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Association of the Vitamin D Metabolism Gene CYP27B1 With Type 1 Diabetes

¹ Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, U.K
² Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London, U.K
³ Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K
⁴ Department of Internal Medicine I, Division of Endocrinology, Diabetes, and Metabolism, University Hospital, Frankfurt, Germany

Address correspondence and reprint requests to Prof. John A. Todd, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, WT/MRC building, Addenbrooke's Hospital, Cambridge, CB2 0XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk

Abbreviations: 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; EFSD, European Foundation for the Study of Diabetes; IL, interleukin; MAF, minor allele frequency; NCBI, National Center for Biotechnology Information; SNP, single nucleotide polymorphism; VDR, vitamin D receptor

OBJECTIVE—Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1,25-dihydroxyvitamin D (1,25(OH)₂D) could protect from immune destruction of the pancreatic ß-cells. 1,25(OH)₂D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes.

RESEARCH DESIGN AND METHODS—We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms –1260C>A (rs10877012) and +2838T>C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene.

RESULTS—We found evidence of association with type 1 diabetes for CYP27B1 –1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 –1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 x 10^–4) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 x 10^–3). The combined P value for an association with type 1 diabetes was 3.8 x 10^–6. For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23).

CONCLUSIONS—The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes.

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