Vitamin D-related Polymorphisms Research Articles

Serum vitamin D concentration, vitamin D-related polymorphisms, and colorectal cancer risk.

Serum 25-hydroxyvitamin D (25(OH)D) has been demonstrated to be associated with risk of colorectal cancer (CRC). However, it remains unclear whether this association was modified by vitamin D-related polymorphisms. We evaluated association of serum 25(OH)D concentration with CRC risk among 403 170 participants from UK Biobank Project. Two variants of vitamin D binding protein (VDBP), rs4588 and rs7041, were included to estimate the binding affinity of 25(OH)D to VDBP, and three variants of vitamin D receptor (VDR), rs11568820, rs2228570 and rs1544410, which may influence VDR activity, were also investigated. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 4 957 677 person-years of follow-up, 5053 incident CRC cases were documented. Higher serum 25(OH)D concentrations were significantly associated with lower CRC incidence in a dose-response manner, with HR (95% CIs) being 0.94 (0.91-0.97) per 1 SD increment of serum 25(OH)D level (Ptrend < .001). When separated by anatomic site, we observed a significant association between higher 25(OH)D and lower incidence of colon cancer (Ptrend < .001), but not rectal cancer (Ptrend = .880). The inverse associations between 25(OH)D level and CRC risk were demonstrated in almost all individuals carrying different GC or VDR genotypes, except for those with rs1544410 TT or rs4588 TT genotypes. There was no significant interaction between any single variant, or haplotypes of GC or VDR, and 25(OH)D level. Our findings suggest the potential benefits of maintaining adequate vitamin D for CRC prevention, particularly for tumors from colon.

Role of Multiple Vitamin D-Related Polymorphisms in Multiple Sclerosis Severity: Preliminary Findings.

Background: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in genes codifying for molecules involved in vitamin D metabolism have been associated with an increased risk of developing MS. However, few studies assessed the association of such SNPs with the severity of the disease. The aim of this observational study was to evaluate the potential association among vitamin D status, MS severity, and vitamin D-related SNPs, alone or in combination. Methods: In a cohort of 100 MS patients, we genotyped 18 SNPs in the following genes: NAD synthetase 1, CYP2R1, vitamin D binding protein, vitamin D receptor, Retinoid X Receptor-α, KLOTHO, CYP24A1, and CYP27A1. Serum 25(OH)D3 levels were measured by high-performance liquid chromatography. Genotyping was performed by real-time polymerase chain reaction or PCR-RFLP. Results: We did not find any association between SNPs, alone or in combination, and MS severity. Conclusion: In this study, we make an initial evaluation of the possible influence of several SNPs in vitamin D-related genes on MS severity.

Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity

Vitamin D is a fundamental regulator of host defences by activating genes related to innate and adaptive immunity. Previous research shows a correlation between the levels of vitamin D in patients infected with SARS-CoV-2 and the degree of disease severity. This work investigates the impact of the genetic background related to vitamin D pathways on COVID-19 severity. For the first time, the Portuguese population was characterized regarding the prevalence of high impact variants in genes associated with the vitamin D pathways. This study enrolled 517 patients admitted to two tertiary Portuguese hospitals. The serum concentration of 25 (OH)D, was measured in the hospital at the time of patient admission. Genetic variants, 18 variants, in the genes AMDHD1, CYP2R1, CYP24A1, DHCR7, GC, SEC23A, and VDR were analysed. The results show that polymorphisms in the vitamin D binding protein encoded by the GC gene are related to the infection severity (p = 0.005). There is an association between vitamin D polygenic risk score and the serum concentration of 25 (OH)D (p = 0.04). There is an association between 25 (OH)D levels and the survival and fatal outcomes (p = 1.5e−4). The Portuguese population has a higher prevalence of the DHCR7 RS12785878 variant when compared with its prevalence in the European population (19% versus 10%). This study shows a genetic susceptibility for vitamin D deficiency that might explain higher severity degrees in COVID-19 patients. These results reinforce the relevance of personalized strategies in the context of viral diseases.Trial registration: NCT04370808.

ε2 , ε3 , and ε4 variants of ApoE; rs2228570 (VDR), rs4588 and rs7041 (VDBP) polymorphisms in patients with multiple sclerosis: A case-control study in Turkish population.

