Body mass index and all-cause mortality in HUNT and UK biobank studies: revised non-linear Mendelian randomisation analyses.

OBJECTIVES: To estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework. DESIGN: Mendelian randomisation analyses of two prospective population-based cohorts. SETTING: Individuals of European ancestries living in Norway or the UK. PARTICIPANTS: 56 150 participants from the Trøndelag Health Study (HUNT) in Norway and 366 385 participants from UK Biobank recruited by postal invitation. OUTCOMES: All-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer). RESULTS: A previously published non-linear Mendelian randomisation analysis of these data using the residual stratification method suggested a J-shaped association between genetically predicted BMI and mortality outcomes with the lowest mortality risk at a BMI of around 25 kg/m2. However, the 'constant genetic effect' assumption required by this method is violated. The reanalysis of these data using the more reliable doubly-ranked stratification method provided some indication of a J-shaped relationship, but with much less certainty as there was less precision in estimates at the lower end of the BMI distribution. Evidence for a harmful effect of reducing BMI at low BMI levels was only present in some analyses, and where present, only below 20 kg/m2. A harmful effect of increasing BMI for all-cause mortality was evident above 25 kg/m2, for cardiovascular mortality above 24 kg/m2, for cancer mortality above 30 kg/m2 and for non-cardiovascular non-cancer mortality above 26 kg/m2. In UK Biobank, the association between genetically predicted BMI and mortality at high BMI levels was stronger in women than in men. CONCLUSION: This research challenges findings from previous conventional observational epidemiology and Mendelian randomisation investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m2. Our results provide some evidence that reductions in BMI will increase mortality risk for a small proportion of the population, and clear evidence that increases in BMI will increase mortality risk for those with BMI above 25 kg/m2.

Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality.

Importance: Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. Objectives: To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. Design, Setting, and Participants: This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Exposures: Genetically predicted apoB, LDL-C, and TG. Main Outcomes and Measures: The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. Results: This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. Conclusions and relevance: In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.

Inconsistency in UK Biobank Event Definitions From Different Data Sources and Its Impact on Bias and Generalizability: A Case Study of Venous Thromboembolism.

The UK Biobank study contains several sources of diagnostic data, including hospital inpatient data and self-reported conditions for ~500,000 participants, and primary care data for ~177,000 participants (35%). Epidemiological investigations require a primary disease definition, but whether to combine sources to maximize power or focus on one to ensure a consistent outcome is not clear. The consistency of definitions was investigated for venous thromboembolism (VTE) by looking at overlap when defining cases from hospital in-patient data, primary care reports, and self-reported questionnaires. VTE cases showed little overlap between data sources, with only 6% of reported events for those with primary care data identified by all three of hospital, primary care, and self-report, while 71% appeared only in one source. Deep vein thrombosis only events represented 68% of self-reported and 36% of hospital-reported VTE cases, while pulmonary embolism only events represented 20% of self-reported and 50% of hospital-reported VTE cases. Additionally, different distributions of sociodemographic characteristics were observed; for example, 46% of hospital reported VTE cases were female, compared with 58% of self-reported VTE cases. These results illustrate how seemingly neutral decisions taken to improve data quality can affect the representativeness of a dataset.

MendelianRandomization v0.9.0: updates to an R package for performing Mendelian randomization analyses using summarized data.

The MendelianRandomization package is a software package written for the R software environment that implements methods for Mendelian randomization based on summarized data. In this manuscript, we describe functions that have been added or edited in the package since version 0.5.0, when we last described the package and its contents. The main additions to the package since that time are: 1) new robust methods for performing Mendelian randomization, particularly in the cases of bias from weak instruments and/or winner's curse, and pleiotropic variants, 2) methods for performing Mendelian randomization with correlated variants using dimension reduction to summarize large numbers of highly correlated variants into a limited set of principal components, 3) functions for calculating first-stage F statistics, representing instrument strength, in both univariable and multivariable contexts, and with uncorrelated and correlated genetic variants. We also discuss some pragmatic issues relating to the use of correlated variants in Mendelian randomization.

