Single Nucleotide Polymorphisms In CYP2R1 Research Articles

Vitamin D levels and Vitamin D-related gene polymorphisms in Chinese children with type 1 diabetes.

Low vitamin D levels may play a role in type 1 diabetes (T1D) susceptibility. Since 25(OH)D synthesis is genetically regulated, single nucleotide polymorphisms (SNPs) of important genes have also been shown to modulate the risk of T1D, so this study aimed to investigate the relationship between five SNPs in CYP2R1, DHCR7, CYP24A1, VDR genes, serum 25(OH)D levels and T1D in Chinese children. This case-control study included 141 T1D patients and 200 age-matched healthy children.25 (OH) D concentration was determined, genotyping was performed by High resolution melting (HRM). There was a significant difference in the prevalence of vitamin D deficiency, insufficiency, and sufficiency between T1D and healthy controls. (χ2 = 10.86, p = 0.004), however no evidence of the association between any group of SNPs and circulating 25(OH) D levels was observed. The allele distribution of CYP2R1(rs1993116) was significantly different between T1D and control group (p = 0.040), and the C allele carriers of rs1993116 had a higher risk of T1D than the T allele carriers, Carriers of the CC and CT genotypes of rs1993116 have higher T1D risk than those carrying the TT genotype. GMDR analysis revealed a significant interaction between CYP2R1(rs12794714) and CYP2R1(rs1993116) in the risk of T1D with a maximum testing balance accuracy of 60.39%.

SNP rs12794714 of CYP2R1 is associated with serum vitamin D levels and recurrent spontaneous abortion (RSA): a case-control study.

Vitamin D (VD) deficiency seems to be associated with the risk of recurrent spontaneous abortion (RSA). Vitamin D receptor (VDR) and cytochrome P450 family 2 subfamily R member 1 (CYP2R1) are two genes which are vital for VD metabolism and actions. However, whether single-nucleotide polymorphisms (SNPs) in these genes are correlated with the risk of RSA are poorly understood. Therefore, we aimed to characterize the relationships among VDR SNPs, CYP2R1 SNPs and RSA. This case-control study enrolled 75 RSA patients and 83 controls. Serum VD and some cytokines were detected with LC-MS/MS and flow cytometry, respectively. Genotyping for three SNPs of CYP2R1 (rs10741657, rs10766197 and rs12794714) and five SNPs of VDR (rs7975232, rs1544410, rs2189480, rs2228570 and rs2239179) was done with polymerase chain reaction (PCR) and high-throughput sequencing. All the data were analyzed with appropriate methods and in different models. The results revealed a significant correlation between the AG genotype of CYP2R1 rs12794714 and VD levels (OR 0.686; 95% CI 0.49-0.96; p = 0.028). Besides, the AG and GG genotypes of CYP2R1 rs12794714 were markedly related to the risk of RSA (OR 52.394, 59.497; 95% CI 2.683-1023.265, 3.110-1138.367; p = 0.009, 0.007, respectively). Our results indicate that CYP2R1 rs12794714 might be a risk factor for RSA. Hence, early screening of pregnant women for CYP2R1 rs12794714 is necessary to warrant proactive counseling and treatment against RSA.

Association of vitamin D deficiency with vitamin D binding protein (DBP) and CYP2R1 polymorphisms in Iranian population

