Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis

Objectives: In recent years, more and more studies have been focusing on the association between Cytotoxic T lymphocyte antigen-4 (CTLA-4) (+49 A/G) gene polymorphism and autoimmune diseases. However, the results of previous studies are still controversial. The meta-analysis is aiming at determining the association in CTLA-4 (+49 A/G) gene rs231775 polymorphism and ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE).

Methods: We searched PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) up to November 2020, use random or fixed-effect models to perform meta-analysis to compare alleles and other genetic models, including homozygous, heterozygous, recessive and dominant models. The odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the correlation between CTLA-4 (+49 A/G) gene polymorphism and the genetic affectability of AS, RA, and SLE. Meanwhile, we used sequential trial analysis (TSA) to analyze the reliability of the results. Finally, we searched the relevant data of genome-wide association studies (GWAS) to further verify the accuracy of the experimental results.

Results: 47 studies with 11,893 cases and 12,032 healthy controls were included. The rs231775 G allele was relevant to high risk of autoimmune disease over all people (P < 0.05). The G allele of rs231775 was significantly related to RA susceptibility (P < 0.05), but not with AS or SLE. Subgroup analysis by ethnicity indicated that rs231775 G allele was closely related to RA in Caucasian populations and Mongolian populations (P < 0.05). A strong connection within rs231775 G allele and AS affectability was uncovered in Caucasian populations (P < 0.05). The analysis of the TSA shows that the meta-analysis can draw the conclusion.

Conclusion: CTLA-4 (+49 A/G) gene rs231775 G allele increases the risk of autoimmune diseases in Caucasian populations. And it also increases the risk of RA in Caucasian and Mongolian populations. More sample size and more elaborately designed studies are needed to elucidate the relationship in CTLA-4 (+49 A/G) gene rs231775 G allele and autoimmune diseases, especially AS, SLE.