Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity.
Författare
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.
Avdelning/ar
Publiceringsår
2002
Språk
Engelska
Sidor
1609-1617
Publikation/Tidskrift/Serie
Diabetes
Volym
51
Issue
5
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Diabetes Association Inc.
Ämne
- Endocrinology and Diabetes
Nyckelord
- 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
Forskningsgrupp
- Genomics, Diabetes and Endocrinology
- Cardiovascular Research - Hypertension
ISBN/ISSN/Övrigt
- ISSN: 1939-327X