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Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

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Author

  • Mette Andersen
  • Maria Sterner
  • Tom Forsen
  • Annemari Karajamaki
  • Olov Rolandsson
  • Carol Forsblom
  • Per-Henrik Groop
  • Kaj Lahti
  • Peter Nilsson
  • Leif Groop
  • Tiinamaija Tuomi
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Summary, in English

Aims/hypothesis Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). Methods We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n=911) or type 1 diabetes (n=406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n=4,002). Results Variants in the ZMIZ1 (rs12571751, p=4.1 x 10(-5)) and TCF7L2 (rs7903146, p=5.8 x 10(-4)) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p=0.0012), HHEX (rs1111875, p=0.0024 in Finns) and MTNR1B (rs10830963, p=0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p=9.5 x 10(-4) in Finns), TP53INP1 (rs896854, p=0.005), CDKAL1 (rs7756992, p=7.0 x 10(-4); rs7754840, p=8.8 x 10(-4)) and PROX1 (rs340874, p=0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p=3.2 x 10(-6)) and HNF1A (rs2650000, p=0.0012). Conclusions/interpretation LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.

Publishing year

2014

Language

English

Pages

1859-1868

Publication/Series

Diabetologia

Volume

57

Issue

9

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Keywords

  • Adult-onset type 1 diabetes
  • GADA
  • GAD autoantibodies
  • Genetics
  • HNF1A
  • LADA
  • Latent autoimmune diabetes in adults
  • MTNR1B
  • TCF7L2
  • ZMIZ1

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Internal Medicine - Epidemiology

ISBN/ISSN/Other

  • ISSN: 1432-0428