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Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes

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.

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Figure 1: Pairwise r2 LD plots of the IL15RA-IL2RA-RBM17 region.
Figure 2: Results of regression analyses for 305 SNPs in the extended IL2RA region.
Figure 3: Imputed ORs for the minor alleles of 967 SNPs in the IL15RA-IL2RA-RBM17 region.

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Acknowledgements

We acknowledge the participation of all the affected individuals, control subjects and family members and thank the Human Biological Data Interchange and Diabetes UK for the US and UK multiplex families, respectively; the Norwegian Study Group for Childhood Diabetes for the collection of Norwegian families (D. Undlien and K. Rønningen); C. Ionescu-Tîrgovişte and C. Guja for the Romanian samples; T. Valle, J. Tuomilehto and V. Harjutsalo for the Finnish samples and D. Savage, C. Patterson and P. Maxwell for the Northern Irish samples. We acknowledge use of the DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council Grant G0000934 and Wellcome Trust Grant 068545/Z/02 and thank D. Strachan and P. Burton for their help. We also thank The Avon Longitudinal Study of Parents and Children laboratory in Bristol, including S. Ring and W. McArdle for preparing and providing the control DNA samples. We thank T. Willis, M. Faham and P. Hardenbol of Affymetrix for the molecular inversion probe technology. We thank L. Smink, O. Burren, B. Healy, V. Everett and G. Dolman for bioinformatics and IT support. DNA samples were prepared by T. Mistry, T. Hassanali, M. Maisuria, M. Sebastian, S. Wood, P. Lauder and M. Hardy together with G. Coleman, E. King, A. Simpson and H. Stevens, who also prepared the plasma samples with the assistance of H. Schuilenburg. This work was funded by the Wellcome Trust and the Juvenile Diabetes Research Foundation (JDRF) International, the American Diabetes Association (grant 7-06-RA-09) awarded to M.A., as well as funding from the JDRF International Pilot and Feasibility Grant awarded to T.B. and M.A. (7-2006-328).

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Contributions

C.E.L. contributed to the conception, design and coordination of the study, regional annotation, SNP discovery, genotyping, sIL-2RA studies, data analysis and drafting of the manuscript. J.D.C. contributed to the study design, data analysis and drafting of the manuscript. N.M.W. managed the data. D.J.S. and R.B. contributed to SNP discovery and genotyping, K.B. contributed to the plasma sIL-2RA study. S.F. contributed to the genotyping. V.P. and D.G.C. contributed to data analysis. T.B., L.S.W. and M.A. contributed to the design, coordination and analysis of the sIL-2RA studies. J.A.T. participated in the conception, design and coordination of the study, data analysis and drafting of the manuscript.

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Correspondence to John A Todd.

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Lowe, C., Cooper, J., Brusko, T. et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 39, 1074–1082 (2007). https://doi.org/10.1038/ng2102

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