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Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families

Abstract

In recent years the pace of discovery of genetic associations with type I diabetes (T1D) has accelerated, with the total number of confirmed loci, including the major histocompatibility complex (MHC) region, reaching 43. However, much of the deciphering of the associations at these, and the established T1D loci, has yet to be performed in sufficient numbers of samples or with sufficient markers. Here, 257 single-nucleotide polymorphisms (SNPs) have been genotyped in 19 candidate genes (INS, PTPN22, IL2RA, CTLA4, IFIH1, SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21, CAPSL, Q7Z4c4(5Q), FOXP3, EFHB) in 2300 affected sib-pair families and tested for association with T1D as part of the Type I Diabetes Genetics Consortium's candidate gene study. The study had approximately 80% power at α=0.002 and a minor allele frequency of 0.2 to detect an effect with a relative risk (RR) of 1.20, which drops to just 40% power for a RR of 1.15. At the INS gene, rs689 (−23 HphI) was the most associated SNP (P=3.8 × 10−31), with the estimated RR=0.57 (95% confidence interval, 0.52–0.63). In addition, rs689 was associated with age-at-diagnosis of T1D (P=0.001), with homozygosity for the T1D protective T allele, delaying the onset of T1D by approximately 2 years in these families. At PTPN22, rs2476601 (R620W), in agreement with previous reports, was the most significantly associated SNP (P=6.9 × 10−17), with RR=1.55 (1.40–1.72). Evidence for association with T1D was observed for the IFIH1 SNP, rs1990760 (P=7.0 × 10−4), with RR=0.88 (0.82–0.95) and the CTLA4 SNP rs1427676 (P=0.0005), with RR=1.14 (1.06–1.23). In contrast, no convincing evidence of association was obtained for SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21 or CAPSL gene regions (http://www.T1DBase.org).

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Acknowledgements

This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD), the Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. The authors are supported by grants from the the Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Centre. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources.

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Howson, J., Walker, N., Smyth, D. et al. Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families. Genes Immun 10 (Suppl 1), S74–S84 (2009). https://doi.org/10.1038/gene.2009.96

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