44.4) 21 (33.3) 56 (44.4) 70 (55.5) 9 (18.3) 21 (42.8) 19 (38.7) 39 (39.7) 59 (60.2) Reference 1.17 (0.42–3.20) 1.40 (0.49–3.99) Reference 1.21 (0.70–2.06) P = 0.7650 P = 0.5205 P = 0.4851 rs2076311 CC CA AA C A 24 (38.7) 29 (46.7) 9 (14.5) 77 (62.1) 47 (37.9) 24 (48.9) 21 (42.8) 4 (8.1) 69 (70.4) 29 (29.5) Reference 0.72 (0.32–1.60) 0.44 (0.12–1.64) Reference 0.68 (0.39–1.21) P = 0.4274 P = 0.2238 P = 0.1959 rs2228564 CC CT TT C T 9 (13.8) 20 (30.7) 36 (55.3) 38 (29.2) 92 (70.7) 3 (6.2) 19 (39.5) 26 (54.1) 25 (26) 71 (73.9) Reference 2.85 (0.66–12.15) 2.17 (0.53–8.79) Reference 1.17 (0.64–2.12) P = 0.1568 P = 0.2793 P = 0.5973 rs2856836 AA GA GG A G 40 (61.5) 22 (33.8) 3 (4.6) 102 (78.4) 28 (21.5) 24 (51) 20 (42.5) 3 (6.3) 68 (72.3) 26 (27.6) Reference 1.52 (0.69–3.34) 1.67 (0.31–8.93) Reference 1.39 (0.75–2.57) P = 0.3021 P = 0.5508 P = 0.2915 rs4633 CC CT TT C T 21 (32.3) 25 (38.4) 19 (29.2) 67 (51.5) 63 (48.4) 16 (32.6) 23 (46.9) 10 (20.4) 55 (56.1) 43 (43.8) Reference 1.21 (0.51–2.86) 0.69 (0.25–1.89) Reference 0.83 (0.49–1.40) P = 0.6683 P = 0.4705 P = 0.4922 OR: odds ratio; CI 95% confidence interval. Percent does not account of missing alleles at specific loci. Table 4 Genotype and allele frequencies of 5 SNPs demonstrating significant association to disc degenerative disease adjusted for age and sex. Unadjusted Adjusted SNP/ Gene Genotype /Allele Case n (%) Control n (%) OR (95% CI) p-value OR (95% CI) p-value Bonferroni corrected p-values rs1304037 IL-1α TT CT CC T C 37 (57.8) 24 (37.5) 4 (6.2) 98 (75.3) 32 (24.6) 18 (36.7) 26 (53) 5 (10.2) 62 (63.2) 36 (36.7) Reference 2.22 (1.01–4.91) 2.56 (0.61–10.74) Reference 1.77 (1.00-3.15) P = 0.0456 P = 0.1857 P = 0.0476 Reference 2.29 (0.91–5.75) 3.36(0.64–17.44) Reference 1.99 (1.01–3.93) P = 0.0773 P = 0.1491 P = 0.0459 - - P = 0.0918 rs1800587 IL-1α GG GA AA G A 36 (56.9) 22 (33.8) 6 (9) 96 (73.8) 34 (26.1) 17 (34.6) 26 (53) 6 (12.2) 60 (61.2) 38 (38.7) Reference 2.50 (1.11–5.62) 2.11 (0.59–7.54) Reference 1.78 (1.01–3.14) P = 0.0249 P = 0.2409 P = 0.0434 Reference 2.55 (1.00-6.49) 3.50 (0.76–16.01) Reference 2.14 (1.10–4.18) P = 0.0488 P = 0.1063 P = 0.0249 P = 0.0976 - P = 0.0498 rs143383 GDF-5 GG GA AA G A 12 (18.7) 36 (56.2) 16 (25) 60 (46.8) 68 (53.1) 19 (38.7) 21 (42.8) 9 (18.3) 59 (60.2) 39 (39.7) Reference 0.37 (0.15–0.90) 0.36 (0.12–1.06) Reference 0.58 (0.34–0.99) P = 0.0299 P = 0.0629 P = 0.0474 Reference 0.29 (0.08–1.01) 0.178 (0.02–1.13) Reference 0.535 (0.28-1.00) P = 0.0529 P = 0.0673 P = 0.0516 - - - rs162509 ADAMTS-5 GG CG CC G C 24 (37.5) 30 (46.8) 10 (15.6) 78 (60.9) 50 (39) 11 (22.4) 21 (42.8) 17 (34.6) 43 (43.8) 55 (56.1) Reference 1.53 (0.62–3.79) 3.71 (1.29–10.68) Reference 1.99 (1.16–3.40) P = 0.3594 P = 0.0152 P = 0.0112 Reference 2.36 (0.72–7.71) 6.47 (1.54–27.07) Reference 2.59 (1.35–4.96) P = 0.1539 P = 0.0105 P = 0.0040 - P = 0.0210 P = 0.0080 rs632478 MMP-3 GG GT TT G T 25 (42.6) 28 (45.9) 7 (11.4) 80 (65.5) 42 (34.4) 10 (22) 32 (64) 7 (14) 54 (54) 46 (46) Reference 2.70 (1.13–6.44) 2.36 (0.67–8.36) Reference 1.62 (0.94–2.79) P = 0.0249 P = 0.1818 P = 0.0803 Reference 5.17 (1.61–16.61) 2.87 (0.66–12.52) Reference 1.81 (0.94–3.49) P = 0.0057 P = 0.1585 P = 0.0740 P = 0.0114 - - OR: odds ratio; CI 95% confidence interval. percent does not account of missing alleles at specific loci. significance (p < 0.05) is shown in bold. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 17 Sep, 2024 Read the published version in Molecular Biology Reports → Version 1 posted Editorial decision: Revision requested 19 Aug, 2024 Reviews received at journal 18 Aug, 2024 Reviewers agreed at journal 09 Aug, 2024 Reviewers agreed at journal 23 May, 2024 Reviewers invited by journal 10 Apr, 2024 Submission checks completed at journal 10 Apr, 2024 Editor assigned by journal 10 Apr, 2024 First submitted to journal 09 Apr, 2024 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-4241025","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290520873,"identity":"3b9a6925-be32-431d-a0dd-b66f26e112bb","order_by":0,"name":"Keenau Pearce","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBACCSgtR7oWY9K1JDYQrUVydvPBzxU1NukbbiQ/YPhRw2DPT0iztMyxZMkzx9JyN9xIM2DsOcbALHGAgBY5iRwDycaGw7kbbucwMPA2MLAxENaS//lnY8P/dAOgFsa/DQw88oS0SEvksAFtOZAA0sIMtEXCgJAWyTnHzCwbjiUbzrz/zOCwzDEJA0NCWiRuNz++2VBjJ8935vDDh29qbOzlCGmBRwwIHEDlEqNlFIyCUTAKRgFWAABIcT1DUQSLNgAAAABJRU5ErkJggg==","orcid":"","institution":"University of the Western Cape","correspondingAuthor":true,"prefix":"","firstName":"Keenau","middleName":"","lastName":"Pearce","suffix":""},{"id":290520874,"identity":"5b7d6cf3-3c16-429e-a13a-fd72bff33e1e","order_by":1,"name":"Stephanie Less","email":"","orcid":"","institution":"University of the Western Cape","correspondingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Less","suffix":""},{"id":290520875,"identity":"ed1a830b-9f44-4de7-966e-815ce21f4551","order_by":2,"name":"Adriaan W. Liebenberg","email":"","orcid":"","institution":"Health Collective, Panorama Healthcare Building, Cape Town","correspondingAuthor":false,"prefix":"","firstName":"Adriaan","middleName":"W.","lastName":"Liebenberg","suffix":""},{"id":290520876,"identity":"71db11db-41f9-4f7f-89e1-9d12d7fed4bc","order_by":3,"name":"Mongi Benjeddou","email":"","orcid":"","institution":"University of the Western Cape","correspondingAuthor":false,"prefix":"","firstName":"Mongi","middleName":"","lastName":"Benjeddou","suffix":""}],"badges":[],"createdAt":"2024-04-09 09:50:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4241025/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4241025/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11033-024-09930-7","type":"published","date":"2024-09-17T15:57:30+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":65104021,"identity":"d8f36285-2ee7-48cc-9b83-a5e0727e5f11","added_by":"auto","created_at":"2024-09-23 16:10:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":905355,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4241025/v1/8e99cdbe-f619-4dca-8bf0-01b28af7b539.