Association of CTLA-4 Polymorphisms with Type 1 Diabetes in the Egyptian Population

Abstract

Background: Polymorphisms in the cytotoxic T-lymphocyte antigen 4 (CTLA-4) are associated with the risk of type 1 diabetes (T1D). Here, we investigated the most associated variants CT60 and +49 A/G and five other putative promoter SNPs for their association with T1D in the Egyptian population, a multi-ethnic group. The comparison of disease association between populations can provide further evidence for putative disease variants. Methods: Association of seven SNPs (-1722,-1661,-651,-319, +49, -819 and +6230G>A) in the CTLA-4 gene with T1D was investigated in 396 patient and 396 control subjects of Egyptian origin. The diagnosis of T1D was made based on ketoacidosis or ketosis with acute onset and severe symptoms of diabetes mellitus at presentation and continuous dependence on insulin. Controls were negative for anti-GAD antibodies and were older than 24 years of age. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Five of the seven CTLA-4 gene SNPs were associated with T1D with the highest association for +49 A/G in exon 1 (P=0.0002; odds ratio: 1.6, 95% CI 1.3-1.9). Association conditional on SNP +49 A/G was further tested, revealing some independent association for SNPs -1661 and -318. Haplotype analysis of these SNPs demonstrated that no single haplotype was indicative of T1D risk. Conclusion: The results further support the association of T1D with+49 A/G SNP in the CTLA-4 gene in the Egyptian population. The pattern of association specifically differed from that observed in European and other North African populations, providing further opportunity for fine mapping of genetic disease variants of type-I diabetes.