Remapping the Insulin Gene/IDDM2 Locus in Type 1 Diabetes

  1. Bryan J. Barratt1,
  2. Felicity Payne1,
  3. Chris E. Lowe1,
  4. Robert Hermann1,
  5. Barry C. Healy1,
  6. Denise Harold2,
  7. Patrick Concannon3,
  8. Neda Gharani4,
  9. Mark I. McCarthy4,
  10. Mark G. Olavesen2,
  11. Rose McCormack5,
  12. Cristian Guja6,
  13. Constantin Ionescu-Tîrgovişte6,
  14. Dag E. Undlien7,
  15. Kjersti S. Rønningen8,
  16. Kathleen M. Gillespie9,
  17. Eva Tuomilehto-Wolf10,
  18. Jaakko Tuomilehto1011,
  19. Simon T. Bennett2,
  20. David G. Clayton1,
  21. Heather J. Cordell1 and
  22. John A. Todd1
  1. 1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K
  2. 2Oxagen, Abingdon, Oxon, U.K
  3. 3Molecular Genetics Program, Benaroya Research Center and Department of Immunology, University of Washington School of Medicine, Seattle, Washington
  4. 4Imperial College Genetics and Genomics Research Institute, Imperial College Faculty of Medicine, Hammersmith Hospital, London, U.K
  5. 5Department of Medical Genetics, Queen’s University Belfast, Belfast City Hospital, Belfast, U.K
  6. 6Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases “N. Paulescu” Bucharest, Romania
  7. 7Institute of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway
  8. 8Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
  9. 9Diabetes and Metabolism, Division of Medicine, University of Bristol, U.K
  10. 10Diabetes and Genetic Epidemiology Unit, National Public Health Institute, University of Helsinki, Helsinki, Finland
  11. 11Department of Public Health, University of Helsinki, Helsinki, Finland
  1. Address correspondence and reprint requests to Bryan J. Barratt, JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, U.K. E-mail: bryan.barratt{at}cimr.cam.ac.uk

Abstract

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.

Footnotes

  • R.H. is currently affiliated with the Department of Virology, University of Turku, Turku, Finland. D.H. is currently affiliated with the Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, U.K. N.G. is currently affiliated with Rutgers University, Nelson Biological Laboratories, Piscataway, New Jersey. M.I.M. is currently affiliated with the Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K. M.G.O. is currently affiliated with the Wellcome Trust Centre for Human Genetics, Oxford, U.K. S.T.B. is currently located at Solexa, Chesterford Research Park, Little Chesterford, Essex, U.K. R.M. is currently located at AstraZeneca, Alderley Park, Macclesfield, U.K.

    Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. Further information on JDRF/WT Diabetes and Inflammation Laboratory research, including gene annotations and polymorphisms, is available at http://dil-gbrowse.cimr.cam.ac.uk/cgi-bin/DIL_GenomeView.cgi.

    • Accepted March 29, 2004.
    • Received January 28, 2004.
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