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The inflammatory cytokine interleukin-6 (IL-6) is central to orchestrating the immune system [1]. The pathophysiological process underlying severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, consists of an exaggerated host immune response and elevated circulating levels of inflammatory cytokines, including IL-6 [2, 3]. As such, immunomodulatory agents are being investigated for the treatment of COVID-19. Glucocorticoids may limit inflammation-mediated lung injury in patients with severe COVID-19, and consequently reduce progression to respiratory failure and death. The RECOVERY trial found that administration of dexamethasone resulted in lower 28-day mortality among hospitalised COVID-19 patients who were receiving either invasive mechanical ventilation or oxygen alone at randomisation, but not among those who were not receiving any respiratory support [4]. IL-6 receptor (IL6R) inhibition may represent another potential immunomodulatory strategy for treating COVID-19 [5, 6], and a recent meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease [7]., Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 receptor blockade to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19.

Background: The American Heart Association introduced the Life's Simple 7 initiative to improve cardiovascular health by modifying cardiovascular risk factors and lifestyle behaviours. It is unclear whether these risk factors are causally associated with longevity. Objectives: This study aimed to investigate causal associations of Life's Simple 7 modifiable risk factors, as well as sleep and education, with longevity using the two-sample Mendelian randomization design. Methods: Instrumental variables for the modifiable risk factors were obtained from large-scale genome-wide association studies. Data on longevity beyond the 90th survival percentile were extracted from a genome-wide association meta-analysis with 11,262 cases and 25,483 controls whose age at death or last contact was ≤ the 60th survival percentile. Results: Risk factors associated with a lower odds of longevity included the following: genetic liability to type 2 diabetes (OR 0.88; 95% CI: 0.84;0.92), genetically predicted systolic and diastolic blood pressure (per 1-mmHg increase: 0.96; 0.94;0.97 and 0.95; 0.93;0.97), body mass index (per 1-SD increase: 0.80; 0.74;0.86), low-density lipoprotein cholesterol (per 1-SD increase: 0.75; 0.65;0.86) and smoking initiation (0.75; 0.66;0.85). Genetically increased high-density lipoprotein cholesterol (per 1-SD increase: 1.23; 1.08;1.41) and educational level (per 1-SD increase: 1.64; 1.45;1.86) were associated with a higher odds of longevity. Fasting glucose and other lifestyle factors were not significantly associated with longevity. Conclusion: Most of the Life's Simple 7 modifiable risk factors are causally related to longevity. Prevention strategies should focus on modifying these risk factors and reducing education inequalities to improve cardiovascular health and longevity.

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65–0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98–1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

The inflammatory cytokine interleukin-6 (IL-6) is pivotal for orchestrating the immune response. Inhibitors of IL-6 signaling are being investigated as treatments for severe coronavirus disease 2019 (COVID-19). We conducted a Mendelian randomization study investigating the effect of IL-6 signaling on susceptibility to COVID-19 and pneumonia. Our results showed that genetically proxied inhibition of IL-6 signaling was associated with reduced risk of COVID-19, but also with increased risk of pneumonia. Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 signaling inhibitors to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19.

Studies of sleep duration in relation to the risk of site‐specific cancers other than breast cancer are scarce. Furthermore, the available results are inconclusive and the causality remains unclear. We aimed to investigate the potential causal associations of sleep duration with overall and site‐specific cancers using the Mendelian randomization (MR) design. Single‐nucleotide polymorphisms associated with the sleep traits identified from a genome‐wide association study were used as instrumental variables to estimate the association with overall cancer and 22 site‐specific cancers among 367 586 UK Biobank participants. A replication analysis was performed using data from the FinnGen consortium (up to 121 579 individuals). There was suggestive evidence that genetic liability to short‐sleep duration was associated with higher odds of cancers of the stomach (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.15‐4.30; P = .018), pancreas (OR, 2.18; 95% CI, 1.32‐3.62; P = .002) and colorectum (OR, 1.48; 95% CI, 1.12‐1.95; P = .006), but with lower odds of multiple myeloma (OR, 0.47; 95% CI, 0.22‐0.99; P = .047). Suggestive evidence of association of genetic liability to long‐sleep duration with lower odds of pancreatic cancer (OR, 0.44; 95% CI, 0.25‐0.79; P = .005) and kidney cancer (OR, 0.44; 95% CI, 0.21‐0.90; P = .025) was observed. However, none of these associations passed the multiple comparison threshold and two‐sample MR analysis using FinnGen data did not confirm these findings. In conclusion, this MR study does not provide strong evidence to support causal associations of sleep duration with risk of overall and site‐specific cancers. Further MR studies are required., What's new? With the exception of breast cancer, the impact of sleep duration on site‐specific cancer risk remains largely unknown. Here, using Mendelian randomization analysis, the authors investigated the causal role of sleep duration for overall cancer and for 22 site‐specific cancers in more than 367 000 UK Biobank participants. Suggestive associations were detected between certain cancer sites and genetic liability to short or long sleep duration or genetically predicted sleep duration. However, no statistically significant associations were identified between sleep duration and overall or site‐specific cancer risk, indicating that sleep duration does not have a causal influence on cancer.

