Genetic Variation in Cytochrome P450 2R1 and Vitamin D Binding Protein Genes are associated with Vitamin D Deficiency in Adolescents.

Background: Genome Wide Association Studies (GWAS) have evaluated several genes related to vitamin D synthesis, metabolism and transport. They have proposed a genetic basis for low levels of vitamin D in the blood. The current study aims to investigate the relationship between certain vitamin D-associated gene variants and vitamin D deficiency in Iranian adolescents. Methods: In this case-control study, the genomic DNA was extracted by Real Time PCR High Resolution Melt (HRM). All measurements were carried out with triple repetition. The following factors were assessed: single nucleotide polymorphisms (SNPs) in Vitamin D binding protein (DBP, rs2282679), 7-Dehydrocholesterol reductase (DHCR7, rs12785878) and Cytochrome P450 2R1 (CYP2R1, rs10741657). Results: the genomic DNA of blood samples obtained from 481 adolescents. Participants with hypovitaminosis D were compared with a control group. The average vitamin D level of sufficient subjects (controls) was 44.88±14.01 ng/mL, while subjects who were insufficient (cases) had an average vitamin D level of 7.03±1.24 ng/mL. No statistically significant differences were found in the allelic and genotypic distributions between genders. The SNP frequency in CYP2R1 (rs10741657) and DBP (rs2282679) in the vitamin D deficient group was significantly higher than in the control group (p-values < 0.001 and 0.01 respectively). There were no statistically significant differences in the DHCR7 SNP (rs12785878) distributions between the Vitamin D deficient group and control group. Conclusion: The present study demonstrated evidence of the ability of the SNPs under investigation to predict circulating vitamin D concentration. Further study is needed to better understand if and how genetic factors contribute to vitamin D levels, and certain skeletal-associated disorders in adolescents.

A variant in CYP2R1 predicts circulating vitamin D levels after supplementation with high-dose of vitamin D in healthy adolescent girls.

AIM: The determinants of serum vitamin D seems to be the environmental factors (dietary and supplementary intake and exposure to ultraviolet light) and genetic factors. We aimed to study the relationship between a vitamin D-associated genetic polymorphism and serum 25(OH)D concentrations in healthy adolescent girls in Iran, and its effects on a high-dose supplement of vitamin D. MATERIAL AND METHOD: A total of 616 healthy adolescent girls with mean age 15 received 50,000 IU of vitamin D3 weekly over 9 weeks. Serum vitamin D levels and other metabolic factors were measured at baseline and after the intervention. The genotyping of the CYP2R1 variant (rs10741657) was performed by TaqMan genotyping assays. RESULTS: Regardless of the genetic background, at baseline, 87% of adolescent girls were vitamin D deficient (serum 25(OH)D level < 50 nmol/l). High-dose supplementation with VitD reduced the proportion of girls who were deficient substantially to about 24%. The genetic analysis revealed that although at baseline there was not a gene-vitamin D association ( p trend = 0.1), the response to supplementation appeared to be modulated by this variant ( p trend < 0.001). However, other anthropometric and biochemical measures were not affected by this intervention, over this short period. Serum 25(OH)D was increased in all participants although the carriers of the minor A allele seemed to be better responders so that the percentages of the change serum vitamin D in the holder of AA and AG genotypes were 539.4 ± 443.1 and 443.7 ± 384.6, respectively, compared with those with common GG genotype (363.3 ± 354.0). Our regression analysis revealed that the probability of an increase in serum 25(OH)D in a participant with AA genotype was 2.5-fold greater than those with a GG genotype (OR = 2.5 (1.4-4.4); p value = 0.002). CONCLUSION: Based on our findings, it appears that the rs10741657 variant of the CYP2R1 gene modulates the response to high-dose of vitamin D supplementation.

Vitamin D Related Gene Polymorphisms and Cholesterol Levels in a Mediterranean Population.

In addition to its role in bone health, vitamin D (VitD) has been implicated in several pathological conditions. Specifically, VitD deficiency has been linked to an increased risk of dyslipidemia. Atherogenic dyslipidemia is characterized by increased low-density lipoprotein-cholesterol (LDL-C) and decreased high-density lipoprotein-cholesterol (HDL-C). In this study, we examined the association of six single nucleotide polymorphisms (SNPs) in VitD-related genes with VitD and lipid levels, in a cohort of 460 Lebanese participants free from chronic diseases. Our results showed no association of the examined SNPs with VitD concentrations. However, the presence of the minor allele in rs10741657G>A of CYP2R1 was associated with increased levels in LDL-C (ß = 4.95, p = 0.04)] and decreased levels in HDL-C (ß = −1.76, p = 0.007)]. Interestingly, rs10741657G>A interacted with gender to increase LDL-C levels in females (ß = 6.73 and p = 0.03) and decrease HDL-C levels in males HDL-C (ß = −1.09, p = 0.009). In conclusion, our results suggest that rs10741657 G>A in CYP2R1 is associated with circulating LDL-C and HDL-C levels in a Lebanese cohort. Although this association was gender-specific, where rs10741657G>A was associated with increased LDL in females and decreased HDL in males, the presence of the minor allele A was associated with increased cardiovascular risk in both genders. These findings need to be validated in a larger population. Further investigations are warranted to elucidate the molecular mechanism of VitD polymorphism and dyslipidemia.

Genetic Variation in CYP2R1 and GC Genes Associated With Vitamin D Deficiency Status.

This cross-sectional study enrolled 180 patients at a private family practice in Virginia. Total serum vitamin D concentrations were obtained weekly from January 30, 2013, through March 30, 2013, in consecutive patients regularly scheduled for laboratory work at the practice. Patients were categorized into 2 groups and analyzed for variant alleles in vitamin D receptor ( VDR; rs2228570), cytochrome P450 2R1 ( CYP2R1; rs10741657), 7-dehydrocholesterol reductase ( DHCR7; rs12785878), and group-specific component ( GC; rs2282679) to determine whether variants of those alleles influenced total serum 25(OH)D concentrations. One-hundred and eighty patients were enrolled, with 40 (22%) being sufficient, 25-hydroxy vitamin D level 25(OH)D ≥ 30 ng/mL, and 140 (78%) being insufficient, 25(OH)D < 30 ng/mL. Of the 4 genes, 2 genes, CYP2R1 (rs10741657) and GC (rs2282679), demonstrated a significant association related to vitamin D status. Subjects with 1 or more variant alleles at rs10741657 were almost 3.7 (odds ratio [OR] 3.67; 95% confidence interval [CI]: 1.35-9.99) times more likely be insufficient in vitamin D and subjects with 1 or more variant alleles at rs2282679 were about half (OR 0.42; 95% CI: 0.18-0.93) as likely to be insufficient in vitamin D. Allelic variations in CYP2R1 (rs10741657) and GC (rs2282679) affect vitamin D levels, but variant alleles on VDR (rs2228570) and DHCR7 (rs12785878) were not correlated with vitamin D deficiency, 25(OH)D < 30 ng/mL.