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Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study.

ABSTRACT: Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P < 5 × 10-8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87-1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89-1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53-1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer.

SUBMITTER: Kho PF

PROVIDER: S-EPMC6445879 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study.

Kho Pik Fang PF Glubb Dylan M DM Thompson Deborah J DJ Spurdle Amanda B AB O'Mara Tracy A TA

Frontiers in oncology 20190327

Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies ...[more]

PMID: 30972295

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Project description:Background: Low educational attainment has been reported as a risk factor for many diseases. However, conclusion on the association between educational attainment and endometrial cancer (EC) are inconsistent in previous observational studies. This study aims to explore the potential causal association between educational attainment and EC. Methods: A Mendelian Randomization analysis was performed using publicly summary-level data sets of genome-wide association studies (GWAS). A total of 306 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of educational attainment from the Social Science Genetic Association Consortium GWAS summary data of 1,131,881 participants of European ancestry. SNPs of EC were obtained from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium and the UK Biobank involving 121,885 people. We conducted inverse variance weighted (IVW) to estimate the causal effect as our primary outcome. And we perform several sensitivity analyses, including MR-Egger regression, weighted median method, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier) global test, and leave-one-out sensitivity analysis, to evaluate the effect of pleiotropism on the causal estimates. Results: Genetic predisposition towards 4.2 years of additional educational attainment was associated with 38% lower risk of EC. (odds ratio 0.72, 95% confidence interval 0.62 to 0.83; p = 1.65*10-5). The consistent results of sensitivity analyses indicated our causal estimates were reliable. Genetic predisposition towards longer educational attainment was associated with lower risk of obesity, high waist-to-hip ratio (WHR), and diabetes. Conclusion: This study indicated that low educational attainment was a causal risk factor for EC, especially for EC with endometrioid histology. Low educational attainment might lead to EC through the mediator of obesity, high WHR, and diabetes.

Project description:ObjectivesMendelian randomization (MR) was used to estimate the causal relationship between body mass index (BMI), ever smoked, heart failure, alcohol intake frequency, inflammatory bowel disease (IBD), and pulmonary embolism (PE). This study aimed to investigate whether there is a causal relationship between BMI, the presence of smoking, heart failure, frequency of alcohol intake, IBD, and PE.MethodsPooled data on PE from a published GWAS meta-analysis involving approximately 461,164 participants of European ancestry were selected. A publicly available pooled dataset of BMI (461,460), ever smokers (461,066), heart failure (977,323), IBD (75,000), and frequency of alcohol intake (462,346) was used from another independent GWAS. MR was performed using established analysis methods, including Wald ratios, inverse variance weighted (IVW), weighted median (WM), and MR-Egger. Also, the final expansion was validated with multivariate MR.ResultsIn the IVW model, genetically elevated BMI was causally associated with PE [OR = 1.002, 95% CI (1.001, 1004), P = 0.039]. Cochran's Q test was used to detect heterogeneity in the MR-Egger analysis (P = 0.576). Therefore, the effect of gene-level heterogeneity was not considered. In the MR analysis of other risk factors, we observed genes for ever smoking [IVW OR = 1.004, 95% CI (0.997, 1.012)], heart failure [IVW OR = 0.999, 95% CI (0.996, 1.001)], IBD [IVW OR = 1.000, 95% CI (0.999, 1.001)], and frequency of alcohol intake [IVW OR = 1.002, 95% CI (1.000, 1.004)] were not causally associated with PE. Analysis using multivariate MR expansion showed no causal effect of BMI on PE considering the effect of height as well as weight (P = 0.926).ConclusionIn European populations, a causal relationship exists between BMI and PE: increased BMI leads to PE. In contrast, ever smoking, heart failure, frequency of alcohol intake, and IBD are not directly associated with PE. There was no causal effect of BMI with PE in multivariate Mendelian randomized analysis.

Dataset Information

Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study.

Publications

Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study.

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