Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms and HLA Class II Alleles with the Development of Type 1 Diabetes in Korean Children and Adolescents

Abstract

We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.

Association of Single Nucleotide Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Autoimmune Type 1 Diabetes in Tunisians

“…Baniasadi et al showed that the Ϫ318T allele conferred T1D susceptibility on north Indians (6), while Balic et al reported that the Ϫ318C/T variant did not influence the overall risk of T1D in Caucasians (5). In this study, we found no significant association of CTLA-4 Ϫ318C/T polymorphism with T1D in Tunisian patients, in agreement with published reports on populations with diverse ethnic backgrounds (5,6,8,19). Furthermore, a recent meta-analysis of 5,637 T1D patients and 6,759 controls demonstrated no association of the Ϫ318 variant with T1D (OR ϭ 0.92; 95% CI ϭ 0.45 to 1.89) after several confounders were controlled for (20).…”

“…The genetic associations between the CTLA-4 polymorphic variants Ϫ318C/T, ϩ49A/G, and CT60A/G were previously investigated in different ethnic groups, but with inconsistent findings (6,17,19,30,35). CTLA-4 is now among the five replicated and established non-HLA loci, together with INS, PTPN22, IL2RA, and IFIH1 (27).…”

“…This was exemplified by the enrichment of the ϩ49G at-risk allele and G/G genotype in T1D in Chinese patients (17), but mostly in patients of Caucasian descent, including Lebanese (34), Dutch (35), northern European (14), and U.S. whites (10), but not in non-Caucasians, such as Chileans (5), north Indians (6), and Koreans (19), or in Portuguese (22). These apparent discrepancies may be attributed to several factors, including differences in genetic background (16,23), possible linkage to HLAsusceptible haplotypes (19), and patient selection, as T1D is often accompanied by other autoimmune conditions (16,17,35). In support of this was the finding that the association of a a CTLA4 haplotype (ϩ49A/G, Ϫ318C/T, or CT60A/G) frequency determined by the maximum-likelihood method; haplotypes were coded according to the allele at each locus.…”

“…While this association was detected in different ethnic groups (14,23,30), it appears more likely to be Caucasian selective (10,29,33) and absent from non-Caucasians (5,6,8,19,22). A recent report from the Type I Diabetes Genetics Consortium bearing on 2,300 affected sib pair families demonstrated that among the 24 single nucleotide polymorphisms (SNPs) genotyped in the CTLA-4 region, only the ϩ49A/G and CT60 SNPs were replicated in the nine combined collections (27).…”

Significantly association of diabetes mellitus with CTLA-4 gene polymorphisms based on a meta-analysis of epidemiological evidence in Asians and non-Asians

“…A total of 43 published studies between CTLA-4 and T1D were identified according to our inclusion criteria, involving 8021 cases and 9570 controls (Nistico et al, 1996;Donner et al, 1997;Van der Auwera et al, 1997;Krokowski et al, 1998;Djilali-Saiah et al, 1998;Awata et al, 1998;Yanagawa et al, 1999;Hayashi et al, 1999;Abe et al, 1999;Takara et al, 2000;Lee et al, 2000;Ihara et al, 2001;Kamoun et al, 2001;Osei-Hyiaman et al, 2001;McCormack et al, 2001;Kikuoka et al, 2001;Cosentino et al, 2002;Fajardy et al, 2002;Cinek et al, 2002;Ma et al, 2002;Klitz et al, 2002;Wood et al, 2002;Ongagna et al, 2002;Mochizuki et al, 2003;Bouqbis et al, 2003;Zalloua et al, 2004;Haller et al, 2004;Ide et al, 2004;Ahmedov et al, 2006;Baniasadi et al, 2006;Ikegami et al, 2006;Saleh et al, 2008;Douroudis et al, 2009;Balic et al, 2009;Jung et al, 2009;Korolija et al, 2009;Ferreira et al, 2009;Benmansour el al., 2010;Ei Wafai et al, 2011;Philip and Isabel, 2011;…”