Advanced

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

Lindgren, Cecilia LU ; Widén, Elisabeth; Tuomi, Tiinamaija LU ; Li, Haiyan LU ; Almgren, Peter LU ; Kanninen, Timo; Melander, Olle LU ; Weng, Jianping; Lehto, Markku and Groop, Leif LU (2002) In Diabetes 51(5). p.1609-1617
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
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
in
Diabetes
volume
51
issue
5
pages
1609 - 1617
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000175492400039
  • pmid:11978663
  • scopus:0036319126
ISSN
1939-327X
DOI
10.2337/diabetes.51.5.1609
language
English
LU publication?
yes
id
4b9926fd-05d3-4adc-96c8-12e32af3cda2 (old id 115394)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11978663&dopt=Abstract
date added to LUP
2007-07-25 14:40:56
date last changed
2017-12-17 03:52:10
@article{4b9926fd-05d3-4adc-96c8-12e32af3cda2,
  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 &lt; 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 &lt;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 &lt; 0.01) and 16q (D16S419; NPL 2.9; P &lt; 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 &lt; 0.01), 3p (D3S1620; NPL 2.2; P &lt; 0.03), 5q (D5S1465; NPL 2.1; P &lt; 0.03), 7q (D7S820; NPL 2.0; P &lt; 0.03), 18q (D18S535; NPL 1.9; P &lt; 0.04), 20q (D20S195; NPL 2.5; P &lt; 0.02), and 21q (D21S1446; NPL 2.2; P &lt; 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.},
  author       = {Lindgren, Cecilia and Widén, Elisabeth and Tuomi, Tiinamaija and Li, Haiyan and Almgren, Peter and Kanninen, Timo and Melander, Olle and Weng, Jianping and Lehto, Markku and Groop, Leif},
  issn         = {1939-327X},
  keyword      = {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},
  language     = {eng},
  number       = {5},
  pages        = {1609--1617},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity.},
  url          = {http://dx.doi.org/10.2337/diabetes.51.5.1609},
  volume       = {51},
  year         = {2002},
}