Relaxing parametric assumptions for non-linear Mendelian randomization using a doubly-ranked stratification method.

Non-linear Mendelian randomization is an extension to standard Mendelian randomization to explore the shape of the causal relationship between an exposure and outcome using an instrumental variable. A stratification approach to non-linear Mendelian randomization divides the population into strata and calculates separate instrumental variable estimates in each stratum. However, the standard implementation of stratification, referred to as the residual method, relies on strong parametric assumptions of linearity and homogeneity between the instrument and the exposure to form the strata. If these stratification assumptions are violated, the instrumental variable assumptions may be violated in the strata even if they are satisfied in the population, resulting in misleading estimates. We propose a new stratification method, referred to as the doubly-ranked method, that does not require strict parametric assumptions to create strata with different average levels of the exposure such that the instrumental variable assumptions are satisfied within the strata. Our simulation study indicates that the doubly-ranked method can obtain unbiased stratum-specific estimates and appropriate coverage rates even when the effect of the instrument on the exposure is non-linear or heterogeneous. Moreover, it can also provide unbiased estimates when the exposure is coarsened (that is, rounded, binned into categories, or truncated), a scenario that is common in applied practice and leads to substantial bias in the residual method. We applied the proposed doubly-ranked method to investigate the effect of alcohol intake on systolic blood pressure, and found evidence of a positive effect of alcohol intake, particularly at higher levels of alcohol consumption.

What makes a good life: using theatrical performance to enhance communication about polygenic risk scores research in patient and public involvement.

The aim of this patient and public involvement and engagement (PPIE) work was to explore improvised theatre as a tool for facilitating bi-directional dialogue between researchers and patients/members of the public on the topic of polygenic risk scores (PRS) use within primary or secondary care. PRS are a tool to quantify genetic risk for a heritable disease or trait and may be used to predict future health outcomes. In the United Kingdom (UK), they are often cited as a next-in-line public health tool to be implemented, and their use in consumer genetic testing as well as patient-facing settings is increasing. Despite their potential clinical utility, broader themes about how they might influence an individual's perception of disease risk and decision-making are an active area of research; however, this has mostly been in the setting of return of results to patients. We worked with a youth theatre group and patients involved in a PPIE group to develop two short plays about public perceptions of genetic risk information that could be captured by PRS. These plays were shared in a workshop with patients/members of the public to facilitate discussions about PRS and their perceived benefits, concerns and emotional reactions. Discussions with both performers and patients/public raised three key questions: (1) can the data be trusted?; (2) does knowing genetic risk actually help the patient?; and (3) what makes a life worthwhile? Creating and watching fictional narratives helped all participants explore the potential use of PRS in a clinical setting, informing future research considerations and improving communication between the researchers and lay members of the PPIE group.

Demographic characteristics, long-term health conditions and healthcare experiences of 6333 trans and non-binary adults in England: nationally representative evidence from the 2021 GP Patient Survey.