Multiple sclerosis (MS) is a degenerative disease characterized by autoimmune demyelination in the central nervous system. Yet, underlined genetics or environmental markers are still controversial. The impact of vitamin D and cholesterol on disease activity has been phrased by many studies; however, the data available for the Turkish population are very limited. This study aimed to investigate the effect of vitamin D-related polymorphisms (VDBP and VDR) and cholesterol-related variants of ApoE on Turkish MS patients. Total DNAs were extracted from peripheral blood samples of 51 MS patients and 50 healthy volunteers. rs4588 and rs7041 polymorphisms of VDBP, rs2228570 of VDR, as well as ε2, ε3, and ε4 variants of ApoE, were investigated by RT-PCR. Biochemical parameters which thought to be associated with MS were also measured. Results were evaluated statistically. Homozygous mutant genotype and G allele of rs2228570 in VDR, as well as heterozygous genotype of rs4588 in VDBP, were found statistically high in patients. Total cholesterol, triglyceride, and LDL-C levels were found significantly high, whereas HDL-C and vitamin D levels were low in patients. An association was found between rs4588 variation and high triglyceride levels. Similar correlations were found between ε2 genotype and low LDL-C level; ε3 genotype and higher LDL-C. Gender, triglyceride, HDL-C, and AA genotype in rs4588 had a significant effect on MS progression. The variations of rs2228570 and rs4588, vitamin D deficiency, and biological parameters related to cholesterol metabolism may be associated with MS risk.

Vitamin D Receptor Polymorphism and DHCR7 Contribute to the Abnormal Interplay Between Vitamin D and Lipid Profile in Rheumatoid Arthritis

Emerging evidence suggests a role for 7-dehydrocholesterol reductase (DHCR7) in the crosstalk between cholesterol and vitamin D. Our aim was to evaluate the impact of vitamin D-related polymorphisms and DHCR7 levels in the association between vitamin D deficiency and altered lipid profile in rheumatoid arthritis (RA). Serum 25(OH)-vitamin D, DHCR7 levels and vitamin D-related polymorphisms (VDR-rs2228570, CYP27A1-rs933994, CYP2R1-rs10741657 and DHCR7-rs12785878) were analyzed in 211 RA patients,94 controls and in a prospective cohort of 13 RA patients undergoing TNFα-blockade. Vitamin D was decreased in RA (p < 0.001), correlated to HDL-cholesterol (r = 0.217, p < 0.001) and total-/HDL-cholesterol ratio (r = −0.227, p = 0.004). These correlations were restricted to the VDR-rs2228570 status. Vitamin D deficiency was associated with lower HDL-cholesterol (p = 0.028), higher tender (p = 0.005) and swollen (p = 0.002) joint counts, higher DAS28 (p = 0.018) and HAQ (p = 0.024) in AG/AA-patients but not in their GG-counterparts. The associations among DHCR7, vitamin D and lipid profile followed a seasonal pattern, decreased DHCR7 (p = 0.008) and vitamin D (p < 0.001) and increased total-cholesterol (p = 0.025) being found in winter/spring. Increasing vitamin D upon TNFα-blockade paralleled RA clinical improvement (r = −0.610, p = 0.027) and DHCR7 elevation (r = 0.766, p = 0.002). In conclusion, vitamin D-related polymorphisms and DHCR7 are pivotal to understand the complex, seasonal associations between vitamin D and lipid profile in RA.

Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent.

Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case-control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER-/PR-/HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype.

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.

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.

Common Variants in CYP2R1 and GC Genes Predict Vitamin D Concentrations in Healthy Danish Children and Adults

Environmental factors such as diet, intake of vitamin D supplements and exposure to sunlight are known to influence serum vitamin D concentrations. Genetic epidemiology of vitamin D is in its infancy and a better understanding on how genetic variation influences vitamin D concentration is needed. We aimed to analyse previously reported vitamin D-related polymorphisms in relation to serum 25(OH)D concentrations in 201 healthy Danish families with dependent children in late summer in Denmark. Serum 25(OH)D concentrations and a total of 25 SNPs in GC, VDR, CYP2R1, CYP24A1, CYP27B1, C10or88 and DHCR7/NADSYN1 genes were analysed in 758 participants. Genotype distributions were in Hardy–Weinberg equilibrium for the adult population for all the studied polymorphisms. Four SNPs in CYP2R1 (rs1562902, rs7116978, rs10741657 and rs10766197) and six SNPs in GC (rs4588, rs842999, rs2282679, rs12512631, rs16846876 and rs17467825) were statistically significantly associated with serum 25(OH)D concentrations in children, adults and all combined. Several of the SNPs were in strong linkage disequilibrium, and the associations were driven by CYP2R1-rs10741657 and rs10766197, and by GC-rs4588 and rs842999. Genetic risk score analysis showed that carriers with no risk alleles of CYP2R1-rs10741657 and rs10766197, and/or GC rs4588 and rs842999 had significantly higher serum 25(OH)D concentrations compared to carriers of all risk alleles. To conclude, our results provide supporting evidence that common polymorphisms in GC and CYP2R1 are associated with serum 25(OH)D concentrations in the Caucasian population and that certain haplotypes may predispose to lower 25(OH)D concentrations in late summer in Denmark.