The type I diabetes association of the IL2RA locus

Abstract

To confirm and fine map previous reports of association, the Type I Diabetes (T1D) Genetics Consortium (T1DGC) assembled a large collection of DNA samples from affected sib-pair (ASP) families with T1D (5003 affected individuals) and genotyped polymorphic markers. One of these loci, involving the IL2RA gene, had been reported to be due to three independent effects. The T1DGC genotyped 69 single-nucleotide polymorphisms (SNPs) that span B88 kb from the 5 0 flanking to 3 0 flanking region of the IL2RA locus. The most highly associated SNP reported earlier (ss52580101) was not included in the genotyping list; however, a 5-SNP (rs3134883, rs3118470, rs7072793, rs4749955 and rs12251307) haplotype (H5) was identified that strongly tagged its minor allele with r 2 ¼ 0.869 (95% CI, 0.850-0.885). This haplotype was significantly protective (P ¼ 3.2 Â 10 À5) in the T1D ASP families, with an odds ratio virtually identical to that reported for ss52580101. The SNP marking the second independent locus, (rs11594656) showed no association in the T1DGC set and the third (rs2104286) could not be distinguished, by conditional regression, from H5. Instead, the most significant independent effect was detected from the 5 0 flanking IL2RA SNP rs4749955, which remained significant after regression for H5. Thus, we confirm independent effects at the IL2RA locus.

Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population

“…The present results are in line with previous reports on the diabetes association of the IL-2RA/CD25 gene [6,8,18,19]. This is consistent with the role of the human IL-2RA/CD25 protein in the activation, proliferation, and function of T-cells.…”

“…Recently, the Type 1 Diabetes Genetics Consortium (T1DGC) genotyped 69 SNPs and found a 5-SNP (rs3134883, rs3118470, rs7072793, rs4749955, and rs12251307) protective haplotype (H5) that was in perfect linkage disequilibrium with the minor allele of Group I (rs41295061) with an odds ratio virtually identical to that previously reported for Group I (rs41295061). The Group II (rs11594656) SNPs showed no association in the T1DGC set, whereas the group III (rs2104286) SNPs could not be distinguished from H5 [8]. Taking all of these findings into account, the current study considered the analysis of rs41295061 for the IL-2RA/CD25 in type 1 diabetes in the Belgian population.…”

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

“…12 Moreover, healthy controls carrying the T1D-associated rs12722495 susceptible genotype (GG) have diminished IL-2 responsiveness in Tregs, as measured by phosphorylation of STAT5. 14,15 A genotype containing the rs3118470 SNP was shown to be significantly protective in T1D-affected sibling-pair families 16 and this observation has been replicated in Japanese 17 and Polish 18 populations. The rs3118470 SNP has also been associated with differential allele expression of IL2RA messenger RNA.…”

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes

“…Horizontal bars represent means, with SD as error bars; statistical analysis between Tregs and Tconvs by one-way ANOVA with Sidák multiple comparisons test. ****P # 0.0001. with changes in Treg function (24)(25)(26)(27)(28)(29), so future studies to correlate changes in the Treg signature with genetic risk factors are warranted.…”