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

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Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity. / Lindgren, Cecilia; Widén, Elisabeth; Tuomi, Tiinamaija; Li, Haiyan; Almgren, Peter; Kanninen, Timo; Melander, Olle; Weng, Jianping; Lehto, Markku; Groop, Leif.

In: Diabetes, Vol. 51, No. 5, 2002, p. 1609-1617.

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Lindgren, Cecilia ; Widén, Elisabeth ; Tuomi, Tiinamaija ; Li, Haiyan ; Almgren, Peter ; Kanninen, Timo ; Melander, Olle ; Weng, Jianping ; Lehto, Markku ; Groop, Leif. / Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity. In: Diabetes. 2002 ; Vol. 51, No. 5. pp. 1609-1617.

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TY - JOUR

T1 - Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity.

AU - Lindgren, Cecilia

AU - Widén, Elisabeth

AU - Tuomi, Tiinamaija

AU - Li, Haiyan

AU - Almgren, Peter

AU - Kanninen, Timo

AU - Melander, Olle

AU - Weng, Jianping

AU - Lehto, Markku

AU - Groop, Leif

N1 - 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)

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Human

KW - Genome

KW - Genetic Screening

KW - Genetic Predisposition to Disease

KW - Genetic Markers

KW - Genetic Heterogeneity

KW - Female

KW - Insulin-Dependent: genetics

KW - Adult

KW - Diabetes Mellitus

KW - Biological Markers

KW - Autoantibodies: blood

KW - Aged

KW - Age of Onset

KW - Insulin-Dependent: immunology

KW - Family Health

KW - Genotype

KW - HLA-DQ Antigens: genetics

KW - Male

KW - Middle Age

KW - Mutation

KW - Pedigree

KW - Scandinavia

KW - Support

KW - Non-U.S. Gov't

U2 - 10.2337/diabetes.51.5.1609

DO - 10.2337/diabetes.51.5.1609

M3 - Article

VL - 51

SP - 1609

EP - 1617

JO - Diabetes

T2 - Diabetes

JF - Diabetes

SN - 1939-327X

IS - 5

ER -