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Association of circulating 25-Hydroxyvitamin D and its related genetic variations with hepatocellular carcinoma incidence and survival.

ABSTRACT: Background:Vitamin D plays a key role of anti-cancer process, however, the association of vitamin D level and its related genetic variants with hepatocellular carcinoma (HCC) risk and prognosis is not fully understood. Methods:We enrolled 100 HCC patients and 8,242 health controls from Sir Run Run Shaw Hospital. Logistic regression model was used to calculate the odds ratio (OR) and 95% CI for HCC risk according to serum 25(OH)D concentration. Mendelian randomization (MR) approach was also conducted to validate the potential causal association of 25(OH)D with HCC risk. Hazard ratio (HR) for the association of SNPs with overall survival and disease-free survival was assessed by multivariate Cox hazard proportional regression model. Results:Plasma 25(OH)D level greater than 20 ng/mL increased HCC risk (OR =7.56, 95% CI: 4.58-12.50). MR analysis also showed a slightly increased risk of HCC by 25(OH)D increasing, yet did not reach statistical significance (OR =1.03, 95% CI: 0.31-3.47). With regard to HCC survival, compared to patients with rs8018720 GG genotype, patients with rs8018720 CC/CG genotype had a longer disease-free survival time (HR =0.39, 95% CI: 0.18-0.81). There was an interaction between rs12785878 and 25(OH)D level in continuous scale for HCC mortality. An interaction between rs12785878 and dichotomized 25(OH)D concentration for disease-free survival of HCC patients was also confirmed. Conclusions:There is hazard of circulating 25(OH)D concentration for HCC occurrence, but protective effect of the interaction between circulating 25(OH)D concentration and its related genetic variation for HCC prognosis. Further study is needed to confirm or refute these findings in a larger population.

SUBMITTER: Liu H

PROVIDER: S-EPMC7575935 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Association of circulating 25-Hydroxyvitamin D and its related genetic variations with hepatocellular carcinoma incidence and survival.

Liu Hui H Jiang Xia X Qiao Qiaohua Q Chen Liying L Matsuda Koichi K Jiang Guangyi G Yu Tunan T Wang Yifan Y Lin Hui H Liang Xiao X Cai Xiujun X

Annals of translational medicine 20200901 17

<h4>Background</h4>Vitamin D plays a key role of anti-cancer process, however, the association of vitamin D level and its related genetic variants with hepatocellular carcinoma (HCC) risk and prognosis is not fully understood.<h4>Methods</h4>We enrolled 100 HCC patients and 8,242 health controls from Sir Run Run Shaw Hospital. Logistic regression model was used to calculate the odds ratio (OR) and 95% CI for HCC risk according to serum 25(OH)D concentration. Mendelian randomization (MR) approach ...[more]

PMID: 33145299

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Project description:Background and aimsFree and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival.Approach and resultsWe included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum-free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable-adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS.ConclusionsHigher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.

Project description:BackgroundLow circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach.MethodsUsing several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes.FindingsAll four SNPs were associated with 25(OH)D concentrations (p<10(-6)). The mendelian randomisation-derived unconfounded odds ratio for type 2 diabetes was 1·01 (95% CI 0·75-1·36; p=0·94) per 25·0 nmol/L (1 SD) lower 25(OH)D concentration. The corresponding (potentially confounded) relative risk from the meta-analysis of data from observational studies was 1·21 (1·16-1·27; p=7·3 × 10(-19)). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p>0·25).InterpretationThe association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes.FundingUK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.

Project description:Background:The complexity of vitamin D metabolites especially the contribution of C3-epimers of 25-hydroxyvitamin D (C3-epimers) in human sera remains unclear. We hypothesized that genetic polymorphisms in the vitamin D-related gene pathway contribute to variation in C3-epimer levels. Therefore, we investigated candidate single nucleotide polymorphisms (SNPs) concerning C3-epimer levels. Methods:The candidate SNPs, including DHCR7/NADSYN1 (rs12785878), CYP2R1 (rs2060793) and GC (rs2282679), were genotyped in 1727 members of the third project of the Electricity Generating Authority of Thailand 3/1 cohort investigation. Each SNP was tested under three genetic effects (dominant, recessive and additive models) concerning the levels of total serum 25(OH)D [the sum of 25(OH)D2+3 and 3-epi-25(OH)D2+3], non-C3-epimers [25(OH)D2+3] and C3-epimers [3-epi-25(OH)D2+3], using linear regression analysis. Results:Among the participants, the median (range) levels of non-C3-epimers and C3-epimers were 22.7 (6.4-49.2)?ng/mL and 1.3 (0.01-14.2)?ng/mL, respectively. In regression analysis, we found the genetic variation of two SNPs, the DHCR7/NADSYN1 (rs12785878; G?>?T) and GC (rs2282679; T?>?G) under additive genetic models, explained the variation of C3-epimer levels about 1.5% (p?=?1.66?×?10-7) and 1.1% (p?=?1.10?×?10-5), respectively. Interestingly, participants carrying the minor T-allele of rs12785878 exhibited a trend to increase C3-epimer levels, while those carrying the minor G-allele of rs2282679 exhibited a trend to decrease levels of both non-C3-epimers and C3-epimers. In addition, CYP2R1 (rs2060793; G?>?A) was clearly associated only with non-C3-epimer levels (p?=?2.46?×?10-8). In multivariate analyses, sex, age and BMI were predictors for variation in C3-epimer concentration; sex and age for variation in non-C3-epimers. Conclusion:To the best of our knowledge, this is the first study to demonstrate genetic models concerning the variation in C3-epimer levels. Our results emphasize that genetic determinants and the potential factors of C3-epimers differ from non-C3-epimers. This study contributes fundamental knowledge of the endogenous vitamin D pathway.

Dataset Information

Association of circulating 25-Hydroxyvitamin D and its related genetic variations with hepatocellular carcinoma incidence and survival.

Publications

Association of circulating 25-Hydroxyvitamin D and its related genetic variations with hepatocellular carcinoma incidence and survival.

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