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Disc degenerative disease in South Africa: A case-control analysis of selected gene variants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDisc degenerative disease and related back pain are either acute or chronic forms of disease that may be caused by various factors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Globally, these conditions represent a significant cause of diminished quality of life, morbidity, and mortality. Lower back pain (LBP), in particular, is a common debilitating musculoskeletal condition and affects approximately 637\u0026nbsp;million people, globally\u0026ndash;with a lifetime prevalence of approximately 80% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In South Africa, the prevalence of diagnosed spinal degenerative disease in the urban population is estimated to range from 48-78.2% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Many causes for LBP exist, but disc degeneration has been found to be a more common diagnosis among individuals who suffer from LBP than those who do not. Back pain may not always be a symptom of disc degeneration, although it is often an early sign of degenerative spine pathologies. The intervertebral disc (IVD) is among the most pivotal biological structures of the human body [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eProgressive degradation of IVD structures that leads to disruption of the homeostasis of the spine is clinically known as disc degeneration and is often associated with severe pain [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. IVDs are composed of fibrocartilaginous tissue that assists in maintaining stability and flexibility of the entire spine [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The primary role of the IVD is to connect two adjacent vertebral bodies while acting as a cushion that carries weight and pressure attributed to mechanical load. An intact and healthy IVD is comprised of three main structures: the central nucleus pulposus, the external annulus fibrosus, and endplates [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These structures provide the IVD with high compressive and tensile strength, support axial compression of the spine, and allow multiaxial flexibility [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDisc degenerative disease is a multifactorial disease often emerging due to several factors causing tissue weakening which ultimately results in pathological changes in the IVD\u0026mdash;particularly the production of inflammatory mediators, increased apoptosis, and extracellular matrix loss [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These include endplate damage, nutritional deficiency, abnormal load, smoking, ageing, and genetics [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Genetic factors in particular have been estimated to contribute an estimated 75% to IVD degenerative disease aetiology [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Genetic variation associated with the genes involved in processes that are related to degradation of the extracellular matrix components, apoptosis, and inflammation, have been associated with structural and functional changes within the IVD, which leads to disruption of the disc\u0026rsquo;s metabolic activities and mechanical properties [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, several genes, and their variants, associated with the development and progression of disc degenerative disease have been identified, including COL1A1 and COL11A1, GDF-5, CASP-3 and CASP-9, IL-1α and IL-6, ADAMTS-5, KIAA, CILP, COMT, MMP-3, and MMP-6 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Notably, associated gene variants have been extensively investigated in Asian and European populations, for which risk genotypes and alleles have been identified. It is essential to note, however, that South Africa is home to several genetically diverse population groups representing unique genetic profiles which include novel and rare variants regarding pharmaco-genetically relevant genes [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Moreover, this genomic diversity is a largely understudied domain, as compared to European populations, and within the context of disc degenerative diseases is non-existent in the available literature. It is therefore unclear how previously identified genetic associations to disc degenerative disease relate to the South African population and the unique genetic diversity represented therein. Therefore, this study aimed to investigate selected gene variants with the greatest level of evidence for association with disc degenerative disease within the South African population.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient and study design\u003c/h2\u003e \u003cp\u003e All participants were briefed about the project and a consent form was completed and submitted by each participant before the experiment was conducted. Ethics clearance for this study was obtained from the Senate Research Committee of the University of the Western Cape [Ethics clearance number BM 22/4/7].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eBiological samples were collected in the form of buccal swabs from patients visiting the Health Collective, Panorama Healthcare Building, Cape Town, South Africa. All patients included in this study were confirmed to have disc degenerative disease by magnetic resonance imaging (MRI) and/or radionuclide scans and were confirmed to not have evidence of active cancer(s), a record of spinal trauma, or trauma to the surrounding spinal structures. Convenience sampling was employed for samples collected from healthy volunteers. An ethnically mixed population was utilised for the study cohort, and ethnicities of participants were determined by self-report.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSingle Nucleotide Polymorphism selection and genotyping\u003c/h2\u003e \u003cp\u003eThe 20 relevant genetic variants selected for this study were chosen based upon previous publications, where association was made between single nucleotide polymorphisms (SNPs) and the presence of disc degenerative disease. The Ensembl data-base was also used for cross-referencing the selected SNPs (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ensembl.org\u003c/span\u003e\u003cspan address=\"http://www.ensembl.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGenomic DNA was isolated from buccal swabs using a standard salt-lysis protocol [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Samples were stored at \u0026minus;\u0026thinsp;20\u0026deg;C. DNA was quantified using a NanoDrop\u0026trade;2000/ 2000c UV/VIS Spectrophotometer (Thermo Scientific, Waltham, MA, USA). The SNPs were genotyped using the MassARRAY\u0026reg;System IPLEX extension reaction (Agena Bioscience, San Diego, CA, USA). Genotypes of the selected SNP variants were determined for all the study participants (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis for Hardy-Weinberg equilibrium (HWE), genotype frequencies, and allele frequencies were performed using GenALEx version 6.5 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. For HWE, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant and thus a departure from HWE. For associations between variants and disc degenerative disease, odds ratios, confidence intervals, chi-squared analysis and logistic regression was calculated using IBM Statistical Package for Social Sciences (SPSS) version 26. A significance threshold of 0.05 was employed for association studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eStudy population demographic data are shown in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and age sex and smoking were evaluated as possible covariates. Following analysis, only age (P\u0026thinsp;=\u0026thinsp;0.0056) and sex, i.e. female (P\u0026thinsp;=\u0026thinsp;0.0019), were determined to be covariates within the study population (Table\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The identified covariates were subsequently utilised in logistic regression.