CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis.
Several reports demonstrate association between variants of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune diseases. CTLA-4 may generate autoimmunity by immune dysregulation, making CTLA-4 an attractive candidate gene for systemic lupus erythematosus (SLE) susceptibility. Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 14 independent studies (to July 2004) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at four polymorphic sites found in exon-1 (at +49), the promoter region (at -318 and -1722), and the 3' untranslated region (3'UTR) (dinucleotide repeat). We have evaluated both fixed and random effect models, depending on the presence of between-study heterogeneity. The data demonstrate that the exon-1 +49 polymorphism is significantly associated with SLE susceptibility. The overall risk, measured by odds ratio (OR), for exon-1 +49 GG genotype is 1.287 [95% confidence interval (CI)=1.031-1.562, P=0.011]. Stratification by ethnicity indicates the exon-1 +49 GG genotype is associated with SLE, at least in Asians (OR=1.293, 95% CI=1.031-1.620, P=0.026). European-derived populations have an effect of similar magnitude (OR=1.268, 95% CI=0.860-1.870, P=0.230), though not significant. Similar trends are found in allele-specific risk estimates and disease association. The OR for the exon-1 +49 risk allele (G) in Asians is 1.246 (95% CI=1.057-1.469, P=0.009), while Europeans have no evidence of allelic association (OR=0.978, 95% CI=0.833-1.148, P=0.780). In conclusion, this meta-analysis supports the CTLA-4 exon-1 +49 (A/G) polymorphism influencing the risk for developing SLE, especially in Asians.
Lee
Young Ho
YH
Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, USA.
Harley
John B
JB
Nath
Swapan K
SK
D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D060908:CTLA-4 Antigen; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D011110:Polymorphism, Genetic
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human