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

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 > or =2 members with onset of diabetes < or =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 < or =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 approximately 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.

• Authors: Cecilia M Lindgren, Elisabeth Widén, Tiinamaija Tuomi, Haiyan Li, Peter Almgren, Timo Kanninen, Olle Melander, Jianping Weng, Markku Lehto, Leif C Groop
• Journal: Diabetes (Diabetes) Vol. 51 Issue 5 Pg. 1609-17 (May 2002) ISSN: 0012-1797 [Print] United States
• PMID: 11978663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Biomarkers
• Genetic Markers
• HLA-DQ Antigens
• HLA-DQ beta-Chains
• HLA-DQB1 antigen

Topics

• Adult
• Age of Onset
• Aged
• Autoantibodies (blood)
• Biomarkers
• Diabetes Mellitus, Type 1 (genetics, immunology)
• Family Health
• Female
• Genetic Heterogeneity
• Genetic Markers
• Genetic Predisposition to Disease
• Genetic Testing
• Genome, Human
• Genotype
• HLA-DQ Antigens (genetics)
• HLA-DQ beta-Chains
• Humans
• Male
• Middle Aged
• Mutation
• Pedigree
• Scandinavian and Nordic Countries