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Remapping the Insulin Gene/IDDM2 Locus in Type 1 Diabetes

Bryan J. Barratt¹, Felicity Payne¹, Chris E. Lowe¹, Robert Hermann¹, Barry C. Healy¹, Denise Harold², Patrick Concannon³, Neda Gharani⁴, Mark I. McCarthy⁴, Mark G. Olavesen², Rose McCormack⁵, Cristian Guja⁶, Constantin Ionescu-Tîrgovite⁶, Dag E. Undlien⁷, Kjersti S. Rønningen⁸, Kathleen M. Gillespie⁹, Eva Tuomilehto-Wolf¹⁰, Jaakko Tuomilehto^10,11, Simon T. Bennett², David G. Clayton¹, Heather J. Cordell¹, and John A. Todd¹

¹ Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K
² Oxagen, Abingdon, Oxon, U.K
³ Molecular Genetics Program, Benaroya Research Center and Department of Immunology, University of Washington School of Medicine, Seattle, Washington
⁴ Imperial College Genetics and Genomics Research Institute, Imperial College Faculty of Medicine, Hammersmith Hospital, London, U.K
⁵ Department of Medical Genetics, Queen’s University Belfast, Belfast City Hospital, Belfast, U.K
⁶ Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases "N. Paulescu" Bucharest, Romania
⁷ Institute of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway
⁸ Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
⁹ Diabetes and Metabolism, Division of Medicine, University of Bristol, U.K
¹⁰ Diabetes and Genetic Epidemiology Unit, National Public Health Institute, University of Helsinki, Helsinki, Finland
¹¹ Department of Public Health, University of Helsinki, Helsinki, Finland

Type 1 diabetes susceptibility at the IDDM2 locus was previously mapped to a variable number tandem repeat (VNTR) 5' of the insulin gene (INS). However, the observation of associated markers outside a 4.1-kb interval, previously considered to define the limits of IDDM2 association, raised the possibility that the VNTR association might result from linkage disequilibrium (LD) with an unknown polymorphism. We therefore identified a total of 177 polymorphisms and obtained genotypes for 75 of these in up to 434 pedigrees. We found that, whereas disease susceptibility did map to within the 4.1-kb region, there were two equally likely candidates for the causal variant, –23HphI and +1140A/C, in addition to the VNTR. Further analyses in 2,960 pedigrees did not support the difference in association between VNTR lineages that had previously enabled the exclusion of these two polymorphisms. Therefore, we were unable to rule out –23HphI and +1140A/C having an etiological effect. Our mapping results using robust regression methods show how precisely a variant for a common disease can be mapped, even within a region of strong LD, and specifically that IDDM2 maps to one or more of three common variants in a 2-kb region of chromosome 11p15.

Abbreviations: LD, linkage disequilibrium; PH, protective haplotype; SNP, single nucleotide polymorphism; VNTR, variable number tandem repeat; VPH, very protective haplotype

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