CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibitity to type 1 diabetes and vitamin D levels in Germans

Background The vitamin D system has been implicated in type I diabetes by epidemiological and immune intervention studies as well as by polymorphisms of the vitamin D binding protein (DBP) and CYP27B1 genes. CYP2R1, a cytochrome P450 enzyme, catalyzes the formation of vitamin D-3 to 25-hydroxyvitamin D-3 (25(OH)D-3), the main circulating vitamin D metabolite. Methods Two hundred and three simplex type 1 German diabetes families (609 subjects) were genotyped for the rs10741657 and for the rs12794714 polymorphisms. 25 (OH)D-3 levels were measured and correlated with CYP2R1 polymorphisms in 133 type 1 diabetes patients as well as its mRNA expression from peripheral blood mononuclear cells (PBMCs) in 58 type 1 diabetes patients. Frequencies and genotypes of the CYP2R1 polymorphisms were analyzed using Haploview software version 3.2. The correlation between 25(OH)D-3 and CYP2R1mRNA with the genotypes of the rs10741657 and rs12794714 polymorphism was evaluated by Wilcoxon-Mann-Whitney- and ANOVA test using Bias Statistical package 7.01. Results Whereas the rs12794714 polymorphism was not associated with type 1 diabetes the variant 'G' of the rs10741657 polymorphism was more often transmitted to affected offspring (61% vs; 39% P = 0.004) and was also more frequent in cases than in controls (46.1% vs 35.7%, P = 0.03). Patients carrying the genotype 'GG' or 'GA' of the rs10741657 polymorphism possessed, on average, lower levels of 25(OH)D3 compared to those with the genotype 'AA' (P = 0.003, Pc = 0.01 and P = 0.01, Pc = 0.04, respectively). Conclusion Thus, our findings reveal a novel association of CYP2R1 polymorphisms in patients with type I diabetes and with their circulating levels of 25(OH)D-3. Copyright (D 2007 John Wiley & Sons, Ltd.