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Olle Melander

Principal investigator

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Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity.

Author

  • Cecilia Lindgren
  • Elisabeth Widén
  • Tiinamaija Tuomi
  • Haiyan Li
  • Peter Almgren
  • Timo Kanninen
  • Olle Melander
  • Jianping Weng
  • Markku Lehto
  • Leif Groop

Summary, in English

In an attempt to identify novel susceptibility genes predisposing to early-onset diabetes (EOD), we performed a genome-wide scan using 433 markers in 222 individuals (119 with diabetes) from 29 Scandinavian families with ≥2 members with onset of diabetes ≤45 years. The highest nonparametric linkage (NPL) score, 2.7 (P < 0.01), was observed on chromosome 1p (D1S473/D1S438). Six other regions on chromosomes 3p, 7q, 11q, 18q, 20q, and 21q showed a nominal P value <0.05. Of the EOD subjects in these 29 families, 20% were GAD antibody positive and 68% displayed type 1 diabetes HLA risk alleles (DQB*02 or 0302). Mutations in maturity-onset diabetes of the young (MODY) 1–5 genes and the A3243G mitochondrial DNA mutation were detected by single-strand conformation polymorphism and direct sequencing. To increase homogeneity, we analyzed a subsample of five families with autosomal dominant inheritance of EOD (greater than or equal to two members with age at diagnosis ≤35 years). The highest NPL scores were found on chromosome 1p (D1S438–D1S1665; NPL 3.0; P < 0.01) and 16q (D16S419; NPL 2.9; P < 0.01). After exclusion of three families with MODY1, MODY3, and mitochondrial mutations, the highest NPL scores were observed on chromosomes 1p (D1S438; NPL 2.6; P < 0.01), 3p (D3S1620; NPL 2.2; P < 0.03), 5q (D5S1465; NPL 2.1; P < 0.03), 7q (D7S820; NPL 2.0; P < 0.03), 18q (D18S535; NPL 1.9; P < 0.04), 20q (D20S195; NPL 2.5; P < 0.02), and 21q (D21S1446; NPL 2.2; P < 0.03). We conclude that considerable heterogeneity exists in Scandinavian subjects with EOD; 24% had MODY or maternally inherited diabetes and deafness, and ∼60% were GAD antibody positive or had type 1 diabetes-associated HLA genotypes. Our data also point at putative chromosomal regions, which could harbor novel genes that contribute to EOD.

Department/s

  • Department of Clinical Sciences, Malmö
  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension

Publishing year

2002

Language

English

Pages

1609-1617

Publication/Series

Diabetes

Volume

51

Issue

5

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Keywords

  • Human
  • Genome
  • Genetic Screening
  • Genetic Predisposition to Disease
  • Genetic Markers
  • Genetic Heterogeneity
  • Female
  • Insulin-Dependent: genetics
  • Adult
  • Diabetes Mellitus
  • Biological Markers
  • Autoantibodies: blood
  • Aged
  • Age of Onset
  • Insulin-Dependent: immunology
  • Family Health
  • Genotype
  • HLA-DQ Antigens: genetics
  • Male
  • Middle Age
  • Mutation
  • Pedigree
  • Scandinavia
  • Support
  • Non-U.S. Gov't

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 1939-327X