\u003c/p\u003e \u003cp\u003eGenotype and allele distribution of the 20 SNPs were determined in the study participants (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). All SNPs analysed within the study population were found to be within Hardy-Weinberg equilibrium (HWE), with p-values ranging between 0.1007\u0026ndash;0.9835 (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the SNPs selected for this study, five displayed a significant association between disc degenerative disease and genotype or allele prior to adjustment (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). All non-significant SNPs are displayed in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The five significantly associated genes/SNPs are: IL-1α rs1304037 and rs1800587, GDF-5 rs143383, ADAMTS-5 rs162509, and MMP-3 rs632478.\u003c/p\u003e \u003cp\u003ePrior to adjustment, the heterozygous genotype CT, and the minor allele C of rs1304037 demonstrated significant associations with diagnosis of disc degenerative disease [P\u0026thinsp;=\u0026thinsp;0.0456, (OR: 2.22, 95% CI: 1.01\u0026ndash;4.91) and P\u0026thinsp;=\u0026thinsp;0.0476 (OR:1.77, 95% CI: 1.00-3.15) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). For rs1800587, the heterozygous genotype GA, and the minor allele A demonstrated significant associations with diagnosis of disc degenerative disease [P\u0026thinsp;=\u0026thinsp;0.0249, (OR: 2.50, 95% CI: 1.11\u0026ndash;5.62) and P\u0026thinsp;=\u0026thinsp;0.0434 (OR:1.78, 95% CI: 1.01\u0026ndash;3.14) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). When analysed, the heterozygous genotype GA, and the minor allele A of rs143383 demonstrated significant associations with diagnosis of disc degenerative disease [P\u0026thinsp;=\u0026thinsp;0.0299, (OR: 0.37, 95% CI: 0.15\u0026ndash;0.90) and P\u0026thinsp;=\u0026thinsp;0.0474 (OR:0.58, 95% CI: 0.34\u0026ndash;0.99) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Next, the homozygous minor genotype CC and the minor allele C of rs162509 demonstrated significant associations with diagnosis of disc degenerative disease [P\u0026thinsp;=\u0026thinsp;0.0152, (OR: 3.71, 95% CI: 1.29\u0026ndash;10.68) and P\u0026thinsp;=\u0026thinsp;0.0112 (OR: 1.99, 95% CI: 1.16\u0026ndash;3.40) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Finally, the heterozygous genotype GT of rs632478 demonstrated significant associations with diagnosis of disc degenerative disease [P\u0026thinsp;=\u0026thinsp;0.0249, (OR: 2.70, 95% CI: 1.13\u0026ndash;6.44)] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFollowing adjustment, only the C allele of rs1304037 remained significantly associated [P\u0026thinsp;=\u0026thinsp;0.0459 (OR:1.99, 95% CI: 1.01\u0026ndash;3.93) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). For rs1800587, the heterozygous genotype GA, and the minor allele A remained significantly associated following adjustment [P\u0026thinsp;=\u0026thinsp;0.0249, (OR: 2.55, 95% CI: 1.00-6.49) and P\u0026thinsp;=\u0026thinsp;0.0434 (OR:2.14 95% CI: 1.10\u0026ndash;4.18) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The homozygous minor genotype CC and the minor allele C of rs162509 remained significantly associated with disc degenerative disease following adjustment [P\u0026thinsp;=\u0026thinsp;0.0105, (OR: 6.47, 95% CI: 1.54\u0026ndash;27.07) and P\u0026thinsp;=\u0026thinsp;0.0040 (OR: 2.59, 95% CI: 1.35\u0026ndash;4.96) respectively] (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Once adjusted, only the heterozygous genotype i.e. GT of rs632478 demonstrated a significant association with diagnosis of disc degenerative disease [P\u0026thinsp;=\u0026thinsp;0.0057, (OR: 5.17, 95% CI: 1.61\u0026ndash;16.61) (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLastly, after Bonferroni correction, significance was maintained for the A allele of rs1800587 (P\u0026thinsp;=\u0026thinsp;0.0498), the homozygous minor genotype CC, and the minor allele C of rs162509 (P\u0026thinsp;=\u0026thinsp;0.0210 and P\u0026thinsp;=\u0026thinsp;0.0080), along with the heterozygous GT genotype of rs632478 (P\u0026thinsp;=\u0026thinsp;0.0114) (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eIn this study, the genetic association of 20 possible biomarkers for the presence of disc degenerative disease was determined. All SNPs tested were found to be within HWE and showed p-values ranging between 0.1007\u0026ndash;0.9835 within the study population (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Genotype and allele distribution of the 20 SNPs were determined in study cohort (Tables \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Among the SNPs analysed, 15 of the selected SNPs exhibited no statistically significant association with disc degenerative disease within the study cohort (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The respective genotypes and alleles of the remaining 5 SNPs i.e. rs1304037 (CT P\u0026thinsp;=\u0026thinsp;0.0456; C P\u0026thinsp;=\u0026thinsp;0.0476), rs1800587 (GG P\u0026thinsp;=\u0026thinsp;0.0249; A P\u0026thinsp;=\u0026thinsp;0.0434), rs162509 (GG P\u0026thinsp;=\u0026thinsp;0.0152; C P\u0026thinsp;=\u0026thinsp;0.0112), rs632478 (GT P\u0026thinsp;=\u0026thinsp;0.0249), and rs143383 (GA P\u0026thinsp;=\u0026thinsp;0.0299; A P\u0026thinsp;=\u0026thinsp;0.0474), however demonstrated significant associations between variant and disc degenerative disease, prior to adjustment (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). From our analysis, SNPs rs1304037, rs1800587, rs162509, rs632478 demonstrated increased odds of a positive diagnosis for disc degenerative disease. Conversely, decreased odds of disc degenerative disease were seen for rs143383.\u003c/p\u003e \u003cp\u003eInterleukin-1 (IL-1) is an inflammatory cytokine expressed in the IVD that is tied to the degradation of extracellular matrix components through the production of degradative enzymes, inhibition of proteoglycan resynthesis, cytokine upregulation, and through inhibition of extracellular matrix component production [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The IL-1α gene in particular is linked to an increased risk of disc degenerative disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Hypersensitivity to IL-1α in disc cells has been described as a significant motivator for degeneration, playing a key role in extracellular matrix metabolism and modic changes\u0026mdash;an MRI trait associated with disc degenerative disease [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. To date, several IL-1α polymorphisms have been shown to be associated with IVD severity and modic changes, including the rs1800587 and rs1304037 variants [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe C allele of the IL-1α rs1304037 variant was reported to be associated with increased severity of disc degenerative disease and the accompanying modic changes [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this study, we have similarly shown a significant association