Activation (methylation) of CYP2R1 and CYP24A1 predict response to dose of vitamin D – Oct 2013

DNA Methylation Levels of CYP2R1 and CYP24A1 Predict Vitamin D Response Variation

The Journal of Steroid Biochemistry and Molecular Biology. online 12 October 2013
Yu Zhouc, d, e, 1, Lan-Juan Zhaoc, f, 1 lzhao2 at tulane.edu, Xiaojing Xuc, f,
An Yec, f, Dianne Travers-Gustafson f, Boting Zhou e, Hong-Wei Wang g,
Weidong Zhangc, L. Lee Hamm h, Hong-Wen Deng c, Robert R. Recker f, Joan M. Lappe f
c Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA, USA, 70112
d Cell and Molecular Biology Department, Tulane University, New Orleans, LA, USA, 70118
e Department of Pharmacy, Xiang-Ya Hospital of Central South University, Changsha, Hunan, China
f Osteoporosis Research Center, Creighton University, Omaha, NE, USA, 68131
g Department of Medicine, University of Chicago, Chicago, IL 60637
h School of Medicine, Tulane University, New Orleans, LA, USA, 70112

Highlights

• We examined the methylation levels of CYPs family in patients who had vitamin D supplementation.
• Baseline methylation level of CYP2R1 is negatively associated with vitamin D response variation.
• Baseline methylation level of CYP24A1 is negatively associated with vitamin D response variation.
• Baseline DNA methylation levels of CYP2R1 and CYP24A1 may 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.

(Free figures from the web)

Fig. 1.

Subject frequency distribution of the adjusted 12-month increase of serum 25(OH)D after 1,100 IU/day vitamin D supplementation. Eighteen responders and 18 non-responders were selected out of the extreme tails. Responders were defined as subjects who had the highest adjusted 12-month increase in serum 25(OH)D levels after vitamin D supplementation. Non-responders were subjects who had the lowest increase in adjusted serum 25(OH)D after vitamin D supplementation. Subjects in the validation study came from the remainder of the 446 subjects in the Calcium and Vitamin D Malnutrition in Elderly Women Study (CaMEWS).

Fig. 2.

Methylation levels in responders and non-responders at baseline and after a 12-month vitamin D supplementation. For the CYP2R1 gene, non-responders had significantly higher DNA methylation levels in the promoter region, compared to that in the responders at baseline and 12-month visit

• (A). DNA methylation level of the CYP24A1 gene was significantly higher in the non-responders compared to responders at baseline, but not at 12-month visit
• (B). DNA methylation level of the CYP24A1 gene was significantly reduced in both responders and non-responders at 12-month visit (B).
• For CYP27A1 and CY27B1, no significant differences were identified in DNA methylation levels between responders and non-responders at baseline or 12-month visit (C and D).

“R” denotes responders (n = 18) and “N” denotes non-responders (n = 18). Data are expressed as means ± SE.

Fig. 3.

Methylation levels of CYP2R1 and CYP24A1 at baseline and after a 12-month vitamin D supplementation. For the CYP2R1 gene, DNA methylation levels of each tested CpG site were significantly lower at the 12-month visit compared to the baseline visit (A and B ). For the CYP24A1 gene, CpG sites reacted differently to the vitamin D intervention. Among the 16 tested CpG sites, the DNA methylation levels significantly decreased in two CpG sites, and significantly increased in another eight sites; six were unchanged (C and D). Data are expressed as means ± SD.

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See also Vitamin D Life

• Search Vitamin D Life for CYP2R1 OR CYP24A1 603 items as of Feb 2015
• All items in Genetics and vitamin D 266 items
• CYP2R1 gene probably responsible for low vitamin D response – RCT April 2014
• CYP24A1 enzyme and Vitamin D
• 5.8 X more likely to die in 15 year followup if low vitamin D and poor methylation – July 2018
• 3X higher risk of oral cancer if CYP27B1 and CYP24A1 genes were different – May 2012
• 229 Genes related to vitamin D - Aug 2010 which contains the following graph

A 2010 paper on DNA methylation is attached at the bottom of the page

Talks about health problems, genes, but not vitamin D