Genetic Variation in the Small Heterodimer Partner Gene and Young-Onset Type 2 Diabetes, Obesity, and Birth Weight in U.K. Subjects

Genetic Variation in the Small Heterodimer Partner Gene and Young-Onset Type 2 Diabetes, Obesity, and Birth Weight in U.K. Subjects Simon M.S. Mitchell 1 , Michael N. Weedon 1 , Katharine R. Owen 1 , Beverley Shields 1 , Beverley Wilkins-Wall 1 , Mark Walker 2 , Mark I. McCarthy 3 , Timothy M. Frayl...

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Published inDiabetes (New York, N.Y.) Vol. 52; no. 5; pp. 1276 - 1279
Main Authors Mitchell, Simon M S, Weedon, Michael N, Owen, Katharine R, Shields, Beverley, Wilkins-Wall, Beverley, Walker, Mark, McCarthy, Mark I, Frayling, Timothy M, Hattersley, Andrew T
Format Journal Article
LanguageEnglish
Published Alexandria, VA American Diabetes Association 01.05.2003
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Summary:Genetic Variation in the Small Heterodimer Partner Gene and Young-Onset Type 2 Diabetes, Obesity, and Birth Weight in U.K. Subjects Simon M.S. Mitchell 1 , Michael N. Weedon 1 , Katharine R. Owen 1 , Beverley Shields 1 , Beverley Wilkins-Wall 1 , Mark Walker 2 , Mark I. McCarthy 3 , Timothy M. Frayling 1 and Andrew T. Hattersley 1 1 Centre for Molecular Genetics, Peninsula Medical School, Exeter, U.K 2 Department of Medicine, School of Medicine, Newcastle upon-Tyne, U.K 3 Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, Oxford, U.K Abstract The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a . Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The A allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects ( n = 348), their parents ( n = 272), or young nondiabetic adults ( n = 925). However, the rare (<1%) AA homozygotes had a raised BMI in each cohort; this was significant when all cohorts were combined ( Z score = 0.67 AA vs. −0.05 G/x, P = 0.02). There was no association with corrected birth weight in 382 normal babies, but the only AA baby was 4,069 g. Our study suggests that genetic variation in SHP is unlikely to be common in the predisposition to diabetes, obesity, or increased birth weight in U.K. Caucasians. Footnotes Address correspondence and reprint requests to Dr. Timothy M. Frayling, Diabetes and Vascular Medicine, Peninsula Medical School, Barrack Road, Exeter EX2 5AX, U.K. E-mail: t.m.frayling{at}exeter.ac.uk . Received for publication 9 August 2002 and accepted in revised form 20 December 2002. HNF, hepatocyte nuclear factor; LOD, logarithm of odds; MODY, maturity-onset diabetes of the young; SHP, small heterodimer partner; TDT, transmission disequilibrium test. DIABETES
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ISSN:0012-1797
1939-327X
DOI:10.2337/diabetes.52.5.1276