title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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. aa22@aub.edu.lb.
authors.forename: A
authors.identifier: 0000-0001-6608-8242
authors.initials: A
authors.lastname: Arabi
authors.affiliation: Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon.
authors.forename: N
authors.initials: N
authors.lastname: Khoueiry-Zgheib
authors.affiliation: Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon.
authors.forename: Z
authors.initials: Z
authors.lastname: Awada
authors.affiliation: Division of Molecular Diagnostics, Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: R
authors.initials: R
authors.lastname: Mahfouz
authors.affiliation: Vascular Medicine Program and Scholars in Health Research Program, American University of Beirut, Beirut, Lebanon.
authors.forename: L
authors.initials: L
authors.lastname: Al-Shaar
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Hoteit
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Rahme
authors.affiliation: Department of Rheumatology, Saint Joseph University, Philadelphia, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Baddoura
authors.affiliation: Department of Endocrinology, Saint Joseph University, Beirut, Lebanon.
authors.forename: G
authors.initials: G
authors.lastname: Halabi
authors.affiliation: Mayo Clinic Foundation, Rochester, MN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.affiliation: 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. gf01@aub.edu.lb.
authors.forename: G
authors.initials: G
authors.lastname: El Hajj Fuleihan
mesh_terms: D000368:Aged; D002762:Cholecalciferol / Q000627:therapeutic use; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2 / Q000235:genetics*; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012621:Seasons; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D014808:Vitamin D Deficiency / Q000097:blood / Q000188:drug therapy / Q000235:genetics*
chemical_list: D014807:Vitamin D; D002762:Cholecalciferol; C104450:25-hydroxyvitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase
keywords: 25(OH) vitamin D; CYP2R1; Genetic polymorphisms; Metabolic pathway; Vitamin D supplementation