Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes

Joanna M.M. Howson, Jason D. Cooper, Deborah J. Smyth, Neil M. Walker, Helen Stevens, Jin Xiong She, George S. Eisenbarth, Marian Rewers, John A. Todd, Beena Akolkar, Patrick Concannon, Henry A. Erlich, Cécile Julier, Grant Morahan, Jørn Nerup, Concepcion Nierras, Flemming Pociot, Stephen S. Rich

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46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3012-3017
Number of pages6
JournalDiabetes
Volume61
Issue number11
DOIs
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Howson, J. M. M., Cooper, J. D., Smyth, D. J., Walker, N. M., Stevens, H., She, J. X., Eisenbarth, G. S., Rewers, M., Todd, J. A., Akolkar, B., Concannon, P., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Pociot, F., & Rich, S. S. (2012). Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes. Diabetes, 61(11), 3012-3017. https://doi.org/10.2337/db11-1694