Skip to main content
SpringerLink
Log in

CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

We studied the association between CYP2R1 genetic polymorphisms and circulating 25-hydroxyvitamin D [25(OH)D] before and after supplementation with vitamin D3 in 218 elderly. We found differences between 3 and 8 ng/ml in circulating levels at baseline in women but not in the response after 1 year of supplementation.

Introduction

This study evaluated the association between polymorphisms in four single nucleotide polymorphisms (SNPs) of the CYP2R1 gene and 25(OH)D levels before and 1 year after supplementation with two different doses of vitamin D3 (600 IU daily or a dose equivalent to 3750 IU daily), in a cohort of 218 (96 men and 122 women) Lebanese elderly overweight subjects.

Methods

Genotyping was performed for rs12794714, rs10741657, rs1562902, and rs10766197 SNPs using real-time PCR. The 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry.

Results

At baseline, the mean ± SD age was 71.0 ± 4.7 years, BMI 30.3 ± 4.6 kg/m2, and 25(OH)D level was 20.5 ± 7.6 ng/ml. There were significant differences in mean 25(OH)D levels between genotypes in women, but not in men. After adjustment for age, season, and BMI, the homozygous for the low frequency gene variant (HLV) of rs1562902 and rs10741657 SNPs had the highest mean 25(OH)D levels with difference of 7.6 ng/ml for rs1562902 SNP (p < 0.01) and of 5.9 ng/ml for rs10741657 (p = 0.05) compared to the homozygous for the major polymorphisms (HMPs). Conversely, for rs10766197 and rs12794714 SNPs, HMP had the highest mean 25(OH)D levels with difference of 6 ng/ml for rs10766197 (p = 0.003) and of 4.8 ng/ml (p = 0.02) for rs12794714, compared to the HLV. CYP2R1 genetic polymorphisms explained 4.8 to 9.8 % of variability in 25(OH)D in women. After 1 year, there was no difference in the response to vitamin D3 supplementation between genotypes in either gender.

Conclusion

This study showed a difference in 25(OH)D levels between CYP2R1 genotypes that equates a daily supplementation of 400–800 IU vitamin D, depending on genotype. It underscores possible important genetic contributions for the high prevalence of hypovitaminosis D in the Middle East.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mason RS, Sequeira VB, Gordon-Thomson C (2011) Vitamin D: the light side of sunshine. Eur J Clin Nutr 65:986–993

    Article  CAS  PubMed  Google Scholar 

  2. Ross C, Taylor CL, Yaktine AL, Del Valle HB (2011) Dietary reference intakes for calcium and vitamin D. National Academies Press, USA

    Google Scholar 

  3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930

  4. Holick MF (1994) Vitamin D: photobiology, metabolism and clinical application. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA (eds) The liver: biology and photobiology. Raven Press, New York, pp. 543–562

    Google Scholar 

  5. Awada Z, Ossaily S, Zgheib N (2014) The nutrigenetics and pharmacogenetics of vitamin d pathways. Current Pharmacogenomics and Personalized Medicine 12:89–103

    Article  CAS  Google Scholar 

  6. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003) De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 278:38084–38093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K (2004) Metabolism of vitamin D by human microsomal CYP2R1. Biochem Biophys Res Commun 324:451–457

    Article  CAS  PubMed  Google Scholar 

  8. Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF (2013) CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci U S A 110:15650–15655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, OReilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E, Spector TD (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376:180–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bouillon R (2010) Genetic and environmental determinants of vitamin D status. Lancet 376:148–149

    Article  PubMed  Google Scholar 

  11. Bu FX, Armas L, Lappe J, Zhou Y, Gao G, Wang HW, Recker R, Zhao LJ (2010) Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Hum Genet 128:549–556

    Article  CAS  PubMed  Google Scholar 

  12. Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19:2739–2745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Elkum N, Alkayal F, Noronha F, Ali MM, Melhem M, Al-Arouj M, Bennakhi A, Behbehani K, Alsmadi O, Abubaker J (2014) Vitamin D insufficiency in Arabs and South Asians positively associates with polymorphisms in GC and CYP2R1 genes. PLoS One 9:e113102

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K (2007) CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev 23:631–636

