Article
Overview of the Type I Diabetes Genetics Consortium.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Genes and immunity (impact factor:
4.22).
12/2009;
10 Suppl 1:S1-4.
DOI:10.1038/gene.2009.84
pp.S1-4
Source: PubMed
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Article: Association analysis of SNPs in the IL4R locus with type I diabetes.
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ABSTRACT: The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have all been genotyped for the HLA class I and class II loci and a subset of samples has been typed for an major histocompatibility complex (MHC) single-nucleotide polymorphism (SNP) panel. In addition, the T1DGC has genotyped SNPs in candidate genes to evaluate earlier reported T1D associations. Individual SNPs and SNP haplotypes in IL4R, which encodes the alpha-chain of the IL4 and IL13 receptors, have been associated with T1D in some reports, but not in others. In this study, 38 SNPs in IL4R were genotyped using the Sequenom iPLEX Gold MassARRAY technology in 2042 multiplex families from nine cohorts. Association analyses (transmission-disequilibrium test and parental-disequilibrium test) were performed on individual SNPs and on three-SNP haplotypes. Analyses were also stratified on the high-risk HLA DR3/DR4-DQB1*0302 genotype. A modest T1D association in HBDI families (n=282) was confirmed in this larger collection of HBDI families (n=424). The variant alleles at the non-synonymous SNPs (rs1805011 (E400A), rs1805012 (C431R), and rs1801275 (Q576R)), which are in strong linkage disequilibrium, were negatively associated with T1D risk. These SNPs were more associated with T1D among non-DR3/DR4-DQB1*0302 genotypes than DR3/DR4-DQB1*0302 genotypes. This association was stronger, both in terms of odds ratio and P-values, than the initial report of the smaller collection of HBDI families. However, the IL4R SNPs and the three-SNP haplotype containing the variant alleles were not associated with T1D in the total data. Thus, in the overall families, these results do not show evidence for an association of SNPs in IL4R with T1D.Genes and immunity 12/2009; 10 Suppl 1:S33-41. · 4.22 Impact Factor -
Article: The type I diabetes association of the IL2RA locus.
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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 approximately 88 kb from the 5' flanking to 3' 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)=0.869 (95% CI, 0.850-0.885). This haplotype was significantly protective (P=3.2 x 10(-5)) 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' flanking IL2RA SNP rs4749955, which remained significant after regression for H5. Thus, we confirm independent effects at the IL2RA locus.Genes and immunity 12/2009; 10 Suppl 1:S42-8. · 4.22 Impact Factor -
Article: No association of the IRS1 and PAX4 genes with type I diabetes.
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ABSTRACT: To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. Both genes are biological candidate genes for T1D. Genotyping was performed in 2300 T1D families on both Illumina and Sequenom genotyping platforms. Data quality and concordance between the platforms were assessed for each SNP. Transmission disequilibrium testing neither show T1D association of SNPs in the two genes, nor did haplotype analysis. In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. This highlights the importance of thorough quality control, selection of tagging SNPs, more than one genotyping platform in high throughput studies, and sufficient power to draw solid conclusions in genetic studies of human complex diseases.Genes and immunity 12/2009; 10 Suppl 1:S49-53. · 4.22 Impact Factor
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Keywords
autoimmune diseases
beta-cell function
candidate gene
candidate genes
case-control collections
Consortium activities
Consortium Agreement
EBV-transformed cell lines
first goal
genome-wide association scan
genomic regions
multicenter research program
own investigations
parent-child trios
research community
research data available
researchers
sib-pair families
T1DGC collection
type II diabetes