Knee Osteoarthritis Susceptibility Research Articles

A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

Role of resistin genetic variations in knee osteoarthritis pathogenesis, a cross sectional study.

Osteoarthritis (OA) is a serious health concern globally and is recognized by degradation of articular cartilage, bone remodeling and synovial inflammation. Resistin is an adipokine that shown to be involved in inflammatory process associated with OA. Aim of the current study was to estimate the link of resistin gene polymorphisms (- 420 C>G, + 299 G>A) with genetic susceptibility of knee OA in a Pakistani population. 280 patients and 308 age and sex matched controls were recruited in this case-control study. Genotype and allele frequencies were evaluated by Polymerase chain reaction-Restriction Fragment Length Polymorphism. Resistin concentration was measured by immunoassay. A significant difference in allele and genotype frequency was observed for both study groups. Resistin - 420 mutant genotype was associated with an increased susceptibility to OA (p = 0.001). Similarly, resistin + 299 GA + AA genotypes showed a relation with an elevated risk of knee OA compared to GG genotype (p = 0.01). Moreover, the mutant alleles frequency was significantly high in patient group as compared to healthy individuals for both loci (p < 0.01). Resistin - 420/+ 299 alleles haplotype analysis demonstrated that mutant alleles were more prevalent in OA affected individuals compared to healthy subjects (p < 0.05). The serum resistin levels were not remarkably different in patient vs. control group (p = 0.9). Further, the circulating resistin level was not found to be influenced by - 420G and + 299A alleles and non significant differences were observed in resistin concentration in mutant vs. wild type genotypes for both SNPs (p > 0.05). Our data suggest an association between investigated resistin genetic variants and knee OA susceptibility in our population. This is the first report to show association between investigated single nucleotide polymorphisms and OA among any population.

Association of IL-6, IL-8, MMP-13 gene polymorphisms with knee osteoarthritis susceptibility in the Chinese Han population.

Objective: To identify the association between the interleukin (IL) 6 (IL-6) rs1800795 (-174 G>C), IL-8 rs4073 (-251T>A), and matrix metalloproteinase-13 (MMP-13) rs2252070 (-77G>A) gene polymorphisms and knee osteoarthritis (KOA) susceptibility in the Chinese Han population. Methods: Genomic DNA was extracted from a total of 400 KOA patients and 400 healthy subjects. Sanger sequencing was performed to determine the genotypes of the IL-6 rs1800795 (-174 G/C), IL-8 rs4073 (-251A/T), and MMP-13 rs2252070 (-77A/G) loci. The mRNA expression levels of IL-6, IL-8, and MMP-13 in osteoblasts and the protein expression levels of IL-6, IL-8, and MMP-13 in the synovial fluids of KOA patients were analyzed. Results: The recessive model of IL-6 rs1800795 locus was found to be associated with KOA risk (adjusted odds ratio (OR) = 1.657, 95% confidence interval (CI) = 1.396–1.866, P<0.001). The IL-8 rs4073 locus dominant and recessive model showed no significant association with KOA risk (P>0.05). The dominant and recessive models of the MMP-13 rs2252070 locus showed higher risk for developing KOA (dominant model: adjusted OR = 1.271, 95%CI = 1.095–1.480, P=0.001; recessive model: adjusted OR = 1.361 95%CI = 1.151–1.569, P<0.001). The G>C mutation in IL-6 rs1800795 and the G>A mutation in MMP-13 rs2252070 were associated with significantly higher KOA disease severity. The G>C mutation in the IL-6 rs1800795 locus was associated with up-regulation of IL-6 expression. The G>A mutation in the MMP-13 rs2252070 locus was associated with up-regulation of MMP-13 expression. Conclusion: The IL-8 rs4073 (-251T>A) mutation was not associated with KOA susceptibility. The IL-6 rs1800795 (-174 G>C) and MMP-13 rs2252070 (-77G>A) mutations were associated with KOA susceptibility, increased disease severity, and up-regulation of IL-6 and MMP-13 expression levels.