    Article  CAS  PubMed  Google Scholar 

  15. Simon KC, Munger KL, Kraft P, Hunter DJ, De Jager PL, Ascherio A (2011) Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis. J Neurol 258:1676–1682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang Z, He JW, Fu WZ, Zhang CQ, Zhang ZL (2013) An analysis of the association between the vitamin D pathway and serum 25-hydroxyvitamin D levels in a healthy Chinese population. J Bone Miner Res 28:1784–1792

    Article  CAS  PubMed  Google Scholar 

  17. Wjst M, Altmuller J, Braig C, Bahnweg M, Andre E (2007) A genome-wide linkage scan for 25-OH-D(3) and 1,25-(OH)2-D3 serum levels in asthma families. J Steroid Biochem Mol Biol 103:799–802

    Article  CAS  PubMed  Google Scholar 

  18. Jolliffe DA, Walton RT, Griffiths CJ, Martineau AR (2015) Single nucleotide polymorphisms in the vitamin D pathway associating with circulatingconcentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2015.12.007

  19. Ye Z, Sharp SJ, Burgess S, Scott RA, Imamura F, Langenberg C, Wareham NJ, Forouhi NG (2015) Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol 3:35–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Barry EL, Rees JR, Peacock JL, Mott LA, Amos CI, Bostick RM, Figueiredo JC, Ahnen DJ, Bresalier RS, Burke CA, Baron JA (2014) Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab 99:E2133–E2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nissen J, Vogel U, Ravn-Haren G, Andersen EW, Madsen KH, Nexo BA, Andersen R, Mejborn H, Bjerrum PJ, Rasmussen LB, Wulf HC (2015) Common variants in CYP2R1 and GC genes are both determinants of serum 25-hydroxyvitamin D concentrations after UVB irradiation and after consumption of vitamin D(3)-fortified bread and milk during winter in Denmark. Am J Clin Nutr 101:218–227

    Article  CAS  PubMed  Google Scholar 

  22. Sollid ST, Hutchinson MY, Fuskevag OM, Joakimsen RM, Jorde R (2016) Large individual differences in serum 25-hydroxyvitamin D response to vitamin D supplementation: effects of genetic factors, body mass index, and baseline concentration. Results from a randomized controlled trial. Horm Metab Res 48(1):27–34

    CAS  PubMed  Google Scholar 

  23. Arabi A, El RR, El-Hajj FG (2010) Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes. Nat Rev Endocrinol 6:550–561

    Article  CAS  PubMed  Google Scholar 

  24. El-Hajj FG, Nabulsi M, Choucair M, Salamoun M, Hajj SC, Kizirian A, Tannous R (2001) Hypovitaminosis D in healthy schoolchildren. Pediatrics 107:E53

    Article  Google Scholar 

  25. Bassil D, Rahme M, Hoteit M, Fuleihan G (2013) Hypovitaminosis D in the Middle East and North Africa: prevalence, risk factors and impact on outcomes. Dermatoendocrinol 5:274–298

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hoteit M, Al-Shaar L, Yazbeck C, Bou SM, Ghalayini T, Fuleihan G (2014) Hypovitaminosis D in a sunny country: time trends, predictors, and implications for practice guidelines. Metabolism 63:968–978

    Article  CAS  PubMed  Google Scholar 

  27. Gannage-Yared MH, Chemali R, Yaacoub N, Halaby G (2000) Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res 15:1856–1862

    Article  CAS  PubMed  Google Scholar 

  28. Lips P (2010) Worldwide status of vitamin D nutrition. J Steroid Biochem Mol Biol 121:297–300

    Article  CAS  PubMed  Google Scholar 

  29. Kuhn T, Kaaks R, Teucher B, Hirche F, Dierkes J, Weikert C, Katzke V, Boeing H, Stangl GI, Buijsse B (2014) Dietary, lifestyle, and genetic determinants of vitamin D status: a cross-sectional analysis from the European prospective investigation into cancer and nutrition (EPIC)-Germany study. Eur J Nutr 53:731–741

