Lack of Association of the Ala45Thr Polymorphism and Other Common Variants of the NeuroD Gene With Type 1 Diabetes
- Adrian Vella1,
- Joanna M.M. Howson1,
- Bryan J. Barratt1,
- Rebecca C.J. Twells1,
- Helen E. Rance1,
- Sarah Nutland1,
- Eva Tuomilehto-Wolf2,
- Jaakko Tuomilehto23,
- Dag E. Undlien4,
- Kjersti S. Rønningen5,
- Cristian Guja6,
- Constantin Ionescu-Tîrgovişte6,
- David A. Savage7 and
- John A. Todd1
- 1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K
- 2Diabetes and Genetic Epidemiology Unit, National Public Health Institute, University of Helsinki, Helsinki, Finland
- 3Department of Public Health, University of Helsinki, Helsinki, Finland
- 4Institute of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway
- 5Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
- 6Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases ‘N. Paulescu,’ Bucharest, Romania
- 7Department of Medical Genetics, Queen’s University Belfast, Belfast City Hospital, Belfast, Northern Ireland
- Address correspondence and reprint requests to Professor John A. Todd, JDRF/WT Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk
Abstract
Variation in genes necessary for normal functioning and development of β-cells, e.g., NEUROD1, which encodes a transcription factor for the insulin gene and is important in β-cell development, causes maturity-onset diabetes of the young. Some studies have reported an association between a nonsynonymous Ala45Thr (+182G→A) single nucleotide polymorphism (SNP) in NEUROD1 and type 1 diabetes, but this result has not been consistently found. To clarify this, we genotyped Ala45Thr in 2,434 type 1 diabetic families of European descent and Caucasian ethnicity from five different countries. Taking the allele frequency of 36% for Thr45 and an odds ratio (OR) of 1.2, this sample provided >99% power to detect an association (P < 0.05). We could not confirm the association (P = 0.77). No evidence of population heterogeneity in the lack of association of Thr45 with type 1 diabetes was observed. To evaluate the possibility that another NEUROD1 variant was associated with type 1 diabetes, we resequenced the gene in 32 U.K. affected individuals and identified and genotyped all common SNPs (minor allele frequency >10%; n = 5) in 786 families. We report no evidence of association of these common variants in NEUROD1 and type 1 diabetes in these samples.
- MODY, maturity-onset diabetes of the young
- SNP, single nucleotide polymorphism
- TDT, transmission disequilibrium test
Footnotes
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Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
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- Accepted January 5, 2004.
- Received December 18, 2003.
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