Putative functional variants of lncRNA identified by RegulomeDB were associated with knee osteoarthritis susceptibility

BackgroundKnee osteoarthritis (KOA) is the most common form of chronic degenerative joint disease worldwide. Its incidence has increased in recent years. Aberrant expression profile of lncRNAs in damaged bone and cartilage of KOA patients has been reported recently, indicating its potential contributions in KOA development and a promising target for disease diagnosis and treatment. The aim of this study was to identify the association between genetic variation in lncRNA and KOA.MethodsWe retrieved relevant articles from the PubMed, Medline and Embase databases up to Jul 2017 investigating the association between lncRNA and the risk of osteoarthritis. There are 15 lncRNAs which show connection with osteoarthritis. We selected potential functional polymorphisms identified by RegulomeDB database in these lncRNAs. A case-control study was conducted which contained 278 KOA patients and 289 OA-free controls.ResultsLogistic regression analyses revealed that H19 rs2067051 T allele was significantly associated with decreased risk of KOA after adjusted for age, gender and BMI in recessive genetic model (OR = 0.63, P = 0.03) and additive genetic model (OR = 0.79, P = 0.03). MEG3 rs4378559 T allele was significantly associated with increased risk of KOA in additive genetic model (OR = 1.32, P = 0.04). Heterogeneity tests proved that H19 rs2067051, MEG3 rs4378559 and HOTTIP rs202384’s risk effects on KOA were more remarkable for female, BMI ≥ 25 and younger age (age < 60), respectively.ConclusionThe results indicate that potential functional genetic variation in lncRNA plays an important role in the pathogenesis of KOA.

Common gene variants interactions related to uric acid transport are associated with knee osteoarthritis susceptibility

ABSTRACTBackground: The presence of genetic variants in uric acid (UA) transporters can be associated with hyperuricemia, and therefore with an increased risk of monosodium urate (MSU) crystal precipitation. The inflammatory process triggered by these crystals leads to cartilage damage, which, in turn, could promote knee osteoarthritis (KOA).Objective: To determine whether genetic polymorphisms of the UA transporters and their interactions are associated with KOA.Materials and Methods: Two hundred forty-three unrelated Mexican-mestizo individuals were recruited for this case-control study. Ninety-three of them were KOA patients but without gout, and one hundred and fifty healthy individuals with no symptoms or signs of KOA were recruited as controls. Forty-one single-nucleotide polymorphisms (SNPs) involved in the UA transporters were genotyped with OpenArray technology in a QuantStudio 12K flex-System with both cases and controls.Results: After adjusting by age, gender, BMI, and ancestry, significant associations were found for eight SNPs: rs1260326 (GCKR), rs780093 (GCKR), rs17050272 (INHBB), rs1471633 (PDZK1), rs12129861 (PDZK1), rs7193778 (IGF1R), rs17786744 (STC1), and rs1106766 (R3HDM2). With respect to gene–gene interactions, the pairwise interactions of rs112129861 (PDZK1) and rs7193778 (IGF1R); rs17050272 (INHBB) and rs1106766 (R3HDM2); rs1106766 (R3HDM2) and rs780093 (GCKR); rs1260326 (GCKR) and rs17786744 (STC1); and rs17786744 (STC1) and rs1106766 (R3HDM2) make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles on KOA development.Conclusions: Our preliminary results show that the common gene variants related to UA transport are associated with KOA in the Mexican population. Further studies must be carried out to corroborate it.

Genome-wide association study of knee osteoarthritis: present and future

Knee osteoarthritis (KOA) is a complex disease. Although the genome-wide association study (GWAS) has elucidated many KOA susceptibility genes, they explain only a small part of heritability of KOA and their replicability is low. The sample size and phenotype definition are important factors to improve statistical power of the GWAS. The low replicability of the KOA GWASs would be mainly caused by their small sample size and the indistinct definition of KOA. We seek to establish the more distinct KOA definition to improve OA GWAS. We reveal the effectiveness of the ultrasonography (US) to evaluate the early change of OA cartilage and conduct the epidemiological study of KOA defined by US in a cohort (Shimane COHRE study). Now we are performing the GWAS for early KOA based on the cohort study.