    Article  PubMed  Google Scholar 

  30. Signorello LB, Shi J, Cai Q, Zheng W, Williams SM, Long J, Cohen SS, Li G, Hollis BW, Smith JR, Blot WJ (2011) Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D levels among African Americans. PLoS One 6:e28623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Engelman CD, Fingerlin TE, Langefeld CD, Hicks PJ, Rich SS, Wagenknecht LE, Bowden DW, Norris JM (2008) Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. J Clin Endocrinol Metab 93:3381–3388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Arguelles LM, Langman CB, Ariza AJ, Ali FN, Dilley K, Price H, Liu X, Zhang S, Hong X, Wang B, Xing H, Li Z, Liu X, Zhang W, Xu X, Wang X (2009) Heritability and environmental factors affecting vitamin D status in rural Chinese adolescent twins. J Clin Endocrinol Metab 94:3273–3281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu W, Sun J, Wang W, Wang X, Jiang Y, Huang W, Zheng X, Wang Q, Ning Z, Pei Y, Nie M, Li M, Wang O, Xing X, Yu W, Lin Q, Xu L, Xia W (2014) Association of genetic variants of vit D binding protein (DBP/GC) and of the enzyme catalyzing its 25-hydroxylation (DCYP2R1) and serum vit D in postmenopausal women. Hormones (Athens) 13:345–352

    Google Scholar 

  34. Xu X, Mao J, Zhang M, Liu H, Li H, Lei H, Han L, Gao M, Vitamin D (2015) Deficiency in Uygurs and Kazaks is associated with polymorphisms in CYP2R1 and DHCR7/NADSYN1 genes. Med Sci Monit 21:1960–1968

    Article  PubMed  PubMed Central  Google Scholar 

  35. Robien K, Butler LM, Wang R, Beckman KB, Walek D, Koh WP, Yuan JM (2013) Genetic and environmental predictors of serum 25-hydroxyvitamin D concentrations among middle-aged and elderly Chinese in Singapore. Br J Nutr 109:493–502

    Article  CAS  PubMed  Google Scholar 

  36. Arabi A, Mahfoud Z, Zahed L, El-Onsi L, El-Hajj FG (2010) Effect of age, gender and calciotropic hormones on the relationship between vitamin D receptor gene polymorphisms and bone mineral density. Eur J Clin Nutr 64:383–391

    Article  CAS  PubMed  Google Scholar 

  37. Arabi A, Zahed L, Mahfoud Z, El-Onsi L, Nabulsi M, Maalouf J, Fuleihan G (2009) Vitamin D receptor gene polymorphisms modulate the skeletal response to vitamin D supplementation in healthy girls. Bone 45:1091–1097

    Article  CAS  PubMed  Google Scholar 

  38. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A 101:7711–7715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Levine M, Dang A, Ding C, Fischer P, Singh R, Thacher T (2007) Tropical rickets in Nigeria: mutation of the CYP2R1 gene encoding vitamin D 25-hydroxylase as a cause of vitamin D dependent rickets. Bone 40:S60–S61

    Article  Google Scholar 

  40. Dong Q, Miller WL (2004) Vitamin D 25-hydroxylase deficiency. Mol Genet Metab 83:197–198

    Article  CAS  PubMed  Google Scholar 

  41. Abdullah MA, Salhi HS, Bakry LA, Okamoto E, Abomelha AM, Stevens B, Mousa FM (2002) Adolescent rickets in Saudi Arabia: a rich and sunny country. J Pediatr Endocrinol Metab 15:1017–1025

    Article  PubMed  Google Scholar 

  42. Lafi ZM, Irshaid YM, El-Khateeb M, Ajlouni KM, Hyassat D (2015) Association of rs7041 and rs4588 polymorphisms of the vitamin D binding protein and the rs10741657 polymorphism of CYP2R1 with vitamin D status among Jordanian patients. Genet Test Mol Biomarkers 19:629–636

    Article  CAS  PubMed  Google Scholar 

  43. Al Mutair AN, Nasrat GH, Russell DW (2012) Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency. J Clin Endocrinol Metab 97:E2022–E2025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nissen J, Rasmussen LB, Ravn-Haren G, Andersen EW, Hansen B, Andersen R, Mejborn H, Madsen KH, Vogel U (2014) Common variants in CYP2R1 and GC genes predict vitamin D concentrations in healthy Danish children and adults. PLoS One 9:e89907

