Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis.
Ontology highlight
ABSTRACT:
SUBMITTER: Yarmolinsky J
PROVIDER: S-EPMC6685606 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis.
Yarmolinsky James J Relton Caroline L CL Lophatananon Artitaya A Muir Kenneth K Menon Usha U Gentry-Maharaj Aleksandra A Walther Axel A Zheng Jie J Fasching Peter P Zheng Wei W Yin Ling Woo W Park Sue K SK Kim Byoung-Gie BG Choi Ji-Yeob JY Park Boyoung B Davey Smith George G Martin Richard M RM Lewis Sarah J SJ
PLoS medicine 20190807 8
<h4>Background</h4>Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observat ...[more]
Similar Datasets
Project description:To determine the causality of micro-nutrients concentrations and risk of ovarian cancer using the Mendelian randomization approach. Analyses were conducted using summary statistics data for SNPs robustly associated with concentrations of thirteen micro-nutrients (iron, copper, zinc, calcium, magnesium, phosphorus, selenium, vitamin A, β-carotene, vitamin B6, vitamin B12, vitamin E, folate). The corresponding data for ovarian cancer were obtained from the Ovarian Cancer Association Consortium (25,509 cases and 40,941 controls). In standard Mendelian randomization analysis, the odds ratios (OR) of invasive epithelial ovarian cancer were 0.14 (95% CI, 0.03-0.70; P = 0.02) per 0.1 mmol/L (about one standard deviation, SD) increase in genetically predicted magnesium concentration, 1.04 (95% CI, 1.00-1.09; P = 0.03) per 0.3 μmol/liter (about one SD) increase in genetically predicted β-carotene concentration. The OR of low malignant potential tumours were 0.82 (95% CI, 0.76-0.90; P = 1.01 × 10-5) per 0.3 μmol/liter (about one SD) increase in β-carotene concentration, 1.42 (95% CI, 1.21-1.68; P = 3 × 10-5) per 153 pmol/L (about one SD) increase in vitamin B12 concentration, 0.21 (95% CI, 0.06-0.76; P = 0.02) per 6 mg/L (about one SD) increase in vitamin E concentration. No significant associations of other micro-nutrients and ovarian cancer were observed. This study found that an increased risk of invasive epithelial ovarian cancer was observed with a genetically higher concentration of β-carotene, whereas a decreased risk of invasive epithelial ovarian cancer was found with a higher concentration of magnesium. As for low malignant potential tumours, increased concentration of vitamin B12 could increase the risk of low malignant potential tumours, while increased concentrations of β-carotene and vitamin E could lower the risk of low malignant potential tumours.
| S-EPMC7193611 | biostudies-literature
Project description:ObjectiveMenopause at a young age is associated with many health problems in women, including osteoporosis, depressive symptoms, coronary disease, and stroke. Many traditional observational studies have reported some potential risk factors for early menopause but have drawn different conclusions. This inconsistency can be attributed mainly to unmodified confounding factors. Identifying the factors causally associated with age at menopause is important for early intervention in women with abnormal menopause timing, and for improving the quality of life for postmenopausal women. This study aims to appraise whether the previously reported risk factors are causally associated with early age at natural menopause (ANM) susceptibility.MethodsWe used Mendelian randomization, a statistical method wherein genetic variants are used to determine whether an observational association between a risk factor and an outcome is consistent with a causal effect.ResultsWomen with earlier age at menarche (β = 0.34, se = 0.16, p = 0.035), lower education level (β = 1.19, se = 0.41, p = 0.004) and higher body mass index (β = -0.05, se = 0.02, p = 0.027) had greater risk for early ANM. The causal link between early age at menarche and early ANM was replicated using ReproGen consortium data (β = 0.23, se = 0.07, p = 0.001). However, a current smoking habit, one of previously reported risk factors, was less likely to be correlated causally with early ANM, suggesting that previous observational studies may not have sufficiently adjusted for confounders.ConclusionOur results help to identify the risk factors of ANM via a genetics approach and future research into the biological mechanism could further help with targeted prevention for early menopause.
| S-EPMC7274172 | biostudies-literature
Project description:BACKGROUND: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. METHODS: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. RESULTS: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. CONCLUSION: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.
| S-EPMC3584055 | biostudies-other
Project description:Metabolic traits are associated with the risk of developing glaucoma in observational studies. To assess whether theses associations reflect causality, we conducted a Mendelian randomization (MR) study. Our study included up to 20,906 glaucoma cases and 438,188 controls. Genetic instruments associated with the concerned 11 exposures at the genome-wide significance level were selected from corresponding genome-wide association studies. Summary-level data for glaucoma were obtained from the UK Biobank, the GERA study, and the FinnGen consortium. Univariable and multivariable MR analyses were conducted separately in two populations. Our results showed that higher genetic liability to type 2 diabetes (T2D) was causally and independently associated with an increased risk of glaucoma (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.06-1.16; p = 4.4 × 10-6). The association for T2D persisted after multivariable adjustment. In addition, higher genetically predicted systolic blood pressure (SBP), fasting glucose (FG), and HbA1c, were also suggestively associated with glaucoma risk. The OR was 1.08 (95% CI, 1.01-1.16; p = 0.035) for SBP, 1.24 (95% CI, 1.05-1.47; p = 0.011) for FG, and 1.28 (95% CI, 1.01-1.61; p = 0.039) for HbA1c. No evidence was observed to support the causal effects of body mass index and blood lipids for glaucoma. This study suggests a causal role for diabetes, as well as possible roles for higher SBP, FG, and HbA1c in the development of glaucoma. Further validation is needed to assess the potential of these risk factors as pharmacological targets for glaucoma prevention.
| S-EPMC9867384 | biostudies-literature
Project description:BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.
| S-EPMC6186013 | biostudies-literature
Project description:Age at menarche (AAM) was found to be associated with ovarian cancer risk in previous observational studies. However, the causality of this association remains unclear. Here, after systematic meta-analyses, we performed two-sample Mendelian randomization (MR) analyses to evaluate the causal effect of AAM in epithelial ovarian cancer (EOC) etiology. We performed meta-analyses including 11 410 cases and 1 163 117 noncases to quantitatively evaluate the association between AAM and ovarian cancer risk. In MR analyses, we used 25 single nucleotide polymorphisms (SNPs) associated with AAM for Chinese and 390 SNPs for Europeans as instrumental variables. MR estimates were calculated using inverse-variance weighted methods from 1044 cases and 1172 controls in a Chinese genome-wide association study and validated by the Ovarian Cancer Association Consortium and Consortium of Investigators of Modifiers of BRCA1/2 studies with 29 396 cases and 68 502 controls of European ancestry. In meta-analyses, we observed an inverse association (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93 to 1.00, P = 0.036) between per year older AAM and ovarian cancer risk in case-control studies, but no association was observed in cohort studies. In MR analyses, the OR of EOC risk per year increase in AAM was 0.81 (95% CI = 0.67 to 0.97, P = 0.026) in Chinese and 0.94 (95% CI = 0.90 to 0.98, P = 0.003) in Europeans, respectively. Our study supports a causal association between AAM and EOC risk.
| S-EPMC6639189 | biostudies-literature
Project description: Not available
| S-EPMC10713650 | biostudies-literature
Project description: Not available
| S-EPMC10710398 | biostudies-literature
Project description:BackgroundHypertension poses a significant global health challenge, warranting exploration of novel preventive measures. This study aimed to investigate the role of circulating concentrations of various micronutrients in hypertension using a Mendelian randomization (MR) approach.MethodsData on hypertension were obtained from FinnGen, comprising 55,917 cases and 162,837 controls of European ancestry. Fifteen micronutrients were evaluated and selected based on genome-wide association studies (GWAS) data. Instrumental single nucleotide polymorphisms (SNPs) were chosen according to strict criteria. Univariable Mendelian randomization (UVMR) analysis was conducted using the inverse variance weighted (IVW) method, supplemented by sensitivity analyses. Multivariate Mendelian randomization (MVMR) analysis was performed to assess interactions between micronutrients.ResultsIn UVMR analysis, the IVW method revealed a potential influence of copper (OR = 1.052, 95% CI: 1.006-1.099, P = 0.025) and zinc (OR = 1.083, 95% CI: 1.007-1.165, P = 0.031) on hypertension. Sensitivity analyses supported these findings. MVMR analysis confirmed a direct positive effect of zinc on hypertension (OR = 1.087, 95% CI: 1.026-1.151, P = 0.005), while adjusting for zinc attenuated the effect of copper on hypertension (OR = 1.026, 95% CI: 0.987-1.066, P = 0.193).ConclusionCirculating zinc levels may be a potential risk factor for hypertension, while the association with other micronutrients remains inconclusive. These findings suggest that reducing zinc intake within a healthy range may help lower hypertension risk. Future research should further explore the role of zinc and nonlinear associations for a more comprehensive understanding.
| S-EPMC11523844 | biostudies-literature
Project description:BackgroundAlthough several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.MethodsA two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10-8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.ResultsIn total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.ConclusionsThis two-sample MR analysis found no evidence to support causal association of Hcy with AF.
| S-EPMC8189424 | biostudies-literature