Common variants in the GNL3 contribute to the increasing risk of knee osteoarthritis in Han Chinese population

Osteoarthritis (OA) is a complex degenerative joint disorder, which is caused by both environmental and genetic factors. Previous studies have indicated that the GNL3 gene is associated with knee osteoarthritis (KOA) susceptibility in Europeans; however, the exact molecular mechanism is still unclear. In the present study, we investigated the potential genetic association of GNL3 with KOA in a two-stage sample of 6,704 individuals from the Han Chinese population. Subjects containing 1,052 KOA patients and 2,117 controls were considered the discovery dataset, while subjects consisting of 1,173 KOA patients and 2,362 controls were utilized as the replication dataset. Single-SNP association, imputation, and haplotypic association analyses were performed. The SNP of rs11177 in GNL3 was identified to be significantly associated with KOA after accounting for age, gender and BMI in both stages. The imputed SNP of rs6617 in SPCS1 was found to be strongly associated with KOA risk, and the significant association signal was confirmed in the replication stage. Moreover, a haplotype-based analysis also indicated a positive genetic effect of GNL3 on KOA susceptibility. In summary, our results proved that GNL3 plays an important role in the etiology of KOA, suggesting that GNL3 is a potential genetic modifier for KOA development.

Association of two polymorphisms rs3740199 and rs1871054 at ADAM12 with susceptibility of knee osteoarthritis: a systematic review and meta-analysis

Background: Osteoarthritis (OA) is the most common joint disease that mainly influences the knees, hips, hands and spine. However, the pathogenesis of knee OA remains poorly understood. A number of studies have explored the association between ADAM12 polymorphisms and the risk of knee OA in different populations. We aimed to systematically review those observational studies, taking into account the variable quality of studies. Methods: We carried out a systematic review and meta-analysis of these studies based on ADAM12 rs3740199 and rs1871054 genotypes. Four comparisons involving 2 Chinese, 1 Korean and 1 Thai population of 1,241 knee OA patients and 2,316 controls were included in our study. Results: For the SNP rs1871054, the C allele was associated with an increased risk of knee OA in terms of the frequency of allele comparison. For a dominant model of the C allele, the CT + CC genotypes were associated with the risk for knee OA. The CC homozygote genotype was also associated with increased susceptibility to knee OA. However, the ADAM12 rs3740199 polymorphism was suggested not to be related to knee OA susceptibility in all populations. Conclusions: The present results suggested that there existed a positive relationship between the ADAM12 rs1871054 polymorphisms with the susceptibility of knee OA, while the ADAM12 rs3740199 was not observed to be associated with the risk of knee OA.

A case-control study and meta-analysis reveal the association between COX-2G-765C polymorphism and primary end-stage hip and knee osteoarthritis.

Osteoarthritis (OA) is a popular arthrosis featured as pain, limited joint activity, and deformity. Cyclooxygenase-2 (COX-2) has been reported to be up-regulated in arthritic tissues and is integral to the progression of osteoarthritis (OA). Previous studies showed the COX-2 promoter G-765C polymorphism could influence COX-2 expression. However, the relationship between the variant and OA risk is contrasting. We conducted a case-control study with 196 primary end-stage hip and knee OA cases and 196 controls in a Chinese Han population. Subsequently, we integrated this case-control study in a meta-analysis to acquire greater statistical power. The results from our case-control study using MassARRAY genotyping technology and binary logistic regression statistical methods. The variant carriers in the Chinese Han population had a lower primary end-stage hip and knee OA susceptibility (C vs G: OR=0.350, 95%CI: 0.154-0.797, P=.012; GC vs GG: adjusted OR=0.282, 95%CI: 0.118-0.676, P=.005). Stratification studies indicated that a higher GC frequency in women decreased not only knee OA susceptibility but also unilateral knee OA risk. The meta-analysis showed that the variant exhibited a significantly decreased OA risk through comparisons involving allelic, homozygous, heterozygous, and dominant models. Our findings suggest that the COX-2G-765C polymorphism exerts a protective effect against primary end-stage knee osteoarthritis in a female Chinese Han population.

The association of AKNA gene polymorphisms with knee osteoarthritis suggests the relevance of this immune response regulator in the disease genetic susceptibility.

