HUMAN GENOME EPIDEMIOLOGY (HuGE) REVIEW |
CTLA-4 Gene Polymorphisms and Susceptibility to Type 1 Diabetes Mellitus: A HuGE Review and Meta-Analysis
1 Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
2 Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece
3 Institute for Clinical Research and Health Policy Studies, Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA
Correspondence to Dr. John P. A. Ioannidis, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece (e-mail: jioannid{at}cc.uoi.gr).
The authors performed a meta-analysis of 33 studies examining the association of type 1 diabetes mellitus with polymorphisms in the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene, including the A49G (29 comparisons), C(–318)T (three comparisons), and (AT)n microsatellite (six comparisons) polymorphisms. The studies included 5,637 cases of type 1 diabetes and 6,759 controls (4,775 and 5,829, respectively, for analysis of the A49G polymorphism). The random-effects odds ratio for the *G (Ala) allele versus the *A (Thr) allele was 1.45 (95% confidence interval (CI): 1.28, 1.65), with significant between-study heterogeneity (p < 0.001). The effect size tended to be higher in type 1 diabetes cases with age of onset <20 years (odds ratio (OR) = 1.61), and there was a significant association between the presence of glutamic acid decarboxylase-65 autoantibodies and the *G allele among type 1 diabetes cases (OR = 1.49). Larger studies showed more conservative results (p = 0.011). After exclusion of studies with fewer than 150 subjects and studies with significant deviation from Hardy-Weinberg equilibrium in the controls, the summary odds ratio was 1.40 (95% CI: 1.28, 1.54). Available data showed no strong association for the 106-base-pair allele of the microsatellite polymorphism (OR = 0.99, 95% CI: 0.64, 1.55) or the *T allele of the C(–318)T polymorphism (OR = 0.92, 95% CI: 0.45, 1.89). This meta-analysis demonstrates that the CTLA-4*G genotype is associated with type 1 diabetes.
CTLA-4; diabetes mellitus, type 1; epidemiology; genes; meta-analysis; polymorphism, genetic
Abbreviations: bp, base pair; CI, confidence interval; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; GAD-65, glutamic acid decarboxylase-65; IDDM, insulin-dependent diabetes mellitus; OR, odds ratio
Editor's note: This article is also available on the website of the Human Genome Epidemiology Network (http://www.cdc.gov/genomics/hugenet/).
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