between the rs1304037 variant and disc degenerative disease (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), particularly for the CT genotype and C allele prior to adjustment. Following adjustment, the C allele remained significantly associated with disc degenerative disease within the study cohort. Thus, the findings presented here for rs1304037 are in accordance with those reported by Parera \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. With regard to the rs1800587 variant, the TT genotype, as compared to the CC genotype, has previously been shown to be associated with and increased risk of disc degenerative disease in several studies [\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Particularly, this association was demonstrated in a Caucasian population [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], a Chinese Han population [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and a Finnish population in studies investigating middle-aged men [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and young girls aged 12\u0026ndash;14 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Thus, from the available literature, the C and T allele combination is the most reported, however, a G and A combination has also been described. To date, two studies have demonstrated an association with disc degenerative disease for the G and A allelic combination for the variant in a Spanish population [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], as well as a Sri Lankan population [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In their studies, the A allele was shown to be associated with reduced severity of disc degenerative disease and the accompanying modic changes [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Presently, we similarly report the G and A allelic combination for rs1800587 within the study cohort. Unlike previous studies, however, our analysis revealed a significantly increased likelihood of disc degenerative disease for the GA genotype and A allele (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These findings are contradictory to previous reports and thus merit further investigation within a larger study cohort. Nevertheless, the findings presented here reiterate the importance of the interleukins in disc degenerative disease and its progression.\u003c/p\u003e \u003cp\u003eADAMTS form a group of metalloproteinases possessing several important biological functions, such as extracellular matrix remodelling, procollagen processing, cell migration, and inflammatory processes [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The binding of ADAMTS to extracellular matrix components is modulated via a thrombospondin structural domain which may lead to proteolysis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. ADAMTS-5 (aggrecanase-2) in particular has been identified as an important risk factor in the development of disc degenerative disease [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Several studies have shown an association between the ADAMTS-5 rs162509 variant and disc degenerative disease [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Early studies of the ADAMTS-5 rs162509 variant in the Chinese Han population reported the C and G allele combination and further showed no statistically significant association with disc degenerative disease [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Interestingly, however, a later study of the same population reported a G and A allelic combination and further reported the G allele to be significantly higher in patients with disc degenerative disease, as compared to healthy individuals [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Similarly, a study by Rajasekaran \u003cem\u003eet al\u003c/em\u003e also reported a significant association between rs165209 and the severity of disc degenerative disease in an Indian population [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The present analysis demonstrated the C and G allele combination within the study cohort, and further that the CC genotype and C allele were significantly associated with the presence of disc degenerative disease following adjustment and Bonferroni correction (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These findings are contradictory to those reported by Wu \u003cem\u003eet al\u003c/em\u003e, however, and may indicate that the ADAMTS-5 rs165209 variant plays an integral role in the presence of disc degenerative disease within the South African population. Based on this, further, more rigorous investigation of this variant within a larger cohort is essential\u003c/p\u003e \u003cp\u003eMatrix metalloproteinases (MMPs) are the principal catabolic enzymes of the IVD and are the main mediators of extracellular matrix degradation that allow for normal remodelling and the abolishment of pathological tissues [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Degradation of the IVD\u0026rsquo;s extracellular matrix by MMP enzymes is important in the pathogenesis of IVD degeneration [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. MMP-3 is reportedly one of the most significant proteoglycan-degrading enzymes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Specific conditions such as inflammation and mechanical loading can trigger the expression of the MMP-3 gene and the resulting IVD degeneration from this expression may, hereby, increase with time [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. While available literature is limited, the MMP-3 rs63248 variant has been shown to play an integral role toward spinal bone mineral density and degenerative disease [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Investigations into the role of MMP-3 rs63248 variant in disc degenerative disease by Saberi \u003cem\u003eet al\u003c/em\u003e demonstrated a significant association within an Iranian population [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. More specifically, they showed that the CC genotype was associated with a significantly increased risk of disc degenerative disease, relative to the AA genotype, and was further suggested to be a contributing factor toward increased susceptibility within the studied population [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Presently, the alternate G and T allele combination was detected within the SA study cohort, for which our analysis revealed a significant association for the GT genotype (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Furthermore, the GT genotype remained significantly associated with the presence of disc degenerative disease following adjustment and Bonferroni correction (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Accordingly, these findings add a valuable contribution to the limited body of literature associating this variant to the presence of disc degenerative disease, and further highlight the importance of MMP-3 in the aetiology of this disease. Furthermore, these findings may be indicative of an integral role of the variant for disc degenerative disease within the South African population. However, considering the limited size of the studied cohort, further analysis in a larger population is crucial.