Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes.
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 x 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 x 10(-28)), suggesting that an inherited lower immune responsiveness predisposes to T1D.
Lowe
Christopher E
CE
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, UK.
Cooper
Jason D
JD
Brusko
Todd
T
Walker
Neil M
NM
Smyth
Deborah J
DJ
Bailey
Rebecca
R
Bourget
Kirsi
K
Plagnol
Vincent
V
Field
Sarah
S
Atkinson
Mark
M
Clayton
David G
DG
Wicker
Linda S
LS
Todd
John A
JA
D002874:Chromosome Mapping / Q000379:methods*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit