Circulating vitamin E and cardiometabolic measures: a Mendelian randomization analysis.
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ABSTRACT:
SUBMITTER: Fan C
PROVIDER: S-EPMC6769411 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
Publications
Circulating vitamin E and cardiometabolic measures: a Mendelian randomization analysis.
Fan Chuanlong C Huang Tao T Kong Xuejun X Zhang Xiaohong X Zou Zuquan Z Xiao Jing J
Journal of clinical biochemistry and nutrition 20190809 2
Although a large body of literature reported that high intake of vitamin E played a possible role in reducing risk of cardiometabolic diseases, conflicting results were also found in some observational studies due to confounding factors. Hence, we used a Mendelian randomization study as an alternative way to examine the causality between circulating vitamin E and cardiometabolic diseases. Summary-level data were extracted from consortia and three single nucleotide polymorphisms were used as inst ...[more]
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Project description:BackgroundCirculating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe.MethodsWe used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes.ResultsThe MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99).ConclusionsThese findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.
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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.
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Project description:BackgroundThe association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and findingsWe used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n? =? 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p? = ?0.001).ConclusionsWe provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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Project description:Background: The association between circulating vitamin D levels and risk of vitiligo was inconsistent among observational studies, and whether these observed associations were causal remained unclear. Therefore, we aimed to evaluate the effect of vitamin D on the risk of vitiigo using meta-analysis and Mendelian randomization (MR). Methods: At the meta-analysis stage, literature search was performed in PubMed and Web of Science to identify eligible observational studies examining the association of circulating 25-hydroxyvitamin D [25(OH)D] or 25-hydroxyvitamin D3 [25(OH)D3] levels with risk of vitiligo up to April 30, 2021. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) of 25(OH)D and 25(OH)D3 in patients with vitiligo relative to controls were pooled. Then at the MR stage, genetic instruments for circulating 25(OH)D (N = 120,618) and 25(OH)D3 (N = 40,562) levels were selected from a meta-analysis of genome-wide association studies (GWAS) of European descent, and summary statistics of vitiligo were obtained from a meta-analysis of three GWASs including 4,680 cases and 39,586 controls. We used inverse-variance weighted (IVW) as main method, followed by weighted-median and likelihood-based methods. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Results: In the meta-analysis, patients with vitiligo had a lower level of circulating 25(OH)D compared with controls [SMD = -1.40; 95% confidence interval (CI): -1.91, -0.89; P < 0.001], while no statistically significant difference of 25(OH)D3 between vitiligo cases and controls was found (SMD = -0.63; 95% CI: -1.29, 0.04; P = 0.064). However, in the MR analyses, genetically predicted 25(OH)D [odds ratio (OR) = 0.93, 95% CI = 0.66-1.31, P = 0.66] and 25(OH)D3 levels (OR = 0.95, 95% CI = 0.80-1.14, P = 0.60) had null associations with risk of vitiligo using the IVW method. Sensitivity analyses using alternative MR methods and instrumental variables (IV) sets obtained consistent results, and no evidence of pleiotropy or outliers was observed. Conclusion: Our study provided no convincing evidence for a causal effect of 25(OH)D or 25(OH)D3 levels on the risk of vitiligo. Further longitudinal and experimental studies, as well as functional studies are warranted to elucidate the role of vitamin D in the development of vitiligo.
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Project description:Until recently, randomized controlled trials have not demonstrated convincing evidence that vitamin D, or vitamin D in combination with calcium supplementation could improve bone mineral density (BMD), osteoporosis and fracture. It remains unclear whether vitamin D levels are causally associated with total body BMD. Here, we performed a Mendelian randomization study to investigate the association of vitamin D levels with total body BMD using a large-scale vitamin D genome-wide association study (GWAS) dataset (including 79 366 individuals) and a large-scale total body BMD GWAS dataset (including 66,628 individuals). We selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. All these three methods did not show statistically significant association of genetically increased vitamin D levels with total body BMD. Importantly, our findings are consistent with recent randomized clinical trials and Mendelian randomization study. In summary, we provide genetic evidence that increased vitamin D levels could not improve BMD in the general population. Hence, vitamin D supplementation alone may not be associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture.
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Project description:Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes. MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease. However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret. In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease). Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol). We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations. In doing so, we hope to contribute towards more reliable evaluations of MR findings.
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Project description:BackgroundEpidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses.Methods and findingsWe selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10-8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10-5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10-5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null.ConclusionsIn this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.
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