BackgroundMicronutrients are crucial for the promotion of human's well-being via the biological processes. Vitamin D is one of the most important ones with its vital role in calcium homeostasis in our body. Vitamin D deficiencies would definitely bring about various skeletal and non-skeletal disorders. In this study we have assessed the influence of two single-nucleotide polymorphisms (SNPs) of GC gene (vitamin D binding protein gene), and one of the CYP2R1 (Vitamin D 25-Hydroxylase enzyme), on vitamin D deficiency and insufficiency. Methods196 healthy adults' Iranian population (the real Persian race living in Fars province) cases were participated in this study, dividing into three groups of: normal, deficient and insufficient, considering their vitamin D concentration. The blood specimen was obtained and DNA was extracted from leukocytes. Following this, restricted fragment length polymerase chain reaction (RFLP-PCR) was used for genotyping throughout the processes and two SNPs of DBP (vitamin D binding protein), rs4588 and rs7041, and one of CYP2R1, rs10741657, were assessed. Meanwhile, we have evaluated the serum levels of 25-Hydroxy vitamin D3 with ELISA method. ResultsThe results showed no significant differences between three aforementioned groups in terms of seven various nature-nurture factors. Between three SNPs which were genotyped and assessed, rs7041 was the one that have drawn a significant distinction between groups. Its GT and TT genotypes were remarkably higher in insufficient and deficient groups respectively. Moreover, four haplotypes of rs4588 and rs7041 were evaluated and CT and AT ones illustrated a dramatic frequency rates in deficient and insufficient groups in turn. Neither of the remaining haplotypes (CG, AG) revealed significant frequencies among the groups though. ConclusionWe have concluded that both DBP and CYP2R1 SNPs could be effective for the regulation of vitamin D levels, however rs7041 and its genotypes was by far the most effective ones in vitamin D deficiencies.

Polymorphisms in the vitamin D system and mortality – The Tromsø study

Vitamin D deficiency is associated with diabetes, cancer, immunological and cardiovascular diseases as well as increased mortality. It has, however, been difficult to show a causal relation in randomized, controlled trials. Mendelian randomization studies provide another option for testing causality, and results indicate relations between the serum 25-hydroxyvitamin D (25(OH)D) level and some diseases, including mortality. We have from the Tromsø Study in 2012 published non-significant relations been vitamin D related single nucleotide polymorphisms (SNPs) and mortality, but have since then genotyped additional subjects, the observation time is longer and new SNPs have been included. For the present study genotyping was performed for SNPs in the NADSYN1, CYP2R1, GC and CYP24A1, VDR, CUBILIN and MEGALIN genes in 11 897 subjects who participated in the fourth survey of the Tromsø Study in 1994–1995. Serum 25(OH)D levels were measured in 6733 of these subjects. Genetic scores based on SNPs related to the serum 25(OH)D level (NADSYN1 and CYP2R1 SNPs (synthesis score) and GC and CYP24A1 SNPs (metabolism score)) and serum 25(OH)D percentile groups were created. Mortality data was updated till end of March 2017 and survival analysed with Cox regression adjusted for sex and age. During the observation period 5491 subjects died. The 25(OH)D synthesis (but not the metabolism) genetic score and the serum 25(OH)D percentile groups were (without Bonferroni correction) significantly related to mortality in favour of high serum 25(OH)D. None of the SNPs in the VDR or MEGALIN genes were related to mortality. However, for the rs12766939 in the CUBILIN gene with the major homozygote as reference, the hazard ratio for mortality for the minor homozygote genotype was 1.17 (1.06–1.29), P < 0.002. This should be viewed with caution, as rs12766939 was not in Hardy-Weinberg equilibrium. In conclusion, our study confirms a probable causal but weak relation between serum 25(OH)D level and mortality. The relation between rs12766939 and mortality needs confirmation in more homogenous cohorts.

Association of VDBP and CYP2R1 gene polymorphisms with vitamin D status in women with polycystic ovarian syndrome: a north Indian study.