OBJECTIVE: In order to address the lack of data on the health and healthcare needs of trans and non-binary adults, NHS England includes questions asking about both gender and trans status in its surveys to support quality improvement programmes.We used self-reported data from the GP Patient Survey to answer the research question: what are the demographic characteristics, health conditions and healthcare experiences of trans and non-binary adults in England? DESIGN/SETTING: Nationally representative, population-based cross-sectional survey in England with survey data collection from January to March 2021. PARTICIPANTS: 840 691 survey respondents including 6333 trans and non-binary adults. OUTCOMES: We calculated weighted descriptive statistics, and using logistic regression explored 15 long-term physical and mental health conditions, and 18 patient experience items, covering overall experience, access, communication and continuity. RESULTS: Trans and non-binary adults were younger, more likely to be from Asian, black, mixed or other ethnic groups and more likely to live in more deprived parts of the country. Age-specific patterns of long-term conditions were broadly similar among trans and non-binary adults compared with all other survey respondents, with some variation by condition. Overall, inequalities in long-term health conditions were largest for autism: OR (95% CI), 5.8 (5.0 to 6.6), dementia: 3.1 (2.5 to 3.9), learning disabilities: 2.8 (2.4 to 3.2) and mental health: 2.0 (1.9 to 2.2), with variation by age. In healthcare experience, disparities are much greater for interpersonal communication (OR for reporting a positive experience, range 0.4 to 0.7 across items) than access (OR range 0.8 to 1.2). Additionally, trans and non-binary adults report much higher preference for continuity 1.7 (1.6 to 1.8), with no evidence of any differences in being able to see or speak to a preferred general practitioner. CONCLUSION: This research adds up to date evidence about population demographics, health and healthcare needs to support healthcare improvement for trans and non-binary adults.

Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

Morning chronotype and digestive tract cancers: Mendelian randomization study.

Morning chronotype has been associated with a reduced risk of prostate and breast cancer. However, few studies have examined whether chronotype is associated with digestive tract cancer risk. We conducted a Mendelian randomization (MR) study to assess the associations of chronotype with major digestive tract cancers. A total of 317 independent genetic variants associated with chronotype at the genome-wide significance level (P < 5 × 10-8 ) were used as instrumental variables from a genome-wide meta-analysis of 449 734 individuals. Summary-level data on overall and six digestive tract cancers, including esophageal, stomach, liver, biliary tract, pancreatic and colorectal cancers, were obtained from the UK Biobank (11 952 cases) and FinnGen (7638 cases) study. Genetic liability to morning chronotype was associated with reduced risk of overall digestive tract cancer and cancers of stomach, biliary tract and colorectum in UK Biobank. The associations for the overall digestive tract, stomach and colorectal cancers were directionally replicated in FinnGen. In the meta-analysis of the two sources, genetic liability to morning chronotype was associated with a decreased risk of overall digestive tract cancer (odds ratio [OR] 0.94, 95% confidence interval [CI]: 0.90-0.98), stomach cancer (OR 0.84, 95% CI: 0.73-0.97) and colorectal cancer (OR 0.92, 95% CI: 0.87-0.98), but not with the other studied cancers. The associations were consistent in multivariable MR analysis with adjustment for genetically predicted sleep duration, short sleep, insomnia and body mass index. The study provided MR evidence of inverse associations of morning chronotype with digestive tract cancer, particularly stomach and colorectal cancers.

Rheumatoid arthritis and risk of site-specific cancers: Mendelian randomization study in European and East Asian populations.

BACKGROUND: The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of the associations of RA with site-specific cancers in European and East Asian populations. METHODS: Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study (n = 367,561), the FinnGen study (n = 260,405), Biobank Japan (n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis. RESULTS: In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval [CI] 1.03-1.10) for head and neck cancer, 1.06 (95% CI 1.02-1.10) for cervical cancer, 0.92 (95% CI 0.87-0.96) for testicular cancer, and 0.94 (95% CI 0.90-0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06-1.29) for pancreatic cancer, 0.91 (95% CI 0.88-0.94) for breast cancer, and 0.90 (95% CI 0.84-0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed. CONCLUSION: This study suggests that RA may play a role in the development of several site-specific cancers.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Coffee consumption and cancer risk: a Mendelian randomisation study.

