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

Lindgren, Cecilia LU ; Widén, Elisabeth ; Tuomi, Tiinamaija LU orcid ; Li, Haiyan LU ; Almgren, Peter LU ; Kanninen, Timo ; Melander, Olle LU orcid ; 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)
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organization
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Contribution to journal
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published
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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
additional info
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)
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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
2016-04-01 15:55:07
date last changed
2024-03-13 10:25:02
@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}},
  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}},
  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}},
  doi          = {{10.2337/diabetes.51.5.1609}},
  volume       = {{51}},
  year         = {{2002}},
}