Recent studies have identified AKNA as a potential susceptibility gene for several inflammatory diseases. Here, we aimed to assess the potential association of AKNA polymorphisms with knee osteoarthritis (KOA) susceptibility in a Mexican population, following STREGA recommendations. From a DNA bank of 181 KOA patients and 140 healthy controls, two AKNA SNPs were genotyped using TaqMan probes. The association between KOA susceptibility and AKNA polymorphisms genotypes was evaluated by multivariated logistic regression analysis. Information regarding patients' inflammatory biomarkers levels was obtained and their association with AKNA polymorphisms genotypes was assessed by lineal regression. We found a positive association with the recessive inheritance model of both AKNA polymorphisms (A/A genotype for both) and KOA susceptibility adjusting by age, body mass index (BMI), gender and place of birth (OR = 2.48, 95% CI 1.09-5.65 for rs10817595 polymorphism; and OR = 4.96; 95% CI 2.421-10.2 for rs3748176 polymorphism). Additionally these associations were also seen after stratifying patients by KOA severity and age. Furthermore the total leukocyte count was positively associated with rs10817595 AKNA polymorphism (β = 1.39; 95% CI 0.44-2.34) adjusting by age, BMI, gender, place of birth and disease severity. We suggest that regulatory and coding polymorphisms of the inflammatory modulator gene AKNA can influence the development of KOA. Further structural and functional studies might reveal the role of AKNA in OA and other rheumatic diseases.

Association of ESRα Gene Pvu II T>C, XbaI A>G and BtgI G>A Polymorphisms with Knee Osteoarthritis Susceptibility: A Systematic Review and Meta-Analysis Based on 22 Case-Control Studies.

Many studies have reported the association of estrogen receptor α gene (ESRα) ESRα PvuII T>C, XbaI A>G and BtgI G>A polymorphisms with Knee osteoarthritis (KOA) risk, but the results remained controversial. In order to drive a more precise estimation, the present systematic review and meta-analysis was performed to investigate the association between ESRα polymorphisms and KOA susceptibility. Eligible articles were identified by search of databases including PubMed, ISI Web of Knowledge and Google scholar up to March 1, 2017. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. A total of 22 case-control studies in eleven publications with 6,575 KOA cases and 7,459 controls were included in the meta-analysis. By pooling all the studies, either ESRα PvuII T>C and XbaI A>G polymorphisms was not associated with KOA risk in the overall population. However, ESRα BtgI G>A was significantly associated with KOA risk under all five genetic models. In the subgroup analysis by ethnicity, a significant association was observed between ESRα PvuII T>C polymorphism and KOA risk in Asians under heterozygote model. In addition, significant association was found between ESRα XbaI A>G polymorphism and KOA in Caucasians under allelic, homozygote, dominant and recessive models. The present meta-analysis suggests that ESRα BtgI G>A rather than ESRα PvuII T>C and XbaI A>G polymorphisms is associated with an increased KOA risk in overall population. Moreover, we have found that ESRα PvuII T>C and XbaI A>G polymorphisms associated with KOA susceptibility by ethnicity backgrounds.

Association of ADAM12 gene polymorphisms with knee osteoarthritis susceptibility.

Previous studies that evaluated the association between a disintegrin and metalloprotease 12 (ADAM12) gene polymorphisms and knee osteoarthritis (KOA) have given controversial and indefinite results. Therefore, we performed a meta-analysis to confirm this correlation. We searched the PubMed, Embase, and SinoMed databases for all papers published up to April 11, 2017. Overall, five different studies, totaling 2,353 cases and 3,668 controls, were retrieved on the basis of the search criteria for KOA susceptibility related to four polymorphisms (rs3740199, rs1278279, rs1871054, and rs1044122) in the ADAM12 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed using Egger's and Begg's tests. The rs3740199 G/C polymorphism was found to be associated with increased KOA risk in men (e.g., CG versus GG: OR = 1.44, 95% CI = 1.02–2.04, P = 0.040), but not in the overall analysis and in analyses of other subgroups. Significantly increased associations were also found for the rs1871054 polymorphism (e.g., C versus T allele: OR = 1.85, 95% CI = 1.49–2.30, P < 0.001). However, there were no associations for the rs1278279 and rs1044122 polymorphisms. Furthermore, no obvious evidence of publication bias was detected. Our study indicated that the rs1871054 polymorphism of ADAM12 was significantly associated with increased KOA risk.