BACKGROUND: Coffee contains many bioactive chemicals and associations with cancer have been reported in observational studies. In this Mendelian randomisation (MR) study we investigated the causal associations of coffee consumption with a broad range of cancers. MATERIALS AND METHODS: Twelve independent genetic variants proxied coffee consumption. Genetically-predicted risk of any cancer (59,647 cases) and 22 site-specific cancers was estimated in European-descent individuals in UK Biobank. Univariable and multivariable MR analyses were conducted. RESULTS: Genetically-predicted coffee consumption was not associated with risk of any cancer in the main analysis (OR 1.05, 95% CI 0.98-1.14, p = 0.183) but was associated with an increased risk of digestive system cancer (OR 1.28, 95% CI 1.09-1.51, p = 0.003), driven by a strong association with oesophageal cancer (OR 2.79, 95% CI 1.73-4.50, p = 2.5×10-5). This association was consistent after adjustment for genetically-predicted body mass index, smoking and alcohol consumption. There was no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied. However, genetically-predicted coffee consumption was associated with increased risk of multiple myeloma (OR 2.25, 95% CI 1.30-3.89, p = 0.004) and reduced ovarian cancer risk (OR 0.63, 95% CI 0.43-0.93, p = 0.020). CONCLUSIONS: This MR study provides strong support for a causal association of coffee consumption with oesophageal cancer, but not for the majority of cancer types, and the underlying mechanisms require investigation.

Circulating vitamin C and digestive system cancers: Mendelian randomization study.

BACKGROUND & AIMS: Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers. METHODS: Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrumental variables. Effect size estimates for the genetic associations of the vitamin C-associated genetic variants with six major malignancies of digestive system were obtained from the FinnGen (N = 309 154) and UK Biobank (N = 367 542) studies. Results from the two studies were combined using meta-analysis. RESULTS: Genetically predicted higher circulating vitamin C showed a suggestive association with lower risk of small intestine and colorectal cancer after accounting for multiple testing. The odds ratio per 1 standard deviation increment in circulating vitamin C was 0.55 (95% confidence interval 0.32-0.94; P = 0.029) for small intestine cancer and 0.84 (95% confidence interval 0.73-0.96; P = 0.013) for colorectal cancer. There was a suggestive association between genetically predicted higher circulating vitamin C with lower risk of liver cancer in FinnGen but no association in the meta-analysis (odds ratio 0.69; 95% CI 0.36-1.32; P = 0.265). Genetically predicted circulating vitamin C was not associated with cancers of the esophagus, stomach, or pancreas. CONCLUSION: This Mendelian randomization study indicates that vitamin C might play a role in the prevention of small intestine and colorectal cancer.

Differentiating Associations of Glycemic Traits With Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation.

We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2 h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher levels of genetically predicted glycemic traits were consistently associated with increased risk of coronary atherosclerosis-related diseases and symptoms. Genetically predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically predicted FG and 2hGlu were positively associated with risk of large artery stroke. Genetically predicted 2hGlu levels showed positive associations with risk of small vessel stroke. Higher levels of genetically predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically predicted levels of 2hGlu and FI remained after adjustment for other glycemic traits. Increase in glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis but not thrombosis.

Genetic Liability to Rheumatoid Arthritis in Relation to Coronary Artery Disease and Stroke Risk.

OBJECTIVE: To assess the causality of the associations of rheumatoid arthritis (RA) with coronary artery disease (CAD) and stroke using the Mendelian randomization approach. METHODS: Independent single-nucleotide polymorphisms strongly associated with RA (n = 70) were selected as instrumental variables from a genome-wide association meta-analysis including 14,361 RA patients and 43,923 controls of European ancestry. Summary-level data for CAD, all stroke, any ischemic stroke and its subtypes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage were obtained from meta-analyses of genetic studies, international genetic consortia, the UK Biobank, and the FinnGen consortium. We obtained summary-level data for common cardiovascular risk factors and related inflammatory biomarkers to assess possible mechanisms. RESULTS: Genetic liability to RA was associated with an increased risk of CAD and ICH. For a 1-unit increase in log odds of RA, the combined odds ratios were 1.02 (95% confidence interval [1.01, 1.03]; P = 0.003) for CAD and 1.05 (95% confidence interval [1.02, 1.08]; P = 0.001) for ICH. Genetic liability to RA was associated with increased levels of tumor necrosis factor and C-reactive protein (CRP). The association with CAD was attenuated after adjustment for genetically predicted CRP levels. There were no associations of genetic liability to RA with the other studied outcomes. CONCLUSION: This study found that genetic liability to RA was associated with an increased risk of CAD and ICH and that the association with CAD might be mediated by CRP. The heightened cardiovascular risk should be actively monitored and managed in RA patients, and this may include dampening systemic inflammation.

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study.

CONTEXT: The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear. OBJECTIVE: This Mendelian randomization study assessed the causal associations of endogenous 17ß-estradiol (E2), the most potent estrogen, with cancer risk in women. METHODS: As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio. RESULTS: Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10-3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10-13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10-11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers. CONCLUSION: This study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women.

Genetically predicted circulating vitamin C in relation to cardiovascular disease.

AIM: We conducted a two-sample Mendelian randomization (MR) study to assess the associations of genetically predicted circulating vitamin C levels with cardiovascular diseases (CVDs). METHODS AND RESULTS: Ten lead single-nucleotide polymorphisms associated with plasma vitamin C levels at the genome-wide significance level were used as instrumental variables. Summary-level data for 15 CVDs were obtained from corresponding genetic consortia, the UK Biobank study, and the FinnGen consortium. The inverse-variance-weighted method was the primary analysis method, supplemented by the weighted median and MR-Egger methods. Estimates for each CVD from different sources were combined. Genetically predicted vitamin C levels were not associated with any CVD after accounting for multiple testing. However, there were suggestive associations of higher genetically predicted vitamin C levels (per 1 standard deviation increase) with lower risk of cardioembolic stroke [odds ratio, 0.79; 95% confidence interval (CI), 0.64, 0.99; P = 0.038] and higher risk of atrial fibrillation (odds ratio, 1.09; 95% CI, 1.00, 1.18; P = 0.049) in the inverse-variance-weighted method and with lower risk of peripheral artery disease (odds ratio, 0.76, 95% CI, 0.62, 0.93; P = 0.009) in the weighted median method. CONCLUSION: We found limited evidence with MR techniques for an overall protective role of vitamin C in the primary prevention of CVD. The associations of vitamin C levels with cardioembolic stroke, atrial fibrillation, and peripheral artery disease need further study.

Selenium and cancer risk: Wide-angled Mendelian randomization analysis.

Evidence on the association between selenium and cancer risk is inconclusive. We conducted a Mendelian randomization study to examine the associations of selenium levels with 22 site-specific cancers and any cancer. Single nucleotide polymorphisms (SNPs) strongly associated with toenail and blood (TAB) and blood selenium levels in mild linkage disequilibrium (r2 < .3) were used as instrumental variables. Genetic associations of selenium-associated SNPs with cancer were obtained from the UK Biobank including a total of 59 647 cancer cases and 307 914 controls. Associations with P < .1 in UK Biobank were tested for replication in the FinnGen consortium comprising more than 180 000 individuals. The inverse-variance weighted method accounting for linkage disequilibrium was used to estimate the associations. Genetically predicted TAB selenium levels were not associated with the risk of the 22 site-specific cancers or any cancer (all 22 site-specific cancers). Similarly, we observed no strong association for genetically predicted blood selenium levels. However, genetically predicted blood selenium levels showed suggestive associations with risk of kidney cancer (odds ratio [OR] per one-unit increase in log-transformed levels: 0.83; 95% confidence interval [CI]: 0.67-1.03) and multiple myeloma (OR: 1.40; 95% CI: 1.02-1.93). The same direction of association for kidney cancer but not for multiple myeloma was observed in FinnGen. In the metaanalysis of UK Biobank and FinnGen, the OR of kidney cancer was 0.83 (95% CI: 0.69-1.00). Our study suggests that high selenium status may not prevent cancer development. The associations for kidney cancer and multiple myeloma need to be verified in well-powered studies.