Polycystic ovarian syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age and is usually associated with oligo-ovulation/anovulation, obesity, and insulin resistance. Hypovitaminosis D may also be a primary factor in the initiation and development of PCOS. However, little is known about the role of genetic variation in vitamin D metabolism in PCOS aetiology. Therefore, we studied the genetic polymorphisms of CYP2R1 and vitamin D binding protein (VDBP) in an Indian population. Serum vitamin D was measured by ELISA. Genotyping of VDBP single nucleotide polymorphisms (SNPs) rs7041 (HaeIII; G>T) and rs4588 (StyI; A>C) and CYP2R1 SNP rs2060793 (HinfI; A>G) was carried out by restriction fragment length polymorphism in 50 cases of PCOS that were compared with 50 age-matched healthy women. Vitamin D levels were found to be significantly lower in women with PCOS (p=0.008) than in age-matched controls. There was no significant difference in genotype frequencies of all three polymorphisms (rs7041, rs4588, and rs2060793) between PCOS and control women. In women with a vitamin D deficiency (<20ng/ml), the GT allele of the VDBP SNP rs7041 (p value =0.04), the VDBP allelic combination Gc1F/1F (T allele of rs4588 and C allele of rs7041) (p value =0.03), and the GA allele of the CYP2R1 SNP rs2060793 (p=0.05) were associated with an increased risk of developing PCOS. The present study shows that the GT allele of VDBP SNP rs7041, the VDBP allelic combination (GC1F/1F), and GA allele of CYP2R1 SNP rs2060793 in vitamin D deficient women increase the risk of PCOS.

Vitamin D deficiency associates with susceptibility to tuberculosis in Pakistan, but polymorphisms in VDR, DBP and CYP2R1 do not.

BackgroundSingle nucleotide polymorphisms (SNPs) in the genes encoding the vitamin D receptor (VDR) and the vitamin D binding protein (DBP) have been reported to modify the influence of vitamin D deficiency on susceptibility to active tuberculosis (TB) in the UK, but this phenomenon has not been investigated in settings with a high TB burden. SNPs in CYP2R1, which encodes a vitamin D 25-hydroxylase enzyme, are known to influence vitamin D status, but their potential role in determining susceptibility to TB has not previously been investigated in any setting.MethodWe conducted a case–control study in 260 pulmonary TB patients and 112 controls recruited in Lahore, Pakistan. Analyses were conducted to test for main effects of vitamin D status and SNPs in VDR (rs731236, rs2228570 and rs1544410), DBP (rs7041 and rs4588) and CYP2R1 (rs2060793, rs10500804 and rs10766197) on susceptibility to TB, and to investigate whether these SNPs modify the association between vitamin D status and disease susceptibility.ResultsProfound vitamin D deficiency (serum 25-hydroxyvitamin D concentration ≤ 20 nmol/L) was common among TB patients (118/260, 45 %), and was independently associated with susceptibility to TB (adjusted odds ratio 1.87, 95 % CI 1.15 to 3.04, P = 0.01). However, none of the SNPs investigated associated with susceptibility to TB, either in main effects analysis, or in interaction with vitamin D status.ConclusionProfound vitamin D deficiency was common among TB patients in this high-burden setting, and was independently associated with disease susceptibility. However, no statistically significant associations between SNPs in the vitamin D pathway and disease susceptibility was demonstrated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0240-2) contains supplementary material, which is available to authorized users.

Common vitamin D pathway gene variants reveal contrasting effects on serum vitamin D levels in African Americans and European Americans.

Vitamin D deficiency is more common among African Americans (AAs) than among European Americans (EAs), and epidemiologic evidence links vitamin D status to many health outcomes. Two genome-wide association studies (GWAS) in European populations identified vitamin D pathway gene single-nucleotide polymorphisms (SNPs) associated with serum vitamin D [25(OH)D] levels, but a few of these SNPs have been replicated in AAs. Here, we investigated the associations of 39 SNPs in vitamin D pathway genes, including 19 GWAS-identified SNPs, with serum 25(OH)D concentrations in 652 AAs and 405 EAs. Linear and logistic regression analyses were performed adjusting for relevant environmental and biological factors. The pattern of SNP associations was distinct between AAs and EAs. In AAs, six GWAS-identified SNPs in GC, CYP2R1, and DHCR7/NADSYN1 were replicated, while nine GWAS SNPs in GC and CYP2R1 were replicated in EAs. A CYP2R1 SNP, rs12794714, exhibited the strongest signal of association in AAs. In EAs, however, a different CYP2R1 SNP, rs1993116, was the most strongly associated. Our models, which take into account genetic and environmental variables, accounted for 20 and 28 % of the variance in serum vitamin D levels in AAs and EAs, respectively.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-014-1472-y) contains supplementary material, which is available to authorized users.

