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

Mette K. Andersen; Maria Sterner; Tom Forsén; Annemari Käräjämäki; Olov Rolandsson; Carol Forsblom; Per Henrik Groop; Kaj Lahti; Peter M. Nilsson; Leif Groop; Tiinamaija Tuomi

doi:10.1007/s00125-014-3287-8

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

Mette K. Andersen^*, Maria Sterner, Tom Forsén, Annemari Käräjämäki, Olov Rolandsson, Carol Forsblom, Per Henrik Groop, Kaj Lahti, Peter M. Nilsson, Leif Groop, Tiinamaija Tuomi

^*Corresponding author af dette arbejde

34 Citationer (Scopus)

Abstract

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 × 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/ 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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	57
Udgave nummer	9
Sider (fra-til)	1859-1868
Antal sider	10
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-014-3287-8
Status	Udgivet - 1 jan. 2014

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title = "Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes",

abstract = "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 × 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/ 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.",

keywords = "Adult-onset type 1 diabetes, GAD autoantibodies, GADA, Genetics, HNF1A, LADA, Latent autoimmune diabetes in adults, MTNR1B, TCF7L2, ZMIZ1",

author = "Andersen, {Mette K.} and Maria Sterner and Tom Fors{\'e}n and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Olov Rolandsson and Carol Forsblom and Groop, {Per Henrik} and Kaj Lahti and Nilsson, {Peter M.} and Leif Groop and Tiinamaija Tuomi",

year = "2014",

month = jan,

day = "1",

doi = "10.1007/s00125-014-3287-8",

language = "English",

volume = "57",

pages = "1859--1868",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "9",

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TY - JOUR

T1 - Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

AU - Andersen, Mette K.

AU - Sterner, Maria

AU - Forsén, Tom

AU - Käräjämäki, Annemari

AU - Rolandsson, Olov

AU - Forsblom, Carol

AU - Groop, Per Henrik

AU - Lahti, Kaj

AU - Nilsson, Peter M.

AU - Groop, Leif

AU - Tuomi, Tiinamaija

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 × 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/ 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.

AB - 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 × 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/ 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.

KW - Adult-onset type 1 diabetes

KW - GAD autoantibodies

KW - GADA

KW - Genetics

KW - HNF1A

KW - LADA

KW - Latent autoimmune diabetes in adults

KW - MTNR1B

KW - TCF7L2

KW - ZMIZ1

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U2 - 10.1007/s00125-014-3287-8

DO - 10.1007/s00125-014-3287-8

M3 - Journal article

C2 - 24906951

AN - SCOPUS:84905569151

SN - 0012-186X

VL - 57

SP - 1859

EP - 1868

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -

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

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