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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Cecilia Lindgren
  • Elisabeth Widén
  • Tiinamaija Tuomi
  • Haiyan Li
  • Peter Almgren
  • Timo Kanninen
  • Olle Melander
  • Jianping Weng
  • Markku Lehto
  • Leif Groop
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • 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
Original languageEnglish
Pages (from-to)1609-1617
JournalDiabetes
Volume51
Issue number5
Publication statusPublished - 2002
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hypertension and Cardiovascular Disease (013242540), Pediatrics/Urology/Gynecology/Endocrinology (013240400), Diabetes and Endocrinology (013241530)