Toward Further Mapping of the Association Between the <i>IL2RA</i> Locus and Type 1 Diabetes

Qu, Hui‐Qi; Montpetit, Alexander; Ge, Bing; Hudson, Thomas J.; Polychronakos, Constantin

doi:10.2337/db06-1555

Cited by 84 publications

(66 citation statements)

References 12 publications

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“…The two values for the correlation coefficient r 2 have no statistical difference ( p ϭ 0.619). Linkage disequilibrium with AE was also detected from the other T1D-associated SNPs as we reported previously (5). The predisposing allele of each of the T1D-associated SNPs is in linkage disequilibrium with the underexpression phenotype of the IL2RA heteronuclear RNA.…”

Section: Mapping Of the Cis-regulatory Effectmentioning

confidence: 55%

“…Adult CD25-deficient mice are characterized by impaired T cell death after activation and autoimmune disorders (2). In humans, genetic association of noncoding polymorphisms at IL2RA with T1D has been reported (3, 4) and replicated independently (5). Genetic variation of IL2RA has also been reported to be associated with other autoimmune diseases, e.g., multiple sclerosis (6 -8) and juvenile idiopathic arthritis (9).…”

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confidence: 99%

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A cis-Acting Regulatory Variant in the IL2RA Locus

Verlaan

et al. 2009

The Journal of Immunology

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The mechanism for the association of type 1 diabetes (T1D) with IL2RA remains to be clarified. Neither of the two distinct, transmission-disequilibrium confirmed loci mapping to this gene can be explained by a coding variant. An effect on the levels of the soluble protein product sIL-2RA has been reported but its cause and relationship to disease risk is not clear. To look for an allelic effect on IL2RA transcription in cis, we examined RNA from 48 heterozygous lymphocyte samples for differential allele expression. Of the 48 samples, 32 showed statistically significant allelic imbalance. No known single nucleotide polymorphism (SNP) had perfect correlation with this transcriptional effect but the one that showed the most significant (p = 1.6 × 10−5) linkage disequilibrium with it was the SNP rs3118470. We had previously shown rs3118470 to confer T1D susceptibility in a Canadian dataset, independently of rs41295061 as the major reported locus (p = 5 × 10−3, after accounting for rs41295061 by conditional regression). Lower IL2RA levels consistently originated from the T1D predisposing allele. We conclude that an as yet unidentified variant or haplotype, best marked by rs3118470, is responsible for this independent effect and increases T1D risk through diminished expression of the IL-2R, likely by interfering with the proper development of regulatory T cells.

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Section: Mapping Of the Cis-regulatory Effectmentioning

confidence: 55%

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confidence: 99%

A cis-Acting Regulatory Variant in the IL2RA Locus

Verlaan

et al. 2009

The Journal of Immunology

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“…Interestingly, the number of single markers tested by the imputation approach was 2.1M which is approximately the same as the total number of tests (single markers and localized haplotype clusters) performed by Beagle, yet imputation was not able to find significant association for four regions in this data set which were detected by localized haplotype cluster analysis (see Figure 2). Two of these four regions have been convincingly replicated: the IL2RA gene region in chromosome 10p15.1 associated with type 1 diabetes (Lowe et al 2007;Qu et al 2007;Vella et al 2005) and the chromosome 9p21.3 region associated with type 2 diabetes (Saxena et al 2007;Scott et al 2007;Zeggini et al 2007). Thus the localized haplotype cluster analysis had greater success detecting disease-associated variants than the analysis of non-genotyped, imputed HapMap SNPs: a greater number of truly associated regions were identified and the localized haplotype clusters had a much more marked decrease in p-values relative to single marker analysis.…”

Section: Comparison With Analysis Of Imputed Hapmap Snpsmentioning

confidence: 98%

“…The association of variants in the IL2RA gene region in chromosome 10p15.1 with type 1 diabetes has been well established (Lowe et al 2007;Qu et al 2007;Vella et al 2005). Although single marker allelic and genotypic tests of genotyped SNPs and imputed HapMap SNPs only showed marginal significance for this loci (genotyped SNP minimum p = 7.3 × 10 -6 ; imputed SNP minimum p = 1.1 × 10 -6 ), the localized haplotype cluster tests yielded strong evidence of association (p = 5.1 × 10 -9 ) with a p-value more than 2 orders of magnitude smaller than the smallest single marker p-value in the region.…”

Section: Associated Regionsmentioning

confidence: 99%

Haplotypic analysis of Wellcome Trust Case Control Consortium data

Browning

2008

Hum Genet

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We applied a recently developed multilocus association testing method (localized haplotype clustering) to Wellcome Trust Case Control Consortium data (14,000 cases of seven common diseases and 3,000 shared controls genotyped on the Affymetrix 500K array). After rigorous data quality filtering, we identified three disease-associated loci with strong statistical support from localized haplotype cluster tests but with only marginal significance in single marker tests. These loci are chromosomes 10p15.1 with type 1 diabetes (p = 5.1 × 10 -9 ), 12q15 with type 2 diabetes (p = 1.9 × 10 -7 ) and 15q26.2 with hypertension (p = 2.8 × 10 -8 ). We also detected the association of chromosome 9p21.3 with type 2 diabetes (p = 2.8 × 10 -8 ), although this locus did not pass our stringent genotype quality filters. The association of 10p15.1 with type 1 diabetes and 9p21.3 with type 2 diabetes have both been replicated in other studies using independent data sets. Overall, localized haplotype cluster analysis had better success detecting disease associated variants than a previous single-marker analysis of imputed HapMap SNPs. We found that stringent application of quality score thresholds to genotype data substantially reduced false-positive results arising from genotype error. In addition, we demonstrate that it is possible to simultaneously phase 16,000 individuals genotyped on genome-wide data (450K markers) using the Beagle software package.

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“…In this regard, a recent review providing a diagram of potential synthesis of SLE and RA molecular mechanisms/pathways may be instructive. 23 Arguably, even the modest effect (amount of genetic variation explained) of many of the emerging genetic risk factors will be critical in our understanding of the etiopathogenesis of these diseases. Some caution is of course needed, as in many cases, the actual gene(s) affected by specific sequence or haplotype variations is not yet clear.…”

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confidence: 99%