\u003c/p\u003e \u003cp\u003eMembers of the growth differentiation factor (GDF) family are the most significant signalling molecules that maintain the homeostasis of the IVD, and its upregulation increases the expression of healthy cell marker genes [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Growth differentiation factor-5 (GDF-5), which is present in both normal and degenerated IVDs, has the capacity to regulate the composition of the extracellular matrix and plays an important role in the formation of soft tissues and the development of bones, cartilage, and ligaments [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The polymorphism on rs143383 is located in the 5\u0026rsquo; non-coding region of GDF-5 gene and is thought to yield downregulation of GDF-5 gene expression, ultimately yielding an increased onset risk of disc degenerative disease [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The rs143883 variant has, accordingly, been shown to have a strong association with the development of hip dysplasia, osteoarthritis, and lumbar-related disease in several populations [\u003cspan additionalcitationids=\"CR39 CR40 CR41\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. A study by Williams \u003cem\u003eet al\u003c/em\u003e linked the rs143383 variant with disc degenerative disease, reporting a significantly increased risk of disc-space narrowing and osteophyte formation in Northern European women expressing the T allele [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Subsequent meta-analysis has similarly shown an association between the rs143383 variant and susceptibility to disc degenerative disease, with the T allele conferring risk and the C allele protection [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. A more recent meta-analysis has shown the CC genotype to confer an increased incidence of disc degenerative disease in the Chinese Han population [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePresent analysis of the rs143383 variant in the South African cohort reveals a G and A allelic combination for the rs143383 variant, along with a significant association with the presence of disc degenerative disease prior to adjustment (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In particular, low odds ratios for the GA genotype (OR: 0.38) and A allele (OR: 0.57) were observed. These findings may be indicative of a potential protective function toward GDF-5 gene dysfunction in those expressing the G/A allelic combination, and further that GDF-5 may ultimately not be involved in the presence of disc degenerative disease within the South African population. While interesting, adjusting for age and sex diminished the statistical significance of these observations\u0026mdash;an occurrence likely due to the limited sample size used in this study. It is therefore imperative that the relationship of the rs143383 GDF-5 variant within the SA population be evaluated within a larger cohort. Moreover, determining if this potential protective function is unique to any specific racial group within the SA population would be beneficial.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo the best of our knowledge, this study represents the first of its kind to investigate the association of gene variants with disc degenerative disease within the South African population. This study has shown that 5 of these gene variants were significantly associated with the presence of disc degenerative disease, reflecting their integral roles in the development and possible progression of the disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their immense gratitude to the Health Collective for their expertise, access to patient samples and records, and for their continued research support.\u003c/p\u003e\n\u003cp\u003eKeenau Pearce was partially supported as a Post-Doctoral Fellow by funding from the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development under the Research Capacity Development Initiative (RCDI) Programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data is available from the author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis study was made possible through funding by the South African Medical Research Counsil through its Division of Research Capacity Development under funding received from the South African National Treasury (Cape Town, Western Cape, South Africa).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Keenau Pearce and Stephanie Less. The first draft of the manuscript was written by Keenau Pearce, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Senate Research Ethics Committee of the University of the Western Cape, South Africa [Ethics clearance number BM 22/4/7]. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSamples were obtained from the participants with informed consent.\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKos N, Gradisnik L, Velnar T (2019) A Brief Review of the Degenerative Intervertebral Disc Disease. 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J Bone Res 05. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4172/2572-4916.1000183\u003c/span\u003e\u003cspan address=\"10.4172/2572-4916.1000183\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Li Y, Wang Y et al (2018) Association between GDF5 single nucleotide polymorphism rs143383 and lumbar disc degeneration. Exp Ther Med 16:1900\u0026ndash;1904. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3892/etm.2018.6382\u003c/span\u003e\u003cspan address=\"10.3892/etm.2018.6382\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy population demographic data.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal patients (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDiagnosed disc degenerative disease\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo disc degenerative disease\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.5\u0026thinsp;\u0026plusmn;\u0026thinsp;18.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39.2\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0056\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24\u003c/p\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.1390\u003c/p\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.2498\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHWE and SNP information.