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Analysis of the Vitamin D Receptor Gene Sequence Variants in Type 1 Diabetes

Sergey Nejentsev, Jason D. Cooper¹, Lisa Godfrey¹, Joanna M.M. Howson¹, Helen Rance¹, Sarah Nutland¹, Neil M. Walker¹, Cristian Guja², Constantin Ionescu-Tirgovite², David A. Savage³, Dag E. Undlien⁴, Kjersti S. Rønningen⁵, Eva Tuomilehto-Wolf⁶, Jaakko Tuomilehto^6,7, Kathleen M. Gillespie⁸, Susan M. Ring⁹, David P. Strachan¹⁰, Barry Widmer¹¹, David Dunger¹¹, and John A. Todd¹

¹ Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, U.K
² Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases "N. Paulescu," Bucharest, Romania
³ Department of Medical Genetics, Queen’s University, Belfast, U.K
⁴ Institute of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway
⁵ Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
⁶ Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Helsinki, Finland
⁷ Department of Public Health, University of Helsinki, Helsinki, Finland
⁸ Department of Clinical Science at North Bristol, Division of Medicine, University of Bristol, Bristol, U.K
⁹ Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC), University of Bristol, Bristol, U.K
¹⁰ Department of Community Health Sciences, St. George’s Hospital Medical School, London, U.K
¹¹ Department of Paediatrics, University of Cambridge, Cambridge, U.K

Vitamin D is known to modulate the immune system, and its administration has been associated with reduced risk of type 1 diabetes. Vitamin D acts via its receptor (VDR). Four single nucleotide polymorphisms (SNPs) of the VDR gene have been commonly studied, and evidence of association with type 1 diabetes has been reported previously. We sequenced the VDR gene region and developed its SNP map. Here we analyzed association of the 98 VDR SNPs in up to 3,763 type 1 diabetic families. First, we genotyped all 98 SNPs in a minimum of 458 U.K. families with two affected offspring. We further tested eight SNPs, including four SNPs associated with P < 0.05 in the first set and the four commonly studied SNPs, in up to 3,305 additional families from the U.K., Finland, Norway, Romania, and U.S. We only found weak evidence of association (P = 0.02–0.05) of the rs4303288, rs12721366, and rs2544043 SNPs. We then tested these three SNPs in an independent set of 1,587 patients and 1,827 control subjects from the U.K. and found no evidence of association. Overall, our results indicate that common sequence variation in the VDR gene has no major effect in type 1 diabetes in the populations tested.

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