CYP24A1 Rs6013897 Research Articles

DHCR7 rs12785878 T>C Polymorphism Is Associated With an Increased Risk of Early Onset of Alzheimer's Disease in Chinese Population

Background: Vitamin D insufficiency has been considered a risk factor for Alzheimer's disease (AD) in several studies. Recently, four single-nucleotide polymorphisms (SNPs) to be genome-wide significant for 25-hydroxyvitamin D [25(OH)D] were identified to have an association with the risk of AD. These include GC rs2282679 A>C, CYP2R1 rs10741657 T>C, DHCR7 rs12785878 T>C, and CYP24A1 rs6013897 T>A. However, the association between these polymorphisms and AD susceptibility in the Chinese population remains unclear.Methods: A case-control cohort study was conducted in 676 AD patients (mean age at onset was 69.52 ± 10.90 years, male: 39.2%) and 551 healthy controls (mean age was 67.73 ± 6.02 years, male: 44.8%). Genotyping was determined by PCR and SNaPshot sequencing. To determine whether the four SNPs account for risks in AD in Chinese population, multivariate logistic regression models were performed. Stratified analysis was performed based on gender and age of onset of AD, separately. Statistical significance was set at 0.0125 (0.05/4) based on Bonferroni correction.Findings: DHCR7 rs12785878 T>C was found to be significantly associated with an increased risk of early-onset Alzheimer's disease (EOAD) (n = 300, risk allele C, adjusted OR = 1.542, adjusted 95% CI = 1.176–2.023, p = 0.002). There was no statistical significance of the other three SNPs between the two groups.Interpretation: Our results suggested that DHCR7 rs12785878 T>C might be associated with an increased risk of EOAD in the Chinese population, while other polymorphisms related to vitamin D insufficiency might not be. However, due to the limited data in this study, replication studies in a larger sample are required.

Brief Report: CYP27B1 rs10877012 T Allele Was Linked to Non-AIDS Progression in ART-Naïve HIV-Infected Patients: A Retrospective Study.

HIV/AIDS progression is linked to vitamin D, which is regulated by several key cytochromes P450 (CYP). Single nucleotide polymorphisms (SNPs) in CYP genes influence vitamin D metabolism and serum levels. The objective of this study was to evaluate the association between CYP SNPs and the clinical AIDS progression in antiretroviral treatment (ART)-naïve HIV-infected patients. We performed a retrospective study in 661 ART-naïve HIV-infected patients who were stratified by their AIDS progression pattern [181 long-term nonprogressors (LTNPs), 332 moderate progressors, and 148 rapid progressors (RPs)]. Four CYP SNPs (CYP2R1 rs10500804, CYP2R1 rs1993116, CYP27B1 rs10877012, and CYP24A1 rs6013897) were genotyped using Agena Bioscience's MassARRAY platform. Correction for multiple testing was performed using the false discovery rate (Benjamini-Hochberg procedure). The adjusted regression showed a significant association only for CYP27B1 rs10877012 SNP. When analyzing all HIV patients, the rs10877012 T allele was protective against AIDS progression (ordinal outcome) under the dominant [adjusted odds ratio (aOR) = 0.69; P = 0.021) and additive (aOR) = 0.75; P = 0.025] inheritance models. When analyzing LTNPs versus RPs, the rs10877012 T allele also showed a significant protective association under the dominant (aOR = 0.45; P = 0.004) and additive (aOR = 0.54; P = 0.008) inheritance models. P values remained significant after correcting by multiple comparisons only for the comparison of LTNPs versus RPs (extreme phenotypes). The CYP27B1 rs10877012 T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients. The rs10877012 SNP seems to have an impact on the clinical AIDS progression, possibly modifying vitamin D levels, which could be relevant for the pathogenesis of HIV infection.