Environmental, Personal, and Genetic Determinants of Response to Vitamin D Supplementation in Older Adults

Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

Vitamin D Intake and Season Modify the Effects of the GC and CYP2R1 Genes on 25-Hydroxyvitamin D Concentrations

Vitamin D deficiency {defined by the blood concentration of 25-hydroxyvitamin D [25(OH)D]} has been associated with many adverse health outcomes. Genetic and nongenetic factors account for variation in 25(OH)D, but the role of interactions between these factors is unknown. To assess this, we examined 1204 women of European descent from the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative Observational Study. Twenty-nine single nucleotide polymorphisms (SNPs) in 4 genes, GC, CYP2R1, DHCR7, and CYP24A1, from recent meta-analyses of 25(OH)D genome-wide association studies were genotyped. Associations between these SNPs and 25(OH)D were tested using generalized linear regression under an additive genetic model adjusted for age, blood draw month, and ancestry. Results were stratified by season of blood draw and, separately, vitamin D intake for the 6 SNPs showing a significant association with 25(OH)D at the P < 0.01 level. Two nonsynonymous SNPs in GC and 4 SNPs in CYP2R1 were strongly associated with 25(OH)D in individuals whose blood was drawn in summer (P ≤ 0.002) but not winter months and, independently, in individuals with vitamin D intakes ≥400 (P ≤ 0.004) but not <400 IU/d (10 μg/d). This effect modification, if confirmed, has important implications for the design of genetic studies for all health outcomes and for public health recommendations and clinical practice guidelines regarding the achievement of adequate vitamin D status.

Associations Between Genetic Variants in Vitamin D Metabolism and Asthma Characteristics in Young African Americans

IntroductionLow vitamin D levels have been associated with asthma severity in children. Young, urban African Americans (AAs) have high rates of hypovitaminosis D and asthma. Our objective was to determine...

A rare haplotype of the vitamin D receptor gene is protective against diabetic nephropathy

Vitamin D and its analogues are reported to have renoprotective effects in chronic kidney disease including diabetic nephropathy (DN). Vitamin D(3) is converted to 1,25(OH)D(3) by CYP2R1 and CYP27B1. The biological action of 1,25(OH)D(3) is mediated via its receptor. VDR, CYP27B1 or CYP2R1 gene variants could modify the biological activity of vitamin D(3). We have conducted the first case-control association study to determine the relationship between polymorphisms in VDR, CYP27B1 and CYP2R1 genes, and the risk of DN in individuals with type 1 diabetes. Eight VDR single-nucleotide polymorphisms (SNPs) rs10735810 FokI C>T, rs1544410 BsmI G>A, rs7975232 ApaI G>T, rs731236 TaqI T>C, rs4303288 G>T, rs11168275 C>T, rs12721366 G>A and rs2544043 G>C were investigated with CYP27B1 rs4646536 T>C and CYP2R1 rs10741657 G>A. Genotyping was performed using pyrosequencing, Taqman, Sequenom or direct sequencing technologies in 1329 type 1 diabetics (655 nephropaths, 674 non-nephropaths). No significant differences were observed in genotype or allele frequencies between case and control groups for VDR, CYP27B1 or CYP2R1 SNPs, either before or after stratification by recruitment centre or when restricted to patients with end-stage renal disease. A previously identified haplotype block from rs1544410 to rs731236 was confirmed at the 3'-end of VDR. Comparison of haplotype frequencies identified the rare AGT haplotype as significantly protective against DN, 3.1% cases versus 5.8% controls; chi(2) = 11.05, Pc = 0.009 by the permutation test. Our study has identified a rare VDR haplotype that is protective against DN in patients with type 1 diabetes. Replication in a large, independent cohort is required to confirm this finding.