Association of single-nucleotide polymorphisms in RHOB and TXNDC3 with knee osteoarthritis susceptibility: two case-control studies in East Asian populations and a meta-analysis.
ABSTRACT: INTRODUCTION: Conflicting findings on the association of single nucleotide polymorphisms (SNPs) in RHOB and TXNDC3 with susceptibility to knee osteoarthritis (OA) have been reported in European Caucasians. To examine the associations of these SNPs with OA in East Asian populations and to evaluate their global significance, we conducted two case-control studies in 955 Chinese and 750 Japanese patients. METHODS: We genotyped the previously implicated SNPs rs585017 (in RHOB) and rs4720262 (in TXNDC3) in patients with primary symptomatic knee OA with radiographic confirmation and in matched control individuals, and analyzed their associations. We further conducted a meta-analysis of the study findings together with those of previously reported European studies using the DerSimonian-Laird procedure. RESULTS: A significant association of RHOB with knee OA was observed in male Chinese patients (P = 0.02). No significant associations were found for RHOB in any other comparisons in the East Asian populations. The association of TXNDC3 was replicated in Chinese female (P = 0.04) and Japanese (P = 0.03) patients, although none of these associations persisted after Bonferroni correction. Significant association (P = 0.02 for the allelic frequency) with nonsignificant heterogeneity was found in the East Asian replication study. No significant association was found in any comparison in the meta-analysis for all studies. CONCLUSION: Our study replicates the association, previously reported in European Caucasians, of TXNDC3 with knee OA susceptibility in an East Asian population.
Project description:Osteoarthritis (OA) is a complex disease of the skeleton and is associated with aging. Both environmental and genetic factors contribute to its pathogenesis. We set out to identify novel genes associated with OA, concentrating on regulatory polymorphisms allowing for differential expression. Our strategy to identify differentially expressed genes included an initial transcriptome analysis of the peripheral blood mononuclear cells of six patients with OA and six age-matched healthy controls. These were screened for allelic expression imbalances and potentially regulatory single-nucleotide polymorphisms (SNPs) in the 5' regions of the genes. To establish disease association, disparate promoter SNP distributions correlating with the differential expression were tested on larger cohorts. Our approach yielded 26 candidate genes differentially expressed between patients and controls. Whereas BLP2 and CIAS1 seem to be trans-regulated, as the absence of allelic expression imbalances suggests, the presence of allelic imbalances confirms cis-regulatory mechanisms for RHOB and TXNDC3. Interestingly, on/off-switching suggests additional trans-regulation for TXNDC3. Moreover, we demonstrate for RHOB and TXNDC3 statistically significant associations between 5' SNPs and the disease that hint at regulatory functions. Investigating the respective genes functionally will not only shed light on the disease association but will also add to the understanding of the pathogenic processes involved in OA and may point out novel therapeutic approaches.
Project description:OBJECTIVE:The etiology of knee osteoarthritis (OA), the most common form of arthritis, is complex and may differ by race or ethnicity. In recent years, genetic studies have identified many genetic variants associated with OA, but nearly all the studies were conducted in European whites and Asian Americans. Few studies have focused on the genetics of knee OA in African Americans. METHODS:We performed a genome-wide association study of radiographic knee OA in 1217 African Americans from 2 North American cohort studies: 590 subjects from the Johnston County Osteoarthritis Project and 627 subjects from the Osteoarthritis Initiative. Analyses were conducted in each cohort separately and combined in an inverse variance fixed effects metaanalysis, which were then included in pathway analyses. We additionally tested 12 single-nucleotide polymorphisms robustly associated with OA in European white populations for association in African Americans. RESULTS:We identified a genome-wide significant variant in LINC01006 (minor allele frequency 12%; p = 4.11 × 10-9) that is less common in European white populations (minor allele frequency < 3%). Five other independent loci reached suggestive significance (p < 1 × 10-6). In pathway analyses, dorsal/ventral neural tube patterning and iron ion transport pathways were significantly associated with knee OA in African Americans (false discovery rate < 0.05). We found no evidence that previously reported OA susceptibility variants in European whites were associated with knee OA in African Americans. CONCLUSION:These results highlight differences in the genetic architecture of knee OA between African American and European whites. This finding underscores the need to include more diverse populations in OA genetics studies.
Project description:Objective To 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. Methods TGF-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. Results A 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. Conclusions The TGF-β1 rs1982073 T to C change and the variant C genotype may contribute to knee OA risk in the Chinese Han population.
Project description:Recently, double von Willebrand factor domain A (DVWA) gene, a previously unknown gene, was revealed to contain several single nucleotide polymorphisms (SNPs) that showed consistent association with knee osteoarthritis (OA) in Japanese and Chinese cohorts. However, subsequent studies failed to confirm this result in several different populations. To deal with the issues raised by inconsistent results among those studies, we investigated the association between DVWA and OA using meta-analytic techniques, combining all published data up to December 2014. 10 independent samples from 4 teams contributed data for a possible association between SNP rs7639618 and knee or hip OA. The total number of cases and controls of this SNP was respectively 4,142 versus 6,575 for knee OA, and 2,325 versus 2,914 for hip OA. A trend of significant association was observed in the combined population with knee OA (P=0.06), and a significant difference was identified between patients with knee OA and controls for the G-allele of rs7639618 (P=0.02). Together with the reported functional studies, our results indicate that DVWA may have a small but strong effect on the susceptibility to knee OA, at least in Asian population. Further functional studies are needed to determine the underlying variation of DVWA and to relate this to the pathophysiology of OA.