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChromosomal position\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAllele change\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHWE p-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1052576\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCASP-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:15506048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9260\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1304037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-1α\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2:112774659\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u0026rsquo; UTR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.6098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1420100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2:102420542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.2543\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers143383\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGDF-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20:35438203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u0026rsquo; UTR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers162509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADAMTS-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21:26953456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.3239\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1676486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOL11A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:102888582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1379\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers16924573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKIAA1217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10:24315964\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.6592\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers16944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-1β\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2:112837290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntergenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers17561\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-1α\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2:112779646\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9750\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers17576\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMP-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20:46011586\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9835\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1800012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOL1A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17:50200388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.3443\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1800587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-1α\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2:112785383\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntergenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.7842\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1800795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7:22727026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.2240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers20575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDR4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8:23201811\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.3416\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2073711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCILP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15:65201874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.2693\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2076311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOL11A2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6:33177592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.8490\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2228564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOL9A2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:40307477\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1320\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2856836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-1α\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2:112774506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u0026rsquo; UTR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.7926\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers4633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOMT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22:19962712\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSynonymous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers632478\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMP-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11:102844950\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntergenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1721\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenotype and allele frequencies of 20 SNPs demonstrating no significant association to disc degenerative disease for 15 SNPs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGenotype/\u003c/p\u003e \u003cp\u003eAllele\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1052576\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003cp\u003eCT\u003c/p\u003e \u003cp\u003eTT\u003c/p\u003e \u003cp\u003eC\u003c/p\u003e \u003cp\u003eT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (43.9)\u003c/p\u003e \u003cp\u003e27 (40.9)\u003c/p\u003e \u003cp\u003e10 (15.1)\u003c/p\u003e \u003cp\u003e85 (64.4)\u003c/p\u003e \u003cp\u003e47 (35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003cp\u003e27 (56.2)\u003c/p\u003e \u003cp\u003e8 (16.6)\u003c/p\u003e \u003cp\u003e53 (55.2)\u003c/p\u003e \u003cp\u003e43 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.23 (0.96\u0026ndash;5.19)\u003c/p\u003e \u003cp\u003e1.78 (0.57\u0026ndash;5.56)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.46 (0.86\u0026ndash;2.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.0625\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.3180\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.1620\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1420100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003cp\u003eAC\u003c/p\u003e \u003cp\u003eCC\u003c/p\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (21.2)\u003c/p\u003e \u003cp\u003e29 (43.9)\u003c/p\u003e \u003cp\u003e23 (34.8)\u003c/p\u003e \u003cp\u003e57 (43.1)\u003c/p\u003e \u003cp\u003e75 (56.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (26.5)\u003c/p\u003e \u003cp\u003e22 (44.8)\u003c/p\u003e \u003cp\u003e14 (28.5)\u003c/p\u003e \u003cp\u003e48 (48.9)\u003c/p\u003e \u003cp\u003e50 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.81 (0.32\u0026ndash;2.08)\u003c/p\u003e \u003cp\u003e0.66 (0.24\u0026ndash;1.79)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.78 (0.46\u0026ndash;1.