DNA methylation levels of CYP2R1 and CYP24A1 predict vitamin D response variation

Factors contributing to the variability of serum 25-hydroxyvitamin D [25(OH)D] in response to a given dose of vitamin D supplementation are largely unknown. We examined whether DNA methylation levels of Cytochrome P450 (CYP) enzymes (CYP2R1, CYP24A1, CYP27A1, and CYP27B1) are potential biomarkers predicting vitamin D response variation. We randomized 446 white postmenopausal women to a calcium and vitamin D (1100 IU/day) intervention for at least 12 months. From these subjects, 18 with the highest 12-month increase in serum 25(OH)D were selected as "responders." Another 18 with the lowest 12-month increase in serum 25(OH)D were selected as "non-responders." DNA methylation levels between the groups were compared. To validate findings in the first study, association between DNA methylation levels and vitamin D response variation was studied in another 145 extended independent white postmenopausal women. In the first study, compared to non-responders, responders had significantly lower baseline DNA methylation levels in the promoter region of CYP2R1 (8% in the responders vs. 30% in the non-responders, P = 0.004), and CYP24A1 (13% in the responders vs. 32% in the non-responders, P = 0.001). In the validation study, for CYP2R1, baseline DNA methylation levels at eight CpG sites were negatively associated with 12-month increases in serum 25(OH)D (P <0.05). For CYP24A1, baseline DNA methylation levels at two CpG sites were also negatively associated with vitamin D response variation (r = -0.151, P = 0.011; r = -0.131, P = 0.025). These negative associations were consistent with the first study's results. Our findings indicate that baseline DNA methylation levels of CYP2R1 and CYP24A1 may predict vitamin D response variation. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.