Project description:Background/aims: Studies have demonstrated that osteopontin (OPN) was associated with the severity and development of knee osteoarthritis (OA). Methods: The purpose of this case-control study was to investigate the association between OPN gene rs11730582 polymorphism and knee OA risk in a Chinese population. Genotyping was analyzed using standard PCR and restriction fragment length polymorphism (PCR-RFLP). Results: The present study found that C allele or CC genotype of OPN gene rs11730582 polymorphism was related to decreased risk for knee OA. Furthermore, positive associations were obtained amongst the females, and body mass index (BMI) < 25 kg/m2 groups. Conclusions: To sum up, the present study reveals that OPN gene rs11730582 polymorphism decreases the risk of knee OA in Chinese Han population.
Project description:Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR) ?=?1.07 (95%CI 0.94 -1.21; p?=?0.28). For rs7775228 the meta-analysis resulted in OR?=?0.94 (95%CI 0.81-1.09; p?=?0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r(2)?=?0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r(2)<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
Project description:A study from Thailand showed no significant association between the adiponectin (ADIPOQ) gene rs1501299 polymorphism and knee osteoarthritis (OA) risk. To investigate this association in a Chinese population, we conducted this case-control study involving 372 knee OA patients and 453 controls. Genotyping via standard PCR and restriction fragment length polymorphism (PCR-RFLP) showed that TT genotype (TT vs. GG: adjusted odds ratio (OR) (95% confidence interval (CI)) = 1.70 (1.01-2.86)) or T allele (T vs. G: adjusted OR (95% CI) = 1.26 (1.02-1.56)) of ADIPOQ gene rs1501299 polymorphism significantly increased the risk of knee OA. Significant associations were also observed in subgroups ?55 years (TT vs. GG: adjusted OR (95% CI) = 2.21 (1.00-4.86)) and body mass index (BMI) < 25 kg/m2 (TT+GT vs. GG: adjusted OR (95% CI) = 1.53 (1.03-2.29)), but not in the subgroup analysis of sex. In conclusion, the ADIPOQ gene rs1501299 polymorphism intensifies the risk of knee OA in this Chinese Han population. Nevertheless, further studies with larger sample sizes in other populations are warranted to verify this finding.
Project description:BACKGROUND: Previous studies investigating the association between GDF5 rs143383 polymorphism and knee osteoarthritis (OA) have suggested stronger associations in Asians than Caucasians, but limitations on the amount of available data have meant that a definitive assessment has not been possible. Given the availability of more recent data, the aim of this meta-analysis was to determine the overall association between GDF5 rs143383 polymorphism and knee OA and whether the association varies by ethnicity. METHODS: Searches of Medline, Embase, and ISI Web of Science were conducted up to July 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association between the GDF5 polymorphism and knee OA risk. RESULTS: A total of 20 studies with 23,995 individuals were included. There were weak but significant associations present between the GDF5 polymorphism and knee OA at the allele level (C vs. T: OR =0.85, 95% CI = 0.80-0.90) and genotype level (CC vs. TT: OR = 0.73; CT vs. TT: OR = 0.84; CC/CT vs. TT: OR = 0.81; CC vs. CT/TT: OR = 0.81) in the overall population. In the subgroup analysis by ethnicity, we observed a strong significant association (OR = 0.60 to 0.80, all P <0.05) in Asian population and weaker associations (OR =0.78 to 0.87, all P <0.05) in Caucasian population; however marked heterogeneity was detected in all models except for CC vs. TT (I2 = 12.9%) and CC vs. CT + TT (I2 = 0.0%) in Asians. CONCLUSIONS: These results strongly suggest that the C allele and CC genotype of the GDF5 gene are protective for knee OA susceptibility across different populations.
Project description:BACKGROUND:Osteoarthritis (OA) is usually recognized to have a genetic factor, and in our study, we performed a case-control study to analyze the association between 14 single nucleotide polymorphisms (SNPs) in OPG and the risk of knee OA in a Chinese Han population. METHODS:Fourteen OPG SNPs were assayed using MassARRAY in 393 patients clinically and radiographically diagnosed with knee OA and in 500 controls. Allelic and genotypic frequencies were compared between the groups. Logistic regression adjusting for age and gender was used to estimate risk associations between specific genotypes and knee OA by computing odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS:We found that the minor alleles of six SNPs in OPG were associated with an increased or decreased risk of knee OA in the allelic model analysis. In the genetic model analysis, we found that rs1905786, rs1032128, rs3134058, rs11573828, rs11573849, rs3134056, and rs1564861 were associated with an increased or decreased risk of knee OA before adjusted by sex and age. And after adjustment, three SNPs (rs1485286, rs1905786, and rs1032128) were identified to have a negative effect on knee OA. CONCLUSION:Our results verify that genetic variants of OPG contribute to knee OA susceptibility in the population of northern China. These genetic associations may identify individuals at a particularly high risk of developing knee OA.