Association of GDF5 rs143383 Polymorphism with Knee Osteoarthritis Risk: an Updated Systematic Review and Meta-Analysis

Abstract

Background: Knee osteoarthritis (KOA) is a major cause of chronic pain and disability, and genetic factors contribute to inter-individual susceptibility. Growth differentiation factor 5 (GDF5), a key regulator of cartilage and skeletal biology, has been widely investigated in KOA; however, findings for the commonly studied rs143383 variant remain inconsistent across studies and populations.

Objective: To update and clarify the association between GDF5 rs143383 and KOA risk using an expanded evidence base with ethnicity-stratified analyses, sensitivity testing, and assessment of small-study effects.

Methods: A PRISMA-aligned systematic review and meta-analysis was conducted using major English-language databases (PubMed, Embase, Web of Science, Cochrane Library) and Chinese databases (CNKI, Wanfang, VIP), supplemented by reference screening. Eligible studies were human case–control investigations evaluating rs143383 in KOA with extractable genotype/allele data. Data were independently extracted and cross-checked for internal consistency; study quality was assessed using the Newcastle–Ottawa Scale. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated under standard genetic models using fixed- or random-effects approaches based on heterogeneity (Q test/I²). Subgroup analyses were performed by ethnicity (Asian vs Caucasian). Leave-one-out sensitivity analysis and publication bias evaluation (Egger’s test/funnel plot) were conducted.

Results: Thirty KOA case–control studies met inclusion criteria, comprising 10,739 cases and 16,281 controls. Overall, rs143383 showed a significant association with KOA susceptibility in key models: allelic contrast OR = 1.3272 (95% CI 1.2045–1.4624; I² = 81.69%), recessive model OR = 1.3783 (95% CI 1.2244–1.5516; I² = 76.56%), and dominant model OR = 1.4788 (95% CI 1.2597–1.7359; I² = 71.12%). The overdominant model suggested a modest protective pattern overall (OR = 0.8953, 95% CI 0.8194–0.9783; I² = 58.96%). In Asians (18 studies), effects were generally stronger but heterogeneous (allelic OR = 1.4378, I² = 87.83%), while in Caucasians (12 studies) associations remained significant with lower heterogeneity in several contrasts (allelic OR = 1.1955, I² = 30.04%; dominant OR = 1.2589, I² = 0%). Sensitivity analysis showed stable pooled estimates (overall fixed-effect OR approximately 1.24, 95% CI 1.19–1.29). Egger’s testing indicated potential small-study effects in some overall models (e.g., allelic P = 0.0182; dominant P = 0.0179), whereas most ethnicity-stratified tests were non-significant.

Conclusion: This updated meta-analysis supports GDF5 rs143383 as a significant genetic susceptibility marker for knee osteoarthritis, with consistent risk direction across major genetic models and across Asian and Caucasian populations. Interpretation should consider substantial heterogeneity in some analyses and evidence of small-study effects in select pooled contrasts.