Article abstract
Nature Genetics 39, 1074 - 1082 (2007)
Published online: 5 August 2007 | doi:10.1038/ng2102
Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes
Christopher E Lowe1,3, Jason D Cooper1,3, Todd Brusko2, Neil M Walker1, Deborah J Smyth1, Rebecca Bailey1, Kirsi Bourget1, Vincent Plagnol1, Sarah Field1, Mark Atkinson2, David G Clayton1, Linda S Wicker1 & John A Todd1
Abstract
Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5' regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70–2.45; P = 1.92 
10-28; control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 10-28), suggesting that an inherited lower immune responsiveness predisposes to T1D.
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OXY, UK.
- University of Florida, College of Medicine, Academic Research Bldg. Rm R2-236, 1600 SW Archer Rd., Gainesville, Florida 32610, USA.
- These authors contributed equally to this work.
Correspondence to: John A Todd1 e-mail: john.todd@cimr.cam.ac.uk
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