Association of Common Variants in TGFA with Increased Risk of Knee Osteoarthritis Susceptibility.

Osteoarthritis (OA) is a complex degenerative joint disorder, which has contributions from both environmental and genetic factors. Several recent publications have established the connection between hip OA susceptibility and genetic markers within the TGFA gene, however, the relationship of these markers with knee OA has not been elucidated. Therefore, the present study was designed to investigate the potential linkage between common variants of the TGFA gene with knee OA in a large sample of Han Chinese individuals. We conducted a case-control study, including 338 knee OA patients and 985 unrelated healthy controls using both single nucleotide polymorphism (SNP) markers and haplotype-based analyses to examine the genotypic and allelic distribution of 19 tagging SNPs. We identified a significant association between the SNP rs2862851 and disease status of knee OA (p = 0.000314, OR = 1.40). Allelic analyses showed that the T allele of this SNP significantly elevated the risks of OA. This result was replicated in genotypic association analyses. In addition, haplotype-based analyses have also identified a strong association signal between one haplotype block, including rs2862851, and the disease status of knee OA (p < 0.00001). Our findings suggest that the rs2862851 allele of the TGFA gene may significantly contribute to the susceptibility to knee OA in the Han Chinese population.

Association of ADAM 12 polymorphisms with the risk of knee osteoarthritis: meta-analysis of 5048 cases and 6848 controls.

Several studies have suggested the association between ADAM 12 polymorphisms and the risk of osteoarthritis (OA), but the results remained controversial. Therefore, we designed a meta-analysis to systematically evaluate the association on this issue. A literature search for eligible studies was conducted in PubMed, Web of Science and Google Scholar databases. The association between ADAM 12 polymorphisms and knee OA risk was calculated by odds ratios (ORs) and 95% confidence intervals (CIs). Study heterogeneity, sensitivity and publication bias analyses were also conducted. Ten articles covering 5048 cases and 6848 controls met our criteria for the final analysis. We found that the rs1871054 was significantly associated with the risk of knee OA (allele model OR 1.72, 95% CI 1.43-2.07, P<0.001; additive model: OR 2.06, 95% CI 1.19-3.56, P=0.010; dominant model: OR 2.45, 95% CI 1.85-3.25, P<0.001; recessive model: OR 1.54, 95% CI 1.13-2.10, P=0.007). rs1044122 was significantly associated with knee OA susceptibility in recessive model (OR 1.45, 95% CI 1.03-2.04, P=0.031). For rs3740199 and rs1278279, no significant associations with knee OA were found. In the stratified analysis by gender, significant association was identified with the risk of knee OA for rs3740199 in men in allele model (OR 2.41, 95% CI 1.51-3.84, P<0.001), dominant model (OR 2.68, 95% CI 1.17-6.14, P=0.02) and recessive model (OR 3.51, 95% CI 1.68-7.36, P=0.001), but not for additive model (OR 1.30, 95% CI 0.81-2.08, P=0.28). This meta-analysis suggests that the ADAM 12 genetic polymorphisms rs1871054 and rs1044122 might be associated with risk of knee OA; rs3740199 might be associated with risk of knee OA in men. Further well-designed and large scale studies are warranted to validate these associations.

Association between transforming growth factor-beta 1 gene single nucleotide polymorphisms and knee osteoarthritis susceptibility in a Chinese Han population.