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.6722\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.4104\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.3830\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1676486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003cp\u003eGA\u003c/p\u003e \u003cp\u003eAA\u003c/p\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (61.5)\u003c/p\u003e \u003cp\u003e24 (36.9)\u003c/p\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003cp\u003e104 (80)\u003c/p\u003e \u003cp\u003e26 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (61.7)\u003c/p\u003e \u003cp\u003e17 (36.1)\u003c/p\u003e \u003cp\u003e1 (2.1)\u003c/p\u003e \u003cp\u003e75 (79.7)\u003c/p\u003e \u003cp\u003e19 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.98 (0.45\u0026ndash;2.14)\u003c/p\u003e \u003cp\u003e1.38 (0.08\u0026ndash;22.97)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.01 (0.52\u0026ndash;1.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.9536\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.8227\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.9687\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers16924573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003cp\u003eAG\u003c/p\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (93.8)\u003c/p\u003e \u003cp\u003e4 (6.1)\u003c/p\u003e \u003cp\u003e126 (96.9)\u003c/p\u003e \u003cp\u003e4 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (89.5)\u003c/p\u003e \u003cp\u003e5 (10.4)\u003c/p\u003e \u003cp\u003e91 (94.7)\u003c/p\u003e \u003cp\u003e5 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.77 (0.45\u0026ndash;6.99)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.73 (0.45\u0026ndash;6.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.4130\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.4231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers16944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003cp\u003eGA\u003c/p\u003e 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(14.5)\u003c/p\u003e \u003cp\u003e77 (62.1)\u003c/p\u003e \u003cp\u003e47 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (48.9)\u003c/p\u003e \u003cp\u003e21 (42.8)\u003c/p\u003e \u003cp\u003e4 (8.1)\u003c/p\u003e \u003cp\u003e69 (70.4)\u003c/p\u003e \u003cp\u003e29 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.72 (0.32\u0026ndash;1.60)\u003c/p\u003e \u003cp\u003e0.44 (0.12\u0026ndash;1.64)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.68 (0.39\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.4274\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.2238\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.1959\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2228564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003cp\u003eCT\u003c/p\u003e \u003cp\u003eTT\u003c/p\u003e \u003cp\u003eC\u003c/p\u003e \u003cp\u003eT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (13.8)\u003c/p\u003e \u003cp\u003e20 (30.7)\u003c/p\u003e \u003cp\u003e36 (55.3)\u003c/p\u003e \u003cp\u003e38 (29.2)\u003c/p\u003e \u003cp\u003e92 (70.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (6.2)\u003c/p\u003e \u003cp\u003e19 (39.5)\u003c/p\u003e \u003cp\u003e26 (54.1)\u003c/p\u003e \u003cp\u003e25 (26)\u003c/p\u003e \u003cp\u003e71 (73.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.85 (0.66\u0026ndash;12.15)\u003c/p\u003e \u003cp\u003e2.17 (0.53\u0026ndash;8.79)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.17 (0.64\u0026ndash;2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.1568\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.2793\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.5973\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2856836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003cp\u003eGA\u003c/p\u003e \u003cp\u003eGG\u003c/p\u003e \u003cp\u003eA\u003c/p\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (61.5)\u003c/p\u003e \u003cp\u003e22 (33.8)\u003c/p\u003e \u003cp\u003e3 (4.6)\u003c/p\u003e \u003cp\u003e102 (78.4)\u003c/p\u003e \u003cp\u003e28 (21.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (51)\u003c/p\u003e \u003cp\u003e20 (42.5)\u003c/p\u003e \u003cp\u003e3 (6.3)\u003c/p\u003e \u003cp\u003e68 (72.3)\u003c/p\u003e \u003cp\u003e26 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.52 (0.69\u0026ndash;3.34)\u003c/p\u003e \u003cp\u003e1.67 (0.31\u0026ndash;8.93)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.39 (0.75\u0026ndash;2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.3021\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.5508\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.2915\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers4633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003cp\u003eCT\u003c/p\u003e \u003cp\u003eTT\u003c/p\u003e \u003cp\u003eC\u003c/p\u003e \u003cp\u003eT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (32.3)\u003c/p\u003e \u003cp\u003e25 (38.4)\u003c/p\u003e \u003cp\u003e19 (29.2)\u003c/p\u003e \u003cp\u003e67 (51.5)\u003c/p\u003e \u003cp\u003e63 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (32.6)\u003c/p\u003e \u003cp\u003e23 (46.9)\u003c/p\u003e \u003cp\u003e10 (20.4)\u003c/p\u003e \u003cp\u003e55 (56.1)\u003c/p\u003e \u003cp\u003e43 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.21 (0.51\u0026ndash;2.86)\u003c/p\u003e \u003cp\u003e0.69 (0.25\u0026ndash;1.89)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.83 (0.49\u0026ndash;1.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.6683\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.4705\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.4922\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOR: odds ratio; CI 95% confidence interval. Percent does not account of missing alleles at specific loci.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenotype and allele frequencies of 5 SNPs demonstrating significant association to disc degenerative disease adjusted for age and sex.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eUnadjusted\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003eAdjusted\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSNP/ Gene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003cp\u003e/Allele\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBonferroni corrected p-values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1304037\u003c/p\u003e \u003cp\u003eIL-1α\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003cp\u003eCT\u003c/p\u003e \u003cp\u003eCC\u003c/p\u003e \u003cp\u003eT\u003c/p\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (57.8)\u003c/p\u003e \u003cp\u003e24 (37.5)\u003c/p\u003e \u003cp\u003e4 (6.2)\u003c/p\u003e \u003cp\u003e98 (75.3)\u003c/p\u003e \u003cp\u003e32 (24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (36.7)\u003c/p\u003e \u003cp\u003e26 (53)\u003c/p\u003e \u003cp\u003e5 (10.2)\u003c/p\u003e \u003cp\u003e62 (63.2)\u003c/p\u003e \u003cp\u003e36 (36.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.22 (1.01\u0026ndash;4.91)\u003c/p\u003e \u003cp\u003e2.56 (0.61\u0026ndash;10.74)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.77 (1.00-3.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0456\u003c/b\u003e\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.1857\u003c/p\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0476\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.29 (0.91\u0026ndash;5.75)\u003c/p\u003e \u003cp\u003e3.36(0.64\u0026ndash;17.44)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.99 (1.01\u0026ndash;3.