Dietary Vitamin D, Vitamin D Metabolism-Related Gene Polymorphisms and Colorectal Cancer Risk in a Chinese Case-Control Study

Abstract Objectives Vitamin D has anticarcinogenic properties. Vitamin D metabolism-related gene polymorphisms can influence vitamin D levels and its impact on carcinogenesis. This study aimed to explore the independent and combined effects of dietary vitamin D and vitamin D metabolism-related gene polymorphisms on colorectal cancer risk in a Chinese population. Methods Incident cases with histologically confirmed colorectal cancer, and sex and age-matched controls were recruited in this ongoing case-control study. Of them, 488 cases and 496 controls were both successfully interviewed and collected blood samples. Vitamin D intake was assessed by a validated food frequency questionnaire. Genotyping was performed for CYP2R1 rs10741657, CYP2R1 rs12794714, CYP24A1 rs6013897, CYP24A1 rs6068816, CYP27B1 rs4646536 and GC rs7041 by using an improved multiplex ligation detection reaction (iMLDR) technique. Unconditional multivariable logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI) after adjusting for various confounders. Results Higher intake of dietary vitamin D was associated with 47% reduction in colorectal cancer with OR of 0.53 (95% CI: 0.34, 0.82) for the highest quartile (vs. lowest quartile) intake. Compared with persons with CYP24A1 rs6068816 CC genotype, lower risk of colorectal cancer was observed among carriers of TT genotype (OR = 0.57, 95%CI 0.36, 0.89). No significant association was found between CYP2R1 rs10741657, CYP2R1 rs12794714, CYP24A1 rs6013897, CYP27B1 rs4646536, GC rs7041 and colorectal cancer risk. No significant interaction was observed between dietary vitamin D intake and six examined single nucleotide polymorphisms on the risk of colorectal cancer. Conclusions Our study supports a protective effect of high intake of dietary vitamin D on colorectal cancer. CYP24A1 rs6068816 TT genotype was significantly associated with a decreased risk of colorectal cancer. No interaction was observed between dietary vitamin D intake and six examined single nucleotide polymorphisms in a Chinese population. Funding Sources Guangdong Natural Science Foundation (No: 2019A1515011931).

Association of Vitamin D Pathway Genetic Variation and Thyroid Cancer.

Vitamin D is mostly known for its role in bone and calcium metabolism. However, studies have suggested that it also has inhibitory effects on tumor development and progression. Genetic variants close to genes that encode crucial enzymes for the synthesis (DHCR7 rs12785878), metabolism (CYP2R1 rs2060793) and degradation (CYP24A1 rs6013897) of vitamin D have been associated with serum levels of vitamin D. The aim of this case-control study was to determine the effect of these variants in the vitamin D pathway on the susceptibility to thyroid cancer. Five hundred patients with differentiated thyroid cancer and 500 controls were genotyped for the DHCR7 rs12785878, CYP2R1 rs2060793, and CYP24A1 rs6013897 variants. Genotype and allele frequencies were compared between patients and controls. The DHCR7 rs12785878 minor allele was associated with thyroid cancer under an additive (OR 1.38, 95% CI 1.15–1.65, p = 0.0004) and codominant (OR 1.88, 95% CI 1.30–2.74, p = 0.0021) model. These findings suggest that DHCR7 polymorphisms may be associated with an increased risk of thyroid cancer due to an effect of this gene on circulating vitamin D levels.

Association of circulating 25-hydroxyvitamin D levels with hypertension and blood pressure values in Korean adults: A Mendelian randomization study on a subset of the Korea National Health and Nutrition Survey 2011-2012 population.

BACKGROUND/OBJECTIVESLower circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with a higher risk of hypertension (HTN); however, it remains unclear whether the relationship is causal. We aimed to evaluate the causal effects of circulating 25(OH)D levels on the prevalence of HTN in the Korean population using the Mendelian randomization (MR) approach.SUBJECTS/METHODSEpidemiological data, serum 25(OH)D data, and genomic DNA biospecimens were obtained from 2,591 participants, a subset of the study population in the Korea National Health and Nutrition Survey 2011-2012. Five 25(OH)D-related single nucleotide polymorphisms (SNPs; DHCR7 rs12785878, CYP2R1 rs10741657, CYP2R1 rs12794714, CYP24A1 rs6013897, and GC rs2282679), identified a priori from genome-wide association studies, were used as instrument variables (IVs) for serum 25(OH)D levels. In the MR analysis, we performed IV analyses using the two-stage least squares method.RESULTSIn the observational analysis, circulating 25(OH)D levels were found to be inversely associated with the HTN prevalence in ordinary least squares models (odds ratio: 0.97, 95% confidence interval: 0.96, 0.99) after adjusting for the potential confounders. There were differences in the circulating 25(OH)D levels across genotypes of individual SNPs. In the MR analysis, using individual SNPs as IVs, 25(OH)D levels were not associated with the HTN prevalence.CONCLUSIONSWe found no association between genetically determined circulating 25(OH)D levels and HTN in Korean adults. Our results are listed owing to the relatively small sample size and possible weak instrument bias; therefore, further studies are needed to confirm these results.

Association among genetic variants in the vitamin D pathway and circulating 25-hydroxyvitamin D levels in Korean adults: results from the Korea National Health and Nutrition Examination Survey 2011-2012.

Vitamin D deficiency affects >60% of the Korean population. Recent reports in Caucasian, African American, and Chinese populations indicate an association between vitamin D status and related single nucleotide polymorphisms (SNPs), but specific associations differ among study populations. We investigated the relationship between five SNPs involved in the vitamin D metabolic pathway (DHCR7 rs12785878, GC rs2282679, CYP2R1 rs12794714, CYP2R1 rs10741657, and CYP24A1 rs6013897) and serum 25-hydroxyvitamin D [25(OH)D] status in Koreans using the Korea National Health and Nutrition Examination Survey, a nationwide database. Whether the association was modified by demographic and lifestyle factors, including sex, body mass index (BMI), smoking status, drinking status, physical activity, and sun exposure, were also investigated. The results showed the serum level of 25(OH)D was associated with rs12785878, rs2282679, and rs12794714 genotypes, but not with rs10741657 or rs6013897. The genetic risk score (GRS) calculated by summing the number of alleles of these 5 SNPs was associated with low circulating levels of 25(OH)D. However, the negative association between 25(OH)D and GRS was modified by obesity and sun exposure. Specifically, negative associations between 25(OH)D and GRS were present in adults with lower BMI (<25 kg/m2) and longer sun exposure time (≥2 h/day). In conclusion, common variants of vitamin D-related SNPs are associated with vitamin D status in Koreans, and this genetic effect was masked when BMI ≥25 kg/m2 or sun exposure <2 h/day. Additionally, seasonal variation must be considered in future studies among Koreans.

Abstract B18: Interactions between finasteride and vitamin D-related polymorphisms is associated with prostate cancer risk in African American men

Abstract Background: The difference in prostate cancer incidence and survival between European American (EuAm) and African American (AfAm) men is an important health disparity. Vitamin D (VitD) has been linked to key carcinogenesis-related processes and there is strong evidence of cross talk between the androgen and VitD signaling pathways. AfAm men are more likely to be VitD deficient compared to EuAm men which could be one reason for the health disparity. The current study examined genetic variability in the VitD pathway in relation to prostate cancer risk and investigated whether finasteride, a 5α-reductase inhibitor that blocks the metabolism of testosterone, influenced the relationship of cancer risk in EA and AfAm men with VitD-related polymorphisms. Materials and Methods: This nested case-control study included 2,356 men (EuAm: 1,091 cases and 1,088 controls; AfAm: 47 cases, 130 controls) from the Prostate Cancer Prevention Trial, a randomized double-blind, placebo-controlled trial of finasteride for the primary prevention of prostate cancer. In EuAm men, controls were frequency matched to cases on distributions of age, first degree family history of prostate cancer and treatment arm. Due to smaller numbers, all available AfAm men were selected. Participants underwent for-cause or end of study prostate biopies with central pathology review to determine case or control status. Twenty-nine SNPs from 14 genes identified from previous studies as being associated with VitD levels and/or prostate cancer were genotyped from buffy coats using the Illumina VeraCode GoldenGate assay (Illumina Inc; San Diego, CA). Odds ratios were calculated to determine associations of SNP genotypes with prostate cancer risk. Interaction was ermined by adding an interaction term to the logistic models. All statistical tests are 2-sided with p&amp;lt;0.05 considered statistically significant. SAS (ver 9.2, Cary NC) and R (2.15.1, Vienna Austria) were used for all analyses. Results: Three SNPs (C1orf88 rs6599638, CYP24A1 rs6013897, HSD3B1 rs1856888) showed significant interaction by treatment group (finasteride vs. placebo) in AfAm men only (p-interaction for rs6599638, rs6013897, rs1856888 was 0.01, 0.02 and 0.02, respectively). None of the SNPs were associated with cancer in EuAm men and there was no evidence of interaction by treatment group in EuAm men. SNPs rs6599638 and rs6013897 were not associated with cancer in AfAm men in the placebo group. In AfAm men taking finasteride, however, the odds ratios (OR) were significant [rs6599638 AA genotype (7 cases/ 5 controls) compared to AG/GG (12 cases/77 controls) OR= 10.84, 95%CI: 2.77, 45.5; p=0.001; for rs6013897 AA/AT genotypes (13 cases/31 controls) compared to TT (7 cases/51 controls) OR= 3.08, 95%CI: 1.10, 8.60; p=0. 03]. For the rs1856888 SNP, the GG/AG genotypes were protective in the AfAm placebo group [GG/AG (11 cases/33 controls) compared to AA (16 cases/17 controls) OR=0.31, 95%CI: 0.11, 0.84, p= 0.02] but the OR increased to 1.98 in the AfAm finasteride group (p=0.23). The potential impact is limited for rs6599638 as only 10% of AfAm controls have the AA genotype. The impact is larger for rs6013897 and rs1856888 with 41% and 62% of controls with the AA/AT and GG/AG genotypes, respectively. Numbers were too small to examine associations by Gleason grade. Conclusions: There appears to be differential response to finasteride by race and genotype in three of the 29 VitD pathway SNPs examined in the current study. In these three SNPs in the presence of finasteride, the risk genotypes were associated with an increased odds for cancer in AfAm men and not EuAm men. This implies that finasteride may need to be prescribed with caution to some AfAm men. These results should be confirmed in a larger sample size. Citation Format: Kathleen C. Torkko, Cathee Till, Phyllis J. Goodman, Catherine M. Tangen, Adrie van Bokhoven, M. Scott Lucia, Ian M. Thompson, Jr., Ulrike Peters, Marian L. Neuhouser. Interactions between finasteride and vitamin D-related polymorphisms is associated with prostate cancer risk in African American men. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B18.

Abstract 2629: Common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome

Abstract Experimental and clinical evidence suggest that vitamin D protects against several types of cancer by promoting cell differentiation and apoptosis and by inhibiting cell proliferation and angiogenesis. In vitro evidence supports a similar protective function in glioma; however, no study has examined whether common genetic variants in the vitamin D pathway are related to glioma risk or patient outcome. We evaluated these potential associations in a clinic-based case-control study conducted at medical centers in the southeastern US. Genotyping was performed in 623 newly diagnosed (eg. nonrecurrent) glioma cases (including 343 WHO grade IV glioblastomas (GBM); 148 WHO grade II or III astrocytomas, 95 oligoastrocytomas and oligodendrogliomas, and 37 gliomas with unspecified histology) and 631 healthy controls with no history of brain tumors. A total of 7 candidate tagging single nucleotide polymorphisms (SNPs) were genotyped in the vitamin D receptor (VDR at 12q13) including rs2107301, rs2238135, rs4516035, rs731236 (Taq1), rs1544410 (Bsm1), rs11568820 (Cdx2), and rs2228570 (Fok1). SNPs associated with serum concentrations of 25-hydroxy vitamin D in genome-wide association studies (GWAS) were also evaluated including rs1155563, rs12512631, rs2282679, and rs7041 in GC (4q12-q13), rs10741657 in CYP2R1 (11p15), rs6013897 in CYP24A1 (20q13), rs3829251 in NADSYN1 (11q13), and rs6599638 at C10orf88 (10q26). Genotyping was performed in oral DNA samples using Illumina GoldenGate and Taqman OpenArray assays. Logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to vitamin D genotypes. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for glioma-related death among 439 patients with high grade tumors including GBM and high grade astrocytomas (331 deaths; median Kaplan-Meier survival: 15.0 months). GWAS SNPs in NADSYN1, GC, and C10ORF88 were not associated with glioma risk or patient survival. Risk associations limited to GBM were observed for rs2238135 in the VDR (G&amp;gt;C; minor allele frequency (MAF) = 0.20) (per variant allele OR = 1.31; 95% CI: 1.01 to 1.71; p for trend = 0.04) and for GWAS SNP rs10741657 located near CYP2R1 (G&amp;gt;A; MAF = 0.40) (per variant allele OR = 0.79; 95% CI: 0.63 to 0.98; p for trend = 0.03). The variant allele in CYP24A1 rs6013897 (T&amp;gt;A; MAF = 0.20) was associated with prolonged survival among patients with high grade tumors (per variant allele HR = 0.79; 95% CI: 0.59 to 0.97; p for trend = 0.03) in patients uniformly treated with the current standard of care (surgery, radiation and temozolomide). To our knowledge this is the first report suggesting that genetic variation in vitamin D related genes may be a determinant of glioma risk and outcome. Further studies are needed to confirm these results and identify the putative causal variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2629. doi:1538-7445.AM2012-2629