Markers for Risk of Type 1 Diabetes in Relatives of Alsacian Patients With Type 1 Diabetes

Abstract

Background: The cytotoxic T lymphocyteassociated antigen 4 gene (CTLA-4) encode the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. The receptor protein is a specific T lymphocyte surface antigen that is detected on cells only after antigen presentation. Thus, CTLA-4 is directly involved in both immune and autoimmune responses and may be involved in the pathogenesis of multiple T cell-mediated autoimmune disorders. There is polymorphism at position 49 in exon 1 of the CTLA-4 gene, providing an A-G exchange. Moreover, we assessed the CTLA-4 49 (Thr/Ala) polymorphism in diabetic patients and first-degree relatives as compared to control subjects. Research design and methods: Three loci (HLA-DQB1, DQA1 and CTLA-4) were analysed in 62 type 1 diabetic patients, 72 firstdegree relatives and 84 nondiabetic control subjects by means of PCR-RFLP. Results: A significant enrichment in DQB1 alleles encoding for an amino acid different from Asp in position 57 (NA) and DQA1 alleles encoding for Arg in position 52 was observed in diabetic subjects and first-degree relatives as compared to controls. The genotype and allele frequencies of these polymorphisms in type 1 diabetic patients and firstdegree relatives differed significantly from those of controls (p< 0.001 and 0.05 respectively). CTLA-49 Ala alleles frequencies were 75.8% in type 1 diabetic patients and 68.1% in first-degree relatives in comparison to 35.7% in control subjects. The Ala/Ala genotype conferred a relative risk of 18.8 (p < 0.001). Conclusion: The CTLA-4 49 Ala allele confers an increased risk of type 1 diabetes, independent of age and HLA-DQ genetic markers.

HLA Class II Allele, Haplotype, and Genotype Associations with Type 1 Diabetes in Benin: A Pilot Study

“…The T1D risk was not significantly associated with DR4 haplotype and DQB1∗03:02 and DQB1∗06:02 alleles in the present study. In contrast, it was reported in the literature that there were positive associations between T1D and DR4 haplotype [ 8 ] and DQB1∗03:02 allele [ 8 , 28 ]. A protective effect of DQB1∗06:02 allele in T1D was also observed [ 29 ].…”

“…These results, together, showed that there is a relationship between the presence of these HLA class II alleles, haplotypes, and genotypes and the risk of developing T1D in Beninese as in Caucasoid population [ 8 ]. Indeed, Fajardy et al showed positive associations between DQA1∗05:01 allele and the T1D onset among French children [ 24 ].…”

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;…”

Genes Mediating Environment Interactions in Type 1 Diabetes

“…This substitution leads to the exchange of a threonine to alanine residue [63]. Most casecontrol studies confirm the link between the G allele of this SNP and several AIDs, including T1D in various populations [36][37][38][39]64]. Interestingly, increased proliferation of T cells was found in G/G homozygotes [65,66] but further functional studies are needed.…”