CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans.
BACKGROUND
The vitamin D system has been implicated in type 1 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 D3 to 25-hydroxyvitamin D3 (25(OH)D3), 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)D3 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)D3 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).


CONCLUSIONS
Thus, our findings reveal a novel association of CYP2R1 polymorphisms in patients with type 1 diabetes and with their circulating levels of 25(OH)D3.
Ramos-Lopez
Elizabeth
E
Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Hospital Frankfurt, Frankfurt am Main, Germany.
Brück
Patrick
P
Jansen
Thomas
T
Herwig
Jürgen
J
Badenhoop
Klaus
K
D002648:Child; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D035781:Siblings; D014807:Vitamin D / Q000097:blood*
D012333:RNA, Messenger; D014807:Vitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase