Vitamin D-related Gene Polymorphisms Research Articles

The symptomatology of Attention-Deficit/Hyperactivity Disorder and the genetic control of vitamin D levels.

Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes. We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software. Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity. Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.

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%.

Effects of vitamin D-related gene polymorphisms on attempted suicide.

Emerging evidence suggests that vitamin D might protect from attempted suicide. The study aimed to investigate the associations between single-nucleotide polymorphisms (SNPs) related to vitamin D levels identified in a large genome-wide association study and attempted suicide in rural China. This 1:1 matched case-control study included altogether 510 suicide attempters and 510 community controls. Genotypes of four target SNPs (DHCR7-rs12785878, CYP2R1-rs10741657, GC-rs2282679, and CYP24A1-rs6013897) were determined, and a genetic risk score (GRS) was constructed to evaluate the combined effect of them. Demographic and psychological information was acquired through face-to-face interviews. The A allele of CYP24A1-rs6013897 was significantly associated with attempted suicide (OR = 1.27, 95% CI, 1.03-1.58, P = 0.029), even after adjusting for demographic and psychological confounders (adjusted OR = 1.53, 95% CI, 1.01-2.30, P = 0.043). The GRS analyses revealed a significantly higher risk of attempted suicide with a greater number of low vitamin D alleles (adjusted OR = 1.33, 95% CI, 1.13-1.58, P < 0.001). Subgroup analyses stratified by sex indicated that the genetic associations were only significant among males with adjusted ORs of 3.77 (95% CI, 1.56-9.10) for the A allele of rs6013897 and 2.04 (95% CI, 1.32-3.17) for GRS. Our findings identity CYP24A1-rs6013897 as a potential biomarker for attempted suicide and indicate that a genetic predisposition to lower vitamin D levels may contribute to attempted suicide. It suggests the possibility that vitamin D may have the preventive potential for attempted suicide.

Effect of cholecalciferol on serum hepcidin and parameters of anaemia and CKD-MBD among haemodialysis patients: a randomized clinical trial

In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563. UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E.

The Role of Polymorphisms in Vitamin D-Related Genes in Response to Vitamin D Supplementation.

Background. Vitamin D deficiency represents a major healthcare problem. Vitamin D status is influenced by genetic and environmental determinants. Several observational studies have evaluated the association of single-nucleotide polymorphisms (SNPs) in vitamin D-related genes and vitamin D levels. Nevertheless, little is known about the role of these SNPs in the response to vitamin D supplementation. We conducted an interventional study to define the association between SNPs in vitamin D-related genes and the response to vitamin D supplementation in 100 self-reported healthy women of Arab ancestry for the majority. Methods. A total of 100 healthy female subjects received a weekly oral dose of 50,000 IU vitamin D for 12 weeks. Serum vitamin D concentration and metabolic profiles were measured at baseline and 12 weeks post-vitamin D supplementation. The genotypes of 37 SNPs selected from previously reported vitamin D-related genes have been assessed by Fluidigm genotyping assay. Results. Rs731236 (VDR gene) and rs7116978 (CYP2R1 gene) showed a significant association with vitamin D status. The rs731236 GG genotype and the rs7116978 CC genotype were associated with a “vitamin D sufficiency” state. Rs731236 GG and rs7116978 CC genotypes showed a higher response to vitamin D supplementation. Transcription factor binding site prediction analysis showed altered binding sites for transcription factors according to the different rs7116978 alleles. Interestingly, the 37 SNPs previously established to play a role in vitamin D-related pathways explained very little of the response to vitamin D supplementation in our cohort, suggesting the existence of alternative loci whose number and effect size need to be investigated in future studies. Conclusion. In this paper, we present novel data on vitamin D-related SNPs and response to vitamin D supplementation demonstrating the feasibility of applying functional genomic approaches in interventional studies to assess individual-level responses to vitamin D supplementation.

The association between vitamin D-related gene polymorphisms and hepatitis B virus-related liver cirrhosis.

ObjectivesTo investigate the relationship between vitamin D-related gene single nucleotide polymorphisms (SNPs) and hepatitis B-related liver cirrhosis.MethodsThis study included patients with chronic hepatitis B who were admitted to the Liver Research Center of the First Affiliated Hospital of Fujian Medical University from July 2012 to August 2016. SNPs rs1544410 and rs2228570 in the vitamin D receptor gene and rs2282679 in the vitamin D-binding protein gene were detected using the imLDR™ multiple SNP typing kit. Genotype and allele frequencies were compared between groups using the chi-square test or Fisher’s exact test.ResultsA total of 226 patients with hepatitis B virus (HBV) infection were enrolled, including 116 with HBV-related cirrhosis and 110 patients without. The distributions of vitamin D-related gene SNPs in both groups were in accordance with the Hardy–Weinberg equilibrium. There was no significant difference in the frequency or allelic distributions of rs1544410, rs2228570, and rs2282679 between the two groups. Additionally, the SNPs were not associated with the severity of cirrhosis.ConclusionNo significant connection was identified between vitamin D-related SNPs and HBV-related liver cirrhosis.

The Association between Vitamin D-Related Gene Polymorphisms and Serum 25-Hydroxyvitamin D Concentration: A Prospective Cohort Study in Pregnant Minangkabau Women, Indonesia.

Several candidate genes in vitamin D synthesis and metabolism have been reported to have a significant association with 25-hydroxyvitamin D (25(OH)D) in Caucasians and African Americans. Few studies have indicated this relationship among Asians, especially in pregnant Minangkabau women, Indonesia. This study was conducted among 180 singleton pregnant women of West Sumatran Vitamin D Pregnant Mother (VDPM) cohort study. Serum 25(OH)D obtained in the third trimester (T3). Genetic risk scores (GRS) were created based on six vitamin D-related SNPs and their association with 25(OH)D levels were tested. Informations on demographics, lifestyle, pregnancy profile, and physical activity were collected using questionnaire. The average of 25(OH)D concentration was 21.21±10.41 ng/mL respectively. Vitamin D-GRS has significantly associated with serum 25(OH)D levels in the third trimester (p=0.006). However, the synthesis-GRS and metabolism-GRS group of vitamin D-related gene polymorphisms had no association with 25(OH)D concentration at T3 (p>0.05). A high prevalence of insufficient-deficient vitamin D status at T3 was common. We observed an association between vitamin D-GRS and 25(OH)D concentration. The results of this study provides additional support for possible role of genetic variants in vitamin D-related gene polymorphisms on 25(OH)D concentration during pregnancy. Further replication studies with larger sample sizes are needed to confirm thefindings.

Vitamin D and Multiple Sclerosis: An Open-Ended Story

Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease of the Central Nervous System (CNS). Genetic, epigenetic and environmental factors interact together, contributing to the complex pathogenesis of the disease. In the last decades, the role of hypovitaminosis D on MS risk was hypothesised. Several factors drive the regulation of vitamin D status, including genetics. The current review summarises the literature evidence on the association between vitamin D and MS, with a focus on the genetic polymorphisms in vitamin D-related genes. The variants of the genes codifying Vitamin D Receptor (VDR), Vitamin D Binding Protein (VDBP) and CYP enzymes have been investigated, but the findings are controversial. Only a few studies have addressed the role of DHCR7 polymorphisms in MS risk.

Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease

BackgroundVitamin D has promising anti-proliferative and anti-fibrotic properties, but its clinical utility in nonalcoholic fatty liver disease (NAFLD) is unclear. AimsThis study aimed to clarify the association between vitamin D levels, single nucleotide polymorphisms (SNPs) in vitamin D-related genes, and the histopathological severity of disease in patients with biopsy-proven NAFLD. MethodsSNPs in CYP2R1, DHCR7, vitamin D binding protein (GC), CYP27B1, and vitamin D receptor (VDR) were determined for 229 consecutive patients with biopsy-proven NAFLD. ResultsIn this study, vitamin D deficiency defined as 25-hydroxyvitamin-D3 levels of ≤20 ng/mL was found in 151 patients (65.9%). Multivariate analysis revealed that cold season, advanced fibrosis, and CYP2R1 rs1993116 genotype non-AA were independent factors significantly associated with vitamin D deficiency. Old age (p = 5.05 × 10−8), high body mass index (p = 2.13 × 10−2), low total-cholesterol (p = 1.46 × 10−4), low serum vitamin D level (p = 7.34 × 10−3), and VDR rs1544410 genotype CC (p = 9.15 × 10−3) were independent factors associated with advanced liver fibrosis. ConclusionSerum 25-hydroxyvitamin-D3 levels and the VDR gene SNP were significantly and independently associated with the severity of liver fibrosis in patients with biopsy-proven NAFLD.

Vitamin D deficiency in hepatitis C virus infection: what is old? what is new?

In the past few years, a growing body of clinical evidence has highlighted the risk of vitamin D deficiency in patients with chronic hepatitis C and that vitamin D levels are associated with the course of hepatitis C virus (HCV) infection, adverse effects, and treatment response to peginterferon/ribavirin. Recently, studies have found that vitamin D status is related to drug resistance and increased risk of infection in patients with liver cirrhosis. Vitamin D-related gene polymorphisms have been found to explain the interactions between vitamin D deficiency and HCV infection, offering a new perspective toward understanding the current problems such as the development of insulin resistance and racial differences in sustained virological response. Studies have been conducted to determine whether vitamin D supplementation as an adjuvant yields a better result compared with traditional HCV treatment. Here, we provide a brief review of the past and present knowledge of vitamin D in HCV infection.

Vitamin D Metabolism-Related Gene Haplotypes and Their Association with Metabolic Disturbances Among African-American Urban Adults

Epidemiological studies have confirmed associations of the vitamin D receptor (VDR) and vitamin D-related gene polymorphisms with adiposity and other metabolic disturbances. Those associations may be sex-specific. We evaluated the cross-sectional and longitudinal relationships between metabolic disturbances and haplotypes constructed from single nucleotide polymorphisms of VDR (BsmI:G/A: rs1544410; ApaI:A/C: rs7975232; and TaqI:G/A: rs731236) and MEGALIN (rs3755166:G/A; rs2075252:C/T and rs2228171:C/T) genes, in a sample of African-American adults. From 1,024 African Americans participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS, 2004–2013, Baltimore, MD), our analyses included 539 participants with complete genetic, baseline covariate and metabolic outcome data (at baseline and follow-up). Mean ± SD period of follow-up was 4.64 ± 0.93 y. Multivariable-adjusted Cox proportional hazards and logistic regression models were conducted. Among key findings, in men, incident hypertension was inversely related to MEGALIN1 (GCC), [HR = 0.45, 95% CI: 0.23–0.90, p = 0.024]. Overall, there was a direct, linear dose-response association between VDR2 (AAG: BAt) and MetS at baseline [OR = 1.60, 95% CI: 1.11–2.31, p = 0.012], while among men, VDR3 (GAA: bAT) was inversely related to baseline MetS [OR = 0.40, 95% CI: 0.19–0.81, p = 0.011]. In conclusion, VDR and MEGALIN gene variations can affect prevalent MetS and the incidence rate of hypertension, respectively, among African-American urban adults.

Vitamin D-Related Gene Polymorphisms, Plasma 25-Hydroxy-Vitamin D, Cigarette Smoke and Non-Small Cell Lung Cancer (NSCLC) Risk.

Epidemiological studies regarding the relationship between vitamin D, genetic polymorphisms in the vitamin D metabolism, cigarette smoke and non-small cell lung cancer (NSCLC) risk have not been investigated comprehensively. To search for additional evidence, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and radioimmunoassay method were utilized to evaluate 5 single-nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR), 6 SNPs in 24-hydroxylase (CYP24A1), 2 SNPs in 1α-hydroxylase (CYP27B1) and 2 SNPs in vitamin D-binding protein (group-specific component, GC) and plasma vitamin D levels in 426 NSCLC cases and 445 controls from China. Exposure to cigarette smoke was ascertained through questionnaire information. Multivariable linear regressions and mixed effects models were used in statistical analysis. The results showed that Reference SNP rs6068816 in CYP24A1, rs1544410 and rs731236 in VDR and rs7041 in GC were statistically significant in relation to reduction in NSCLC risk (p < 0.001–0.05). No significant connection was seen between NSCLC risk and overall plasma 25-hydroxyvitamin D [25(OH)D] concentrations, regardless of smoking status. However, the mutation genotype of CYP24A1 rs6068816 and VDR rs1544410 were also significantly associated with increased 25(OH)D levels only in both the smoker and non-smoker cases (p < 0.01–0.05). Meanwhile, smokers and non-smokers with mutated homozygous rs2181874 in CYP24A1 had significantly increased NSCLC risk (odds ratio (OR) = 2.14, 95% confidence interval (CI) 1.47–3.43; p = 0.031; OR = 3.57, 95% CI 2.66–4.74; p = 0.019, respectively). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). However, smokers with mutated homozygous rs6068816 in CYP24A1 had significantly decreased NSCLC risk (OR = 0.43, 95% CI 0.27–1.02; p = 0.006); and smokers and non-smokers with mutated homozygous rs1544410 in VDR had significantly decreased NSCLC risk (OR = 0.51, 95% CI 0.34–1.17; p = 0.002; OR = 0.26, 95% CI 0.20–0.69; p = 0.001, respectively). There are significant joint effects between smoking and CYP24A1 rs2181874, CYP24A1 rs6068816, VDR rs10735810, and VDR rs1544410 (p < 0.01–0.05). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). In summary, the results suggested that the lower the distribution of vitamin D concentration, the more the genetic variations in CYP24A1, VDR and GC genes may be associated with NSCLC risk. In addition, there are significant joint associations of cigarette smoking and vitamin D deficiency on NSCLC risk.

Abstract 806: SNPs in vitamin D-related genes are associated with prostate cancer aggressiveness in the North Carolina-Louisiana Prostate Cancer Project (PCaP)

Abstract Introduction: African Americans have higher incidence of, and mortality from, prostate cancer (PCa) compared to other racial/ethnic groups. Frequency of polymorphisms in genes involved in vitamin D metabolism, transport, and activity differ by race/ethnicity. Examining the association between polymorphisms in vitamin D-related genes and PCa aggressiveness may explain differing susceptibility to aggressive PCa among individuals and across different racial/ethnic groups. Methods: TagSNPs (n = 315) in 13 genes (VDR, GC, CYP24A1, CYP27A1, CYP27B1, CYP2R1, CYP3A4, DHCR7, CASR, NADSYN1, RXRA, RXRB, RXRG) were genotyped using Illumina GoldenGate or Sequenom assays in 524 African-American and 657 European-American men with newly-diagnosed PCa from PCaP. DNA extracted from blood samples collected at enrollment was stored at -80C prior to analyses. Research subjects were classified as high aggressive if Gleason sum ≥8, or Gleason score (4+3), or PSA &amp;gt;20 ng/ml, or Gleason score (3+4) AND clinical stage = T3-T4. The comparison group (low aggressive) included research subjects with Gleason sum &amp;lt;7 AND Stage T1-T2 AND PSA &amp;lt; 9 ng/ml. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated for high aggressive PCa for each SNP using logistic regression with adjustment for age and proportion of African ancestry. Associations were considered statistically significant at p&amp;lt;0.05. A polygenic score based on a previous study of SNP predictors of serum 25-hydroxy-vitamin D levels was calculated utilizing SNPs in the GC, CYP24A1, CYP2R1, and NADSYN1 genes. Results: Among African Americans, 21 SNPs were associated with PCa aggressiveness. The variant allele was associated negatively or positively with high aggressive PCa in eleven and ten SNPs, respectively. For example, two SNPs in the vitamin D binding protein gene known as GC, were inversely associated (rs222054: OR, 0.55, 95%CI, 0.38-0.80; and rs16847028: OR, 0.61, 95%CI, 0.39-0.94). Among European Americans, the variant allele was inversely associated with high aggressive PCa for four SNPs in three genes (CASRrs3863977; CYP24A1rs4809960; RXRArs1007971; and RXRArs3118526), and positively associated with high aggressive PCa for three SNPs in the CYP27B1 gene (rs703842, rs4646536, and rs10877013). There was no association between higher number of ‘low vitamin D’ alleles in the four SNPs that comprised the polygenic score and PCa aggressiveness for either race. Conclusions: Polymorphisms in genes involved in vitamin D etabolism and activity, the vitamin D binding protein and calcium sensing receptor were associated with PCa aggressiveness, and there was no overlap in SNPs between race groups. Our ongoing work will examine interaction between polymorphisms of vitamin D-related genes and vitamin D metabolite levels on PCa aggressiveness. Citation Format: Susan E. Steck, Anna Woloszynska-Read, Samuel Antwi, Hongmei Zhang, Lenore Arab, Elizabeth T.H. Fontham, James Mohler, L. Joseph Su, Feifei Xiao, Gary Smith, Donald Trump, Candace Johnson, Jeannette Bensen. SNPs in vitamin D-related genes are associated with prostate cancer aggressiveness in the North Carolina-Louisiana Prostate Cancer Project (PCaP). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 806.

Weight Status and Alcohol Intake Modify the Association between Vitamin D and Breast Cancer Risk

Background: Mechanistic hypotheses suggest that vitamin D may contribute to the prevention of breast cancer. However, epidemiologic evidence is inconsistent, suggesting a potential effect modification by individual factors.Objective: Our objective was to perform exploratory analyses on the prospective associations between the plasma 25-hydroxyvitamin D [25(OH)D] concentration, polymorphisms of genes encoding for the vitamin D receptor (VDR) and vitamin D-binding protein (also known as gc-globulin or group-specific component, GC), and breast cancer risk, along with 2 potential modifiers: body mass index (BMI; in kg/m2) and alcohol intake.Methods: A nested case-control study was set up in the SUpplémentation en VItamines et Minéraux Anti-oXydants (SU.VI.MAX) cohort (1994–2007), involving 233 women with breast cancer and 466 matched controls (mean ± SD age: 49 ± 6 y). The plasma total 25(OH)D concentration and gene polymorphisms were assessed on samples obtained at baseline. Conditional logistic regression models were computed.Results: A higher plasma 25(OH)D concentration was associated with a decreased risk of breast cancer for women with a BMI < the median of 22.4 [OR quartile (Q)4 compared with Q1: 0.46; 95% CI: 0.23, 0.89; P-trend = 0.01, P-interaction = 0.002], whereas it was associated with an increased risk for women with a BMI ≥ the median (OR Q4 compared with Q1: 2.45; 95% CI: 1.13, 5.28; P-trend = 0.02, P-interaction = 0.002). A plasma 25(OH)D concentration ≥ 10 ng/mL was associated with a decreased risk of breast cancer for women with alcohol intakes ≥ the median of 7.1 g/d (OR ≥10 compared with <10 ng/mL: 0.50; 95% CI: 0.26, 0.95; P = 0.03, P-interaction = 0.03). The genetic analyses were consistent with the results observed with plasma 25(OH)D.Conclusion: In this prospective study, BMI and alcohol intake modified the association between vitamin D [plasma 25(OH)D and vitamin D-related gene polymorphisms] and breast cancer risk. These effect modifications suggest explanations for discrepancies in results of previous studies. This trial was registered at clinicaltrials.gov as NCT00272428.

Prospective associations between vitamin D status, vitamin D–related gene polymorphisms, and risk of tobacco-related cancers

Experimental evidence has suggested that vitamin D may be protective against tobacco-related cancers through the inhibition of the formation of tumors induced by tobacco carcinogens. To our knowledge, only one previous epidemiologic study investigated the association between vitamin D status and tobacco-related cancer risk, and no study has focused on vitamin D-related gene polymorphisms. Our objective was to prospectively study the association between plasma 25-hydroxyvitamin D [25(OH)D] concentrations, vitamin D-related gene polymorphisms, and risk of tobacco-related cancers. A total of 209 tobacco-related cancers were diagnosed within the SU.VI.MAX (Supplémentation en vitamines et minéraux antioxydants) cohort (1994-2007) and were matched with 418 controls as part of a nested case-control study. Tobacco-related cancers (i.e., cancers for which tobacco is one of the risk factors) included several sites in the respiratory, digestive, reproductive, and urinary systems. Total plasma 25(OH)D was assessed with the use of an electrochemoluminescent assay. Polymorphisms were determined with the use of a TaqMan assay. Conditional logistic regression models were computed. A 25(OH)D concentration ≥30 ng/mL was associated with reduced risk of tobacco-related cancers (OR for ≥30 compared with <30 ng/mL: 0.59; 95% CI 0.35, 0.99; P = 0.046). This association was observed in former and current smokers (OR for ≥30 compared with <30 ng/mL: 0.43; 95% CI: 0.23, 0.84; P = 0.01) but not in never smokers (P = 0.8). The vitamin D receptor (VDR) FokI AA genotype and retinoid X receptor (RXR) rs7861779 TT genotype were associated with increased risk of tobacco-related cancers [OR for homozygous mutant type (MT) compared with wild type (WT): 1.87; 95% CI: 1.08, 3.23; P-trend = 0.02; OR for heterozygous type (HT) plus MT compared with WT: 1.60; 95% CI: 1.07, 2.38; P = 0.02]. In this prospective study, high vitamin D status [25(OH)D concentration ≥30 ng/mL] was associated with decreased risk of tobacco-related cancers, especially in smokers. These results, which are supported by mechanistic plausibility, suggest that vitamin D may contribute to the prevention of tobacco-induced cancers in smokers and deserve additional investigation. The SU.VI.MAX trial was registered at clinicaltrials.gov as NCT00272428.

Abstract 2792: Polymorphisms in vitamin D-related genes and risk of breast cancer

Abstract Vitamin D is hypothesized to decrease breast cancer risk by controlling cell proliferation, differentiation and apoptosis, and estrogen synthesis and signalling in breast tissue. Transport of circulating vitamin D to sites of action is facilitated by vitamin D binding protein, encoded by the GC gene, whereupon it binds to the vitamin D receptor, encoded by the VDR gene. Given that polymorphisms in the GC and VDR gene have not been consistently associated with breast cancer risk, our objective was to assess the associations of vitamin D-related genes with breast cancer risk, accounting for ethnicity and menopausal status, and to determine these associations according to tumour receptor status defined by expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). A case-control study of 1,037 breast cancer cases and 1,050 controls age-frequency matched in Vancouver, British Columbia and Kingston, Ontario was used. The distribution and associations of 21 single nucleotide polymorphisms (SNPs) of the GC and VDR gene with breast cancer risk and breast tumour subtypes were investigated among premenopausal and postmenopausal European and Asian women in stratified analyses. Following false discovery rate adjustment, no SNP was associated with breast cancer risk among any subgroup. However, among European women, two SNPs in the VDR gene, rs1544410 (OR = 0.38, 95% CI: 0.21 - 0.70) and rs7967152 (OR = 2.80, 95% CI: 1.62 - 4.85) were associated with risk of ER-/PR-/HER2+ breast tumour subtype, but not with other breast tumour subtypes. Breast tumour subtypes are proposed to be etiologically distinct disease states, with different risk factors and prognostic outcomes. Interactions between variations in vitamin D-related genes and breast tumour subtypes are biologically plausible given our current understanding of anticarcinogenic properties of vitamin D elicited through the regulation of cell growth and reproductive hormone synthesis. These findings provide additional insight into the etiologic differences among breast tumour subtypes. Citation Format: Joy Shi, Anne Grundy, Harriet Richardson, Angela Brooks-Wilson, John Spinelli, Kristan J. Aronson. Polymorphisms in vitamin D-related genes and risk of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2015-2792

Vitamin D-related gene polymorphisms do not influence the outcome and serum vitamin D level in pegylated interferon/ribavirin therapy combined with protease inhibitor for patients with genotype 1b chronic hepatitis C.

Although several vitamin D-related gene polymorphisms were reported to affect the outcome of pegylated interferon/ribavirin (PR) therapy in chronic hepatitis C patients, there are no reports on the impact of the vitamin D-related gene polymorphisms in PR therapy combined with protease inhibitor (PI). Vitamin D-related gene polymorphisms were determined in 177 genotype 1b-infected chronic hepatitis C patients who received 12 weeks of PR therapy with telaprevir, a first-generation PI, followed by 12 weeks of PR therapy. The sustained virologic response (SVR) rate was 83.1% (147 of 177 patients). The frequencies of vitamin D-related gene polymorphisms were: 83 non-TT and 94 TT genotypes for GC, 97 non-AA and 80 AA genotypes for DHCR7, 151 non-AA and 26 AA genotypes for CYP2R1, 162 non-GG and 15 GG genotypes for CYP27B1, and 105 non-GG and 72 GG genotypes for VDR gene. Multivariate analysis extracted IL28B TT genotype (P = 2.05 × 10(-6)) and serum 25(OH) D3 level (P = 0.024) as independent factors contributing to the achieving of SVR. The SVR rate in IL28B TT genotype patients with serum 25(OH) D3 level of < 25 ng/ml was significantly low compared to other patients. None of the vitamin D-related gene polymorphisms affected the treatment outcome and serum 25(OH) D3 level. In conclusions, the IL28B polymorphism and serum 25(OH) D3 level contributed significantly and independently to SVR in PR combined with PI for genotype 1b-infected chronic hepatitis C patients. However, none of vitamin D-related gene polymorphisms had an impact on the treatment outcome and serum 25(OH) D3 level.

Vitamin D-related gene polymorphisms, plasma 25-hydroxyvitamin D, and breast cancer risk

Vitamin D-related gene polymorphisms, plasma 25-hydroxyvitamin D, and breast cancer risk

Vitamin D-related gene polymorphisms, plasma 25-hydroxyvitamin D, and breast cancer risk.

Studies of vitamin D-pathway genetic variants in relation to cancer risk have been inconsistent. We examined the associations between vitamin D-related genetic polymorphisms, plasma 25-hydroxyvitamin D [25(OH)D], and breast cancer risk. In a population-based case-control study of 967 incident breast cancer cases and 993 controls, we genotyped 25 polymorphisms encoding the vitamin D receptor (VDR) gene, 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D-binding protein (GC) and measured plasma 25(OH)D. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Among CYP24A1 polymorphisms, rs6068816 was associated with a 72% reduction in breast cancer risk (TT vs. CC, OR 0.28, 95% CI 0.10-0.76; p trend=0.01), but for rs13038432, the 46% decrease included the null value (GG vs. AA, OR 0.54, 95% CI 0.17-1.67; p trend=0.03). Increased risk that included the null value was noted for CYP24A1 rs3787557 (CC vs. TT, OR 1.34, 95% CI 0.92-1.89). The VDR polymorphism, TaqI (rs731236), was associated with a 26% risk reduction (TT vs. CC, OR 0.74, 95% CI 0.56-0.98; p trend=0.01). For other polymorphisms, ORs were weak and included the null value. The inverse association for plasma 25(OH)D with breast cancer was more pronounced (OR 0.43, 95% CI 0.27-0.68) among women with the common allele for CYP24A1, rs927650 (p for interaction on a multiplicative scale=0.01). Breast cancer risk may be associated with specific vitamin D-related polymorphisms, particularly CYP24A1. Genetic variation in the vitamin D pathway should be considered when designing potential intervention strategies with vitamin D supplementation.

Influence of Vitamin D-Related Gene Polymorphisms (CYP27B and VDR) on the Response to Interferon/Ribavirin Therapy in Chronic Hepatitis C

Background and AimsVitamin D exerts immunomodulatory effects on the host response against infection with hepatitis C virus (HCV). This study was performed to assess the putative influence of polymorphisms in vitamin D-related genes on the response to antiviral therapy in patients with chronic hepatitis C (CHC).MethodsSingle nucleotide polymorphisms (SNPs) in CYP27B-1260 gene promoter (rs10877012AC) and in vitamin D receptor (VDR) gene rs2228570TC, rs1544410CT, rs7975232AC and rs731236AT were analyzed in a cohort of 238 Caucasian CHC patients treated with pegylated interferon (Peg-IFN) plus ribavirin (RBV). Multivariate analyses were performed to exclude confounding effects of well-known baseline predictors of response to therapy (HCV genotype and load, IL28B genotype, age, and GGT and serum cholesterol).ResultsThree SNPs at the VDR gene (rs1544410, rs7975232 and rs731236) were in strong linkage disequilibrium, with the CCA haplotype predicting therapeutic failure [Odds ratio 2.743; (95% C.I. 1.313–5.731), p = 0.007]. The carrier state of the VDR rs2228570 T allele was inversely related to the probability of therapeutic failure [Odds ratio 0.438; 95 C.I. (0.204–0.882), p = 0.021]. No relation existed between CYP27B-1260 rs10877012 polymorphism and response to therapy. The area under the operating curve (AUROC) based on the model including all variables significantly related to the response to therapy was 0.846 (95% confidence interval = 0.793–0.899).Conclusion VDR gene polymorphisms are independently related to the response to Peg-IFN+RBV therapy in chronic hepatitis C and could be used as complementary biomarkers of response when included in a prediction algorithm in association with demographic, virologic, biochemical and genetic traits.