    Article  PubMed  PubMed Central  Google Scholar 

  45. El-Hajj Fuleihan G, Bouillon R, Clarke B, Chahtoura M, Cooper C, McClung M, Singh RJ (2015) Serum 25-hydroxyvitamin D levels: variability, knowledge gaps, and the concept of a desirable range. J Bone Miner Res 30:1119–1133

    Article  CAS  Google Scholar 

  46. Hassanein SI, Abu El Maaty MA, Sleem HM, Gad MZ (2014) Triangular relationship between single nucleotide polymorphisms in the CYP2R1 gene (rs10741657 and rs12794714), 25-hydroxyvitamin d levels, and coronary artery disease incidence. Biomarkers 19:488–492

    Article  CAS  PubMed  Google Scholar 

  47. Didriksen A, Grimnes G, Hutchinson MS, Kjaergaard M, Svartberg J, Joakimsen RM, Jorde R (2013) The serum 25-hydroxyvitamin D response to vitamin D supplementation is related to genetic factors, BMI, and baseline levels. Eur J Endocrinol 169:559–567

    Article  CAS  PubMed  Google Scholar 

  48. Nasreddine L, Naja F, Chamieh MC, Adra N, Sibai AM, Hwalla N (2012) Trends in overweight and obesity in Lebanon: evidence from two national cross-sectional surveys (1997 and 2009). BMC Public Health 12:798

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The study was supported by grants from the American University of Beirut, the Saint Joseph University, and the Lebanese National Council for Scientific Research. The authors would like to acknowledge study subjects for their participation, the nurse Hanadi Massalkhi at AUBMC, and the support staff from the community health centers sponsored by the Ministry of Public Health, as well as the research assistants from Hotel Dieu de France Hospital and Rafic Hariri Governmental Hospital.

Author information

Authors and Affiliations

  1. Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, Department of Internal Medicine, American University of Beirut-Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon

    A. Arabi, M. Hoteit, M. Rahme & G. El Hajj Fuleihan

  2. Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon

    N . Khoueiry-Zgheib & Z. Awada

  3. Division of Molecular Diagnostics, Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon

    R. Mahfouz

  4. Vascular Medicine Program and Scholars in Health Research Program, American University of Beirut, Beirut, Lebanon

    L. Al-Shaar

  5. Department of Rheumatology, Saint Joseph University, Philadelphia, PA, USA

    R. Baddoura

  6. Department of Endocrinology, Saint Joseph University, Beirut, Lebanon

    G. Halabi

  7. Mayo Clinic Foundation, Rochester, MN, USA

    R. Singh

Authors
  1. A. Arabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N . Khoueiry-Zgheib
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z. Awada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Mahfouz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Al-Shaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Hoteit
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Rahme
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Baddoura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Halabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G. El Hajj Fuleihan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A. Arabi or G. El Hajj Fuleihan.

Ethics declarations

The study was approved by the Institutional Review Board of the American University of Beirut. All subjects signed an informed consent before participation.

Conflicts of interest

None.

Additional information

Asma Arabi and Nathalie Khoueiry-Zgheib contributed equally to the manuscript.

Electronic supplementary material

Supplemental Table 1

(DOCX 27 kb)

Supplemental Table 2

(DOCX 31 kb)

Supplemental Table 3

(DOCX 28 kb)

Supplemental Table 4

(DOCX 25 kb)

Supplemental Table 5

(DOCX 33 kb)

Supplemental Figure 1

Box-plots showing the mean 25(OH)D levels in male group (N = 96) according to CYP2R1 genotypes, using (A) rs1562902, (B) rs10766197, (C) rs10741657, and (D) rs12794714SNPs. Solid black lines represent the median 25(OH)D levels whereas the dotted ones represent 20 ng/ml level. There was no significant difference in mean 25(OH)D levels between genotypes in any of the four SNPs in men. (DOCX 292 kb)

Supplemental Figure 2

LD plots with D’ values of the CYP2R1 gene in (A) the whole cohort, (B) females only, and (C) males only. The figures were generated by Haploview 4.2. Blocks were defined following the rules of solid spine LD. (DOCX 150 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arabi, A., Khoueiry-Zgheib, N..., Awada, Z. et al. CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation. Osteoporos Int 28, 279–290 (2017). https://doi.org/10.1007/s00198-016-3713-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-016-3713-5

Keywords

Search

Navigation