title: Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes.
abstract: OBJECTIVE
  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 × 10(-5)) and TCF7L2 (rs7903146, p = 5.8 × 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 × 10(-4) in Finns), TP53INP1 (rs896854, p = 0.005), CDKAL1 (rs7756992, p = 7.0 × 10(-4); rs7754840, p = 8.8 × 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 × 10(-6)) and HNF1A (rs2650000, p = 0.0012).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland, mette.k.andersen@helsinki.fi.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Andersen
authors.forename: Maria
authors.initials: M
authors.lastname: Sterner
authors.forename: Tom
authors.initials: T
authors.lastname: Forsén
authors.forename: Annemari
authors.initials: A
authors.lastname: Käräjämäki
authors.forename: Olov
authors.initials: O
authors.lastname: Rolandsson
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Kaj
authors.initials: K
authors.lastname: Lahti
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans
chemical_list: D001323:Autoantibodies