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Vitamin D and Nonalcoholic Fatty Liver Disease: Bi-directional Mendelian Randomization Analysis.

ABSTRACT: Vitamin D deficiency is associated with nonalcoholic fatty liver disease (NAFLD) in many cross-sectional studies. However, the causality between them has not been established. We used bi-directional mendelian randomization (MR) analysis to explore the causal relationship between 25-hydroxyvitamin D [25(OH)D] and NAFLD.9182 participants were included from a survey in East China from 2014 to 2016. We calculated weighted genetic risk scores (GRS) for 25(OH)D concentration and NAFLD based on 25(OH)D-related and NAFLD-related single nucleotide polymorphisms. Presence of liver steatosis was assessed using ultrasound. Instrumental variable was used to measure the causal relationship between them.An SD increase in the 25(OH)D GRS was significantly associated with 25(OH)D (? 1.29, 95%CI -1.54, -1.04, P<0.05) but not with NAFLD (OR 0.97, 95%CI 0.92, 1.01). An SD increase in NAFLD GRS was also strongly associated with NAFLD (OR 1.09, 95%CI 1.04, 1.15, P<0.05) but not with 25(OH)D (? -0.15, 95%CI -0.41, 0.10). Using an instrumental variable estimator, no associations were found for genetically instrumented 25(OH)D with NAFLD and for genetically instrumented NAFLD with 25(OH)D.Our results support the conclusion that there is no causal association between vitamin D and NAFLD using a bi-directional MR approach in a Chinese population.

SUBMITTER: Wang N

PROVIDER: S-EPMC5835542 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Vitamin D and Nonalcoholic Fatty Liver Disease: Bi-directional Mendelian Randomization Analysis.

Wang Ningjian N Chen Chi C Zhao Li L Chen Yi Y Han Bing B Xia Fangzhen F Cheng Jing J Li Qin Q Lu Yingli Y

EBioMedicine 20180109

<h4>Background</h4>Vitamin D deficiency is associated with nonalcoholic fatty liver disease (NAFLD) in many cross-sectional studies. However, the causality between them has not been established. We used bi-directional mendelian randomization (MR) analysis to explore the causal relationship between 25-hydroxyvitamin D [25(OH)D] and NAFLD.<h4>Methods</h4>9182 participants were included from a survey in East China from 2014 to 2016. We calculated weighted genetic risk scores (GRS) for 25(OH)D conce ...[more]

PMID: 29339098

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Project description:BackgroundObesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.Methods and findingsWe used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n?=?123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p?=?6.52×10?²?). The BMI allele score was associated both with BMI (p?=?6.30×10??²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p?=?0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p?8.07×10??? for both scores) but not with BMI (synthesis score, p?=?0.88; metabolism score, p?=?0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p?=?0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p?0.57 for both vitamin D scores).ConclusionsOn the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

Project description:BackgroundObservational studies indicated that circulating vitamin C (VitC) levels may be correlated with the risk of endometrial cancer (EC). However, the causal effects and direction between them were still unclear.MethodsIn this study, 11 single nucleotide polymorphisms (SNPs) robustly correlated with plasma VitC levels were extracted from the latest genome-wide association study (GWAS), containing 52,018 individuals. Genetic data of EC were obtained from the Endometrial Cancer Association Consortium (ECAC) (12,906 cases and 108,979 controls). An inverse-variance weighted method was utilized as the primary analysis of Mendelian randomization (MR), supplemented by the weighted median, MR Pleiotropy Residual Sum and Outlier test (MR-PRESSO), and MR-Egger methods. Additional sensitivity analyses excluding 3 SNPs with secondary phenotypes were conducted to rule out the possible pleiotropic effects. Potential impacts of several risk factors of EC, such as obesity, body mass index (BMI), hypertension, and diabetes on VitC levels, were assessed. We additionally evaluated the effects of VitC on LDL cholesterol levels, HDL cholesterol levels, and triglycerides levels to probe into the possible mediators in the VitC-EC pathway.ResultsGenetically predicted higher plasma VitC levels (per 1 SD increase, approximately 20 μmol/L) were causally associated with an increased risk of EC overall [odds ratio (OR) 1.374, 95% CI 1.128-1.674, p = 0.0016], supported by complementary sensitivity analyses. In the subgroup analyses, genetically predicted higher levels of VitC were associated with a tendency of increased risks of both endometrioid (OR SD 1.324, 95% CI 0.959-1.829, p = 0.0881) and non-endometrioid histology (OR SD 1.392, 95% CI 0.873-2.220, p = 0.1647) while without statistical significance. The association remained significant after the exclusion of the three pleiotropic SNPs (OR SD 1.394, 95% CI 1.090-1.784, p = 0.0082). The confounders and mediators were unlikely to affect the VitC-EC relationship. The causal effect of EC on VitC levels was not supported (OR 1.001, 95% CI 0.998-1.004, p = 0.4468).ConclusionsThis bi-directional MR study demonstrated a causal risk role of higher circulating VitC at physiological levels on an increased risk of EC, which was independent of confounders and mediators. Further studies are warranted to elucidate the possible mechanisms.

Project description:Background and aimsSarcopenia has been demonstrated to be closely associated with nonalcoholic fatty liver disease (NAFLD). However, whether there are causal relationships between sarcopenia and NAFLD remains undetermined. Here, we aim to address the question using a two-sample bidirectional Mendelian randomization (MR) analysis approach.MethodsWe performed a two-sample bidirectional MR study using summary-level data from genome-wide association studies (GWAS) of the whole body lean mass (n = 38,292), appendicular (arms and legs) lean mass (n = 28,330), and NAFLD (1,483 biopsy-proven NAFLD cases and 17,781 controls). We first conducted MR analysis with five single nucleotide polymorphisms (SNPs) as genetic instruments for whole body lean mass and three SNPs as instruments for appendicular lean mass to estimate the causal effect of genetically predicted sarcopenia on the risk of NAFLD using the inverse-variance weighted (IVW) method. Then we performed reverse MR analysis with four SNPs as instruments to examine the causality of genetically predicted NAFLD with whole body lean mass and appendicular lean mass. Further sensitivity analysis was conducted to testify the reliability of the MR results.ResultsGenetic predisposition to decreased whole body lean mass was not associated with NAFLD [IVW-random effects, odds ratio (OR) = 1.054, 95%CI: 0.750-1.482, P = 0.761]. Similar results were observed using genetic instruments of appendicular lean mass (IVW-random effects, OR = 0.888, 95%CI: 0.386-2.042, P = 0.780). Reverse MR analysis revealed that genetically predicted NAFLD using four genetic instruments was not associated with whole body lean mass (IVW, β = -0.068, 95%CI: -0.179 to 0.043, P = 0.229) and appendicular lean mass (IVW, β = -0.020, 95%CI: -0.092 to 0.051, P = 0.574). MR analyses using other methods and sensitivity analysis showed consistent results.ConclusionThese results suggested no causal relationships between sarcopenia and NAFLD, indicating that sarcopenia may not be directly involved in the pathogenesis of NAFLD and vice versa.

Dataset Information

Vitamin D and Nonalcoholic Fatty Liver Disease: Bi-directional Mendelian Randomization Analysis.

Publications

Vitamin D and Nonalcoholic Fatty Liver Disease: Bi-directional Mendelian Randomization Analysis.

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