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.0773\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.1491\u003c/p\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0459\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.0918\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1800587\u003c/p\u003e \u003cp\u003eIL-1α\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003cp\u003eGA\u003c/p\u003e \u003cp\u003eAA\u003c/p\u003e \u003cp\u003eG\u003c/p\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (56.9)\u003c/p\u003e \u003cp\u003e22 (33.8)\u003c/p\u003e \u003cp\u003e6 (9)\u003c/p\u003e \u003cp\u003e96 (73.8)\u003c/p\u003e \u003cp\u003e34 (26.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (34.6)\u003c/p\u003e \u003cp\u003e26 (53)\u003c/p\u003e \u003cp\u003e6 (12.2)\u003c/p\u003e \u003cp\u003e60 (61.2)\u003c/p\u003e \u003cp\u003e38 (38.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.50 (1.11\u0026ndash;5.62)\u003c/p\u003e \u003cp\u003e2.11 (0.59\u0026ndash;7.54)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.78 (1.01\u0026ndash;3.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0249\u003c/b\u003e\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.2409\u003c/p\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0434\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.55 (1.00-6.49)\u003c/p\u003e \u003cp\u003e3.50 (0.76\u0026ndash;16.01)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.14 (1.10\u0026ndash;4.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0488\u003c/b\u003e\u003c/p\u003e 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(53.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (38.7)\u003c/p\u003e \u003cp\u003e21 (42.8)\u003c/p\u003e \u003cp\u003e9 (18.3)\u003c/p\u003e \u003cp\u003e59 (60.2)\u003c/p\u003e \u003cp\u003e39 (39.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.37 (0.15\u0026ndash;0.90)\u003c/p\u003e \u003cp\u003e0.36 (0.12\u0026ndash;1.06)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.58 (0.34\u0026ndash;0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0299\u003c/b\u003e\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.0629\u003c/p\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0474\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.29 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\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.0114\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOR: odds ratio; CI 95% confidence interval. percent does not account of missing alleles at specific loci. significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) is shown in bold.\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":"molecular-biology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mole","sideBox":"Learn more about [Molecular Biology Reports](https://www.springer.com/journal/11033)","snPcode":"11033","submissionUrl":"https://submission.nature.com/new-submission/11033/3","title":"Molecular Biology Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Disc degenerative disease, single nucleotide polymorphism, genotype, allele, South Africa","lastPublishedDoi":"10.21203/rs.3.rs-4241025/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4241025/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDisc degenerative disease is a multifactorial disease for which genetics plays an integral role. Several genes, and their variants, associated with the development and progression of disc degenerative disease have been identified. While several studies have investigated these genes in Asian and European populations, no available evidence exists for the South African population. Therefore, this study aimed to investigate these parameters.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods and results\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBiological samples were collected in the form of buccal swabs from patients. DNA extraction was carried out according to established methods. All genotyping was performed using the MassARRAY\u0026reg;System IPLEX extension reaction. or associations between variants and the presence of disc degenerative disease, odds ratios, confidence intervals, chi-squared analysis and logistic regression was calculated. This study found statistically significant associations for five of the evaluated single nucleotide polymorphisms (SNPs) with disc degenerative disease, namely IL-1α rs1304037 and rs1800587, GDF-5 rs143383, ADAMTs-5 rs162509, and MMP-3 rs632478.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this study represents the first of its kind to investigate the association of gene variants associated with disc degenerative disease within the South African population. This study has shown that 5 of these gene variants were significantly associated with the presence of disc degenerative disease, reflecting their integral roles in development and possible progression of the disease.\u003c/p\u003e","manuscriptTitle":"Disc degenerative disease in South Africa: A case-control analysis of selected gene variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-15 08:07:54","doi":"10.21203/rs.3.rs-4241025/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-19T08:11:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-18T19:31:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"149304740713384336465683301722419180709","date":"2024-08-09T17:05:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333039739711892605003346740682598637130","date":"2024-05-23T12:16:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-10T12:19:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-10T06:02:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-10T06:02:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Biology Reports","date":"2024-04-09T09:47:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-biology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mole","sideBox":"Learn more about [Molecular Biology Reports](https://www.springer.com/journal/11033)","snPcode":"11033","submissionUrl":"https://submission.nature.com/new-submission/11033/3","title":"Molecular Biology Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6cb9380d-bdab-40eb-b929-aa72fd23181f","owner":[],"postedDate":"April 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-23T16:02:10+00:00","versionOfRecord":{"articleIdentity":"rs-4241025","link":"https://doi.org/10.1007/s11033-024-09930-7","journal":{"identity":"molecular-biology-reports","isVorOnly":false,"title":"Molecular Biology Reports"},"publishedOn":"2024-09-17 15:57:30","publishedOnDateReadable":"September 17th, 2024"},"versionCreatedAt":"2024-04-15 08:07:54","video":"","vorDoi":"10.1007/s11033-024-09930-7","vorDoiUrl":"https://doi.org/10.1007/s11033-024-09930-7","workflowStages":[]},"version":"v1","identity":"rs-4241025","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4241025","identity":"rs-4241025","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}