Genetic association between TNF-α G-308A and osteoarthritis in Asians: A case-control study and meta-analysis

Abstract

Background: Osteoarthritis (OA) is an important health issue in elderly people. Many studies have suggested that genetic factors are important risk factors for OA, of which tumor necrosis factor-α (TNF-α) is one of the most examined genes. Moreover, several studies have investigated the relationship between TNF-α G-308A polymorphisms and OA risk, but consistent results have not been obtained.

Objective: This study examines the association between TNF-α G-308A polymorphisms and knee OA. Moreover, meta-analysis and trial sequential analysis (TSA) was used to determine whether this is a susceptibility gene for knee OA.

Methods: Between 2015 and 2019, 591 knee OA cases and 536 healthy controls were recruited. The Kellgren-Lawrence grading system was used to identify the knee OA cases. A meta-analysis was conducted including related studies published until 2020 from PubMed, Embase, and previous meta-analysis to improve the evidence level of the current study. The results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) to evaluate the effect of this polymorphism on knee OA risk. The TSA was used to estimate the sample sizes required in this issue.

Results: A nonsignificant association was found between the AA genotype and knee OA [adjusted OR, 0.84; 95% CI, 0.62-1.15) in the recessive model] in the present case-control study, and analysis of other genetic models showed a similar trend. After adding the critical case-control samples for Asians, the TNF-α G-308A, AA genotype exhibited 2.57 times more risk of developing arthritis when compared with the GG + GA genotype (95% CI, 1.56-4.23), and the cumulative samples for TSA (n = 2182) were sufficient to obtain a definite conclusion.

Conclusions: The results of this meta-analysis revealed that the TNF-α G-308A, AA genotype is a susceptible genotype for OA in the Asian population. This study integrated all current evidence to arrive at this conclusion, suggesting that future studies on Asians are not required.

Fig 1. Flow diagram of the identification process for eligible studies.

Fig 2. Forest plot and funnel plot of the correlation between TNF-α G-308A and osteoarthritis.

Selected results from the meta-analysis of TNF-α G-308A and knee osteoarthritis. The top left subplot is a forest plot based on a recessive model assumption (AA vs. GG + AG), and the top right subplot is a funnel plot based on the recessive model assumption. The results obtained with the allele (reference, G allele) and dominant (AG + AA vs. GG) models are presented at the bottom.

Fig 3. Estimation of the Asian sample size for correlation between TNF-α G-308A and osteoarthritis.

A trial sequential analysis using a dominant model assumption was performed. Detailed settings: significance level = 0.05, power = 0.8, least extreme odds ratio to be detected = 1.5, minor allele frequency = 0.11, and I² (heterogeneity) = 65%.

Fig 4. Forest plot and funnel plot for sensitivity analysis of the correlation between TNF-α G-308A and osteoarthritis.

Selected results from the meta-analysis of TNF-α G-308A and knee osteoarthritis. The top left subplot is a forest plot based on a recessive model assumption (AA vs. GG + AG), and the top right subplot is a funnel plot based on the recessive model assumption. The results obtained with the allele (reference. G allele) and dominant (AG + AA vs. GG) models are presented at the bottom.

Fig 5. Estimation of Asian sample size for sensitivity analysis of the correlation between TNF-α G-308A and osteoarthritis.

A trial sequential analysis using a dominant model assumption was performed. Detailed settings: significance level = 0.05, power = 0.8, least extreme odds ratio to be detected = 1.5, minor allele frequency = 0.11, and I² (heterogeneity) = 0%.