ObjectiveTo investigate associations between single polymorphisms (SNPs) rs1800469 and rs1982073 in the transforming growth factor-β1 gene (TGF-β1) and knee osteoarthritis (OA) susceptibility in a Chinese Han population.MethodsTGF-β1 rs1800469 and rs1982073 were genotyped in patients with knee OA and age- and sex-matched OA-free controls from a Chinese Han population. The association was further analyzed according to gender and age.ResultsA total of 765 patients with knee OA and 780 controls were included. CT and CT + CC genotypes of rs1982073, and variant C, were associated with a significantly increased risk of knee OA. Stratification analysis showed that the association between the OA risk and rs1982073 CT heterozygotes compared with TT homozygotes was stronger in females and those aged >65 years. In contrast, CT, TT, and CT + TT genotypes of rs1800469 were not significantly associated with the risk of knee OA, even after further stratification analysis for gender and age.ConclusionsThe TGF-β1 rs1982073 T to C change and the variant C genotype may contribute to knee OA risk in the Chinese Han population.

Association between EN1 rs4144782 and susceptibility of knee osteoarthritis: A case-control study.

Osteoarthritis (OA) is a complex disease that affects the whole joint, resulting from the combined influence of biomechanical factors and genetic factors. The heritable component for primary OA accounts for about 60% of variation in population liability to the disease. So far, genome-wide association studies (GWAS) and candidate gene studies have established many OA-related loci. However, these findings account for only a rather small fraction of the genetic component. To further reveal the genetic architecture of OA, we conducted this case-control study to explore the association of locus EN1 rs4144782 and knee OA susceptibility in a Chinese population. EN1 rs4144782 was significantly associated with increased risk of knee OA (OR=1.26; 95% CI: 1.05-1.50, P value=0.012). In dominant model, compared with carriers of GG genotype, those with AG or AA genotype have an 1.44-fold increased risk of OA (OR: 1.44; 95% CI: 1.10-1.88; P value=0.008). Subgroup analyses didn't change the results materially. This should be the first association study of EN1 locus on risk of OA, and our finding suggested that the EN1 rs4144782 might contribute to the susceptibility of knee OA.

The rs4238326 polymorphism in ALDH1A2 gene potentially associated with non-post traumatic knee osteoarthritis susceptibility: a two-stage population-based study

A recent genome-wide association study reported significant associations of genetic variants within the ALDH1A2 gene with osteoarthritis (OA) of the hand in European populations. However, these findings have not been well generalized to other joints, or to other populations. We performed a two-stage population-based case-control study including 196 non-post traumatic knee OA cases and 442 controls in the first stage and independent 143 non-post traumatic knee OA cases and 238 controls in the second stage in a Chinese population by genotyping eight tagging polymorphisms in ALDH1A2. In the first stage, the single nucleotide polymorphism (SNP) rs4238326 was found to be potentially associated with knee OA risk (additive model: odds ratio [OR]=0.70; 95% confidence interval [95% CI]=0.49-1.01; P=0.055), which was further confirmed in the second stage with similar effect (additive model: OR=0.60; 95% CI=0.38-0.95; P=0.029). After combining the two stages, we found that the variant C allele of rs4238326 was probably associated with decreased risk of knee OA (additive model: OR=0.65; 95% CI=0.49-0.86; P=0.003). Furthermore, interaction analyses showed that rs4238326 interacted multiplicatively with age to contribute to knee OA risk (interaction P=0.041). These findings indicate that the SNP rs4238326 in ALDH1A2 gene may potentially modify individual susceptibility to knee OA in the Chinese population. Beyond that, further studies are warranted to validate and extend our findings, and future functional studies are required to clarify the possible mechanisms.

Association between ADAM12 Single-Nucleotide Polymorphisms and Knee Osteoarthritis: A Meta-Analysis.

Objective ADAM12 polymorphisms may be associated with the risk of knee osteoarthritis (KOA), but currently available evidence remains controversial. We performed this meta-analysis to confirm whether ADAM12 polymorphisms were associated with susceptibility of KOA. Methods A comprehensive literature search in PubMed, EMBASE, and ISI Web of Science was conducted to identify observational studies assessing the association between ADAM12 polymorphisms and susceptibility of KOA. The strength of association was indicated as odds ratio (OR) and the corresponding 95% confidence interval (95%CI). Four types of genetic model (additive model, dominant model, recessive model, and allele model) were evaluated for each included study. Subgroup analysis by ethnicity was performed. Results Seven case-control studies comprising a total of 3512 KOA patients and 5405 healthy controls were included in the meta-analysis. A significant association between rs1871054 and increased KOA risk was found in each genetic model. No significant association was found between KOA and rs3740199, rs1044122, or rs1278279 in any genetic model. Conclusion Based on the findings of our study, there was a modest but statistically significant association between rs1871054 and risk of KOA in Asian population, while other polymorphisms (rs3740199, rs1044122, or rs1278279) in ADAM12 were not associated with KOA in any population.

