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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.

Image
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.

Image
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.

Image
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.


See also VitaminDWiki

see the wiki for review and link to the PDF: http://www.vitamindwiki.com/tiki-index.php?page_id=794

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

Talks about health problems, genes, but not vitamin D

Attached files

ID Name Comment Uploaded Size Downloads
3149 Methylation 2010.pdf admin 17 Oct, 2013 268.10 Kb 1679
3148 Methy F3.jpg admin 17 Oct, 2013 37.93 Kb 1315
3147 Methy F2.jpg admin 17 Oct, 2013 30.01 Kb 1443
3146 Methy F1.jpg admin 17 Oct, 2013 24.96 Kb 1434