title: Meta-analysis of the association of CTLA-4 exon-1 +49A/G polymorphism with rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a common autoimmune disease. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a highly suspected candidate gene for RA susceptibility. However, association studies on the polymorphism of CTLA-4 exon-1 +49A/G in RA have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported association. In order to look for ethnic effect, we performed subgroup meta-analysis in populations of European descent and Asian descent. Meta-regression analysis was also performed to explore the possible heterogeneity between the two subgroups. Ten studies (11 comparisons) with the CTLA-4 exon-1 +49A/G genotyping on 2,315 patients with RA and 2,536 controls were selected for our meta-analysis. Overall, the fixed-effects odds ratio (OR) for the G versus A allele was 1.11 (P=0.02, 95% confidence interval (CI) 1.02-1.21), with no between-study heterogeneity. Subgroup and meta-regression analysis according to the ethnicity (European or Asian) demonstrated different scenarios concerning the CTLA-4 exon-1 +49A/G polymorphism's role in RA susceptibility for the two different subgroups. No effect of G on susceptibility was seen in European descent (five comparisons; OR=1.04, P=0.30, 95% CI 0.95-1.19; no significant between-study heterogeneity). However, there is a significant association in Asian descent under both fixed [OR=1.21, 95% CI (1.06-1.39), P=0.005] and random-effect models [OR=1.19, 95% CI (1.01-1.42), P=0.04]. Meta-regression analysis also supports the heterogeneity between the two subgroups (P=0.082). We also explored the role of this polymorphism on RA risk under other various interested genetic contrasts. These results further support that this polymorphism could not be a risk factor for Europeans. Interestingly, we find that in Asians the G allele has a greater tendency to cause RA in a recessive genetic model. However, sensitivity analysis showed that the combined result of Asian populations was unstable. In conclusion, our meta-analysis results suggest that CTLA-4 exon-1 +49G allele would not be a risk factor for RA in Europeans but might play a role in RA susceptibility for Asians.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, 200433, People's Republic of China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Han
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.forename: Yumin
authors.initials: Y
authors.lastname: Mao
authors.forename: Yi
authors.initials: Y
authors.lastname: Xie
mesh_terms: D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D060908:CTLA-4 Antigen; D005091:Exons; D006801:Humans; D015201:Meta-Analysis as Topic; D011110:Polymorphism, Genetic; D017594:Publication Bias; D012680:Sensitivity and Specificity
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human