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.
To reassess the type I diabetes (T1D) association of the OAS1 locus, the Type I Diabetes Genetics Consortium (T1DGC) genotyped 11 tag single-nucleotide polymorphisms spanning B41 kb from the 5 0 to 3 0 flanking region. For each sample obtained from over 2000 affected sib-pair families from nine cohorts, the genotyping was performed on both the Illumina Golden Gate and Sequenom iPlex platforms. The data suggest that there may be a weak association with T1D for two OAS1 polymorphisms, rs3741981 and rs10774671, in populations of European descent. The OAS1 locus is close to a recently identified T1D-associated linkage disequilibrium (LD) block in human chromosome 12q24. Extended LD in populations earlier examined may account for the prior observation of an association of T1D with OAS1 variants. This possibility needs to be addressed further by fine mapping of the T1D association represented in 12q24.
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