Association between Single Nucleotide Polymorphisms of SMAD3 and BMP5 with the Risk of Knee Osteoarthritis.

The role of genetic factors influencing osteoarthritis (OA) susceptibility is well documented and several candidate genes have been identified to be associated with it. Among these genes are Bone Morphogenetic Protein 5 (BMP5) and Smad family member 3 (SMAD3), all involved in Transforming Growth Factor (TGF) signaling pathway. The knee is the commonly affected joint, and knee OA has an especially high prevalence in Asian population. To investigate associations between Single Nucleotide Polymorphisms (SNPs) rs12901499 in SMAD3 and rs921126 in the BMP5 gene with knee OA susceptibility in and around Lucknow, Uttar Pradesh, India. SNPs rs12901499 in SMAD3 and rs921126 in BMP5 were genotyped in patients with knee OA and age- sex matched OA-free controls from our population. A total of 450 patients with knee OA and 458 controls were enrolled in the study. Venous blood samples were obtained from all cases as well as controls for PCR-RFLP (Polymerase Chain Reaction- Restriction Fragment Length Polymorphism). Data was collected and entered in excel sheets. Statistical analyses of the data were performed using statistical software package SPSS version 16.0. Chi-square, Student's t-test and logistic regression tests were used to analyse the data. GA and GG genotypes of both SNPs (rs12901499 and rs921126), and variant G, were associated with a significantly increased risk of knee OA. A significantly increased risk of knee OA was associated with the genotype GG and GA of rs12901499 (p < 0.03 and p <0.004 respectively) and rs921126 (p< 0.0001 and p<0.001 respectively) compared with the AA genotype. In addition, those bearing at least one G allele (GG + GA) had a significantly increased risk of knee OA compared with those without the G allele (AA) in rs921126 (p< 0.0001). However, in rs12901499, significant association with the risk of knee OA was not found (p<0.4). On age and gender based stratification, the association between the risk of OA and rs921126 GG mutant compared with AA homozygotes was strong in both gender (adjusted OR= 2.93 for male and 2.25 for female) and in those aged >55 years (adjusted OR= 3.4), similarly in rs12901499, GG mutant compared with AA homozygote was strong in female (adjusted OR= 1.5) and in those aged >55 years (adjusted OR= 1.5). The results showed that both in SMAD3 rs12901499 and BMP5 921126, G allele is significantly associated with knee OA. A to G change and variant G genotype may contribute to knee OA risk in our study population of Lucknow.

IL1R1 gene polymorphisms are associated with knee osteoarthritis risk in the Chinese Han population.

IL1R1, encoding interleukin 1 receptor type 1, is located in the IL-1 gene cluster and is involved in the pathogenesis of hand, hip, and knee osteoarthritis (OA) in different ethnicities. However, the link between IL1R1 polymorphisms and OA risk in the Chinese Han population is unknown. We studied the association between five IL1R1 polymorphisms (rs10490571, rs12712127, rs956730, rs3917225, and rs3917318) and OA risk by analyzing the genotypes of 298 knee OA patients and 297 controls using Sequenom MassARRAY technology. Logistic regression analysis after adjusting for gender and age revealed significant differences in the allele frequencies of IL1R1 rs956730 and IL1R1 rs3917225 between patients and controls. In addition, IL1R1 rs3917225 was associated with increased risk of knee OA with or without adjustment by age and gender in the dominant model (adjusted OR= 1.47, 95%CI: 1.04-2.07, P = 0.030), the recessive model (adjusted OR= 1.75, 95%CI: 1.08-2.85, P= 0.023), and the additive model (adjusted OR= 1.40, 95%CI: 1.09-1.79, P = 0.007). This study is the first to report that IL1R1 polymorphisms are associated with knee OA susceptibility in the Northwestern Chinese Han population.