Differential frequency of CYP2R1 variants across populations reveals pathway selection for Vitamin D homeostasis

Abstract

Context: Normal vitamin D homeostasis is necessary to ensure optimal mineral metabolism. Dietary insufficiency of vitamin D and the lack of sunlight each have well understood roles in vitamin D deficiency; however, the extent to which common genetic variations in vitamin D metabolizing enzymes contribute to alterations in vitamin D homeostasis remains uncertain. Objective: To examine the possibility that common coding variation in vitamin D metabolizing enzymes alters vitamin D homeostasis we determined the effect of 44 nonsynonymous polymorphisms in CYP2R1, the vitamin D 25-hydroxylase, on enzyme function. Results: Twenty-one of these polymorphisms decreased activity, while 2 variants increased activity. The frequency of CYP2R1 alleles with decreased 25-hydroxylase activity is 3 in every 1000 Caucasians and 7 in every 1000 African Americans. In populations where exposure to sunlight is high, alleles with decreased function occur at a frequency as high as 8%. The pattern of selected variation as compared to nonselected variation is consistent with it being the result of positive selection for nonfunctional alleles closer to the equator. To examine this possibility, we examined the variation pattern in another protein in the vitamin D pathway, the vitamin D binding protein (GC protein). The pattern of selected variation in the GC protein as compared to nonselected variation is also consistent with it being the result of positive selection for nonfunctional alleles closer to the equator. Conclusions: CYP2R1 polymorphisms have important effects on vitamin D homeostasis, and the geographic variability of CYP2R1 alleles represents an adaptation to differential exposures to UVB irradiation from sunlight.