Evidence of Gene-Gene Interaction and Age-at-Diagnosis Effects in Type 1 Diabetes

  1. and the Type 1 Diabetes Genetics Consortium*
  1. 1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge, Cambridge, U.K.
  2. 2Center for Biotechnology and Genomic Medicine, Georgia Health Sciences University, Augusta, Georgia
  3. 3Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
  4. 4Division of Diabetes, Endocrinology, and Metabolic Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  5. 5Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
  6. 6Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
  7. 7Roche Molecular Systems, Pleasanton, California
  8. 8University Paris 7 Denis-Diderot, Paris, France
  9. 9Centre for Diabetes Research, the Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia
  10. 10Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark
  11. 11Juvenile Diabetes Research Foundation, New York, New York
  12. 12Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark
  13. 13Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia
  1. Corresponding author: Joanna M.M. Howson, joanna.howson{at}


The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1 diabetes samples (6,750 British diabetic individuals and 8,116 affected family samples of European descent) were genotyped at 38 confirmed type 1 diabetes-associated non-HLA regions and used to test for interaction of association with age-at-diagnosis, sex, and HLA class II genotypes using regression models. The alleles that confer susceptibility to type 1 diabetes at interleukin-2 (IL-2), IL2/4q27 (rs2069763) and renalase, FAD-dependent amine oxidase (RNLS)/10q23.31 (rs10509540), were associated with a lower age-at-diagnosis (P = 4.6 × 10−6 and 2.5 × 10−5, respectively). For both loci, individuals carrying the susceptible homozygous genotype were, on average, 7.2 months younger at diagnosis than those carrying the protective homozygous genotypes. In addition to protein tyrosine phosphatase nonreceptor type 22 (PTPN22), evidence of statistical interaction between HLA class II genotypes and rs3087243 at cytotoxic T-lymphocyte antigen 4 (CTLA4)/2q33.2 was obtained (P = 7.90 × 10−5). No evidence of differential risk by sex was obtained at any loci (P ≥ 0.01). Statistical interaction effects can be detected in type 1 diabetes although they provide a relatively small contribution to our understanding of the familial clustering of the disease.


  • Received December 2, 2011.
  • Accepted May 14, 2012.

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  1. Diabetes vol. 61 no. 11 3012-3017
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