Summary Background & aims Arachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers. Methods Two genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10−971] and rs16966952 in PDXDC1 [P = 2.4 × 10−10]) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium were used as genetic instruments. The associations of those variants with cancer were taken from the UK Biobank (n = 367,643), FinnGen consortium (n = 135,638), International Lung Cancer Consortium (n = 27,209), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254), Breast Cancer Association Consortium (n = 228,951), Ovarian Cancer Association Consortium (n = 66,450), and BioBank Japan (n = 212,453). Results Higher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05–1.11; P = 6.3 × 10−8) for colorectal cancer and 1.07 (95%CI 1.05–1.10; P = 3.5 × 10−7) for lung cancer. Genetically predicted AA concentrations had a suggestive positive association with esophageal cancer (odds ratio 1.09; 95% CI 1.02–1.17; P = 0.016) but were not associated with cancers of the stomach, pancreas, bladder, prostate, breast, uterus, or ovary. Conclusion These results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit.

Aims/hypothesis Abnormal serum IGF-1 levels are associated with an increased risk of type 2 diabetes and cardiovascular disease. However, the causal role of IGF-1 levels within the normal range in cardiometabolic disease remains unclear. We employed Mendelian randomisation to explore the associations between genetically predicted serum IGF-1 levels and cardiometabolic diseases. Methods Serum IGF-1 levels were predicted using 416 SNPs associated with IGF-1 levels among 358,072 individuals in UK Biobank. Genetic association estimates for the outcomes were obtained from consortia of type 2 diabetes (74,124 cases, 824,006 controls), coronary artery disease (60,801 cases, 123,504 controls), heart failure (47,309 cases, 930,014 controls), atrial fibrillation (65,446 cases, 522,744 controls), and ischaemic stroke (60,341 cases, 454,450 controls). Results Genetic predisposition to elevated serum IGF-1 levels was associated with higher risk of type 2 diabetes and coronary artery disease. The OR (95% CI) per SD increment in IGF-1 level was 1.14 (1.05, 1.24) for type 2 diabetes and 1.09 (1.02, 1.16) for coronary artery disease. The association between IGF-1 and coronary artery disease was attenuated after adjustment for type 2 diabetes (OR 1.06 [95% CI 1.00, 1.13]), suggesting that the association may be partly mediated via type 2 diabetes. There was limited evidence of associations between IGF-1 levels and heart failure, atrial fibrillation and ischaemic stroke. Conclusions/interpretation This study found evidence that increased IGF-1 levels may be causally associated with higher risk of type 2 diabetes.

Aims: Previous studies have found that excessive sport activities are associated with an increased risk of atrial fibrillation (AF). Whether occupational physical activity (OPA) increases the risk for AF is not well studied. We aimed to examine whether OPA influences the risk of AF. Methods: 80,922 men and women, free from AF, completed in 1997 a questionnaire about their OPA at that time (baseline), and also retrospectively in 1997 their OPA at the age of 30 and 50 years. Participants were categorised into three groups (low, medium and high) based on OPA load. Participants were followed-up in the Swedish National Patient Register for ascertainment of AF. Cox proportional hazards regression models were used to estimate relative risks (RR) with 95% confidence intervals (CI), adjusted for potential confounders. Results: 11,614 cases of AF were diagnosed during follow-up time of up to 17 years. We observed an increased risk of AF in relation to increased load of OPA regardless of age. Compared with men who reported a low load of OPA, the multivariable RR (95% CI) for men with a high load was 1.10 (1.03-1.17) at 30 years, 1.11 (1.04-1.17) at 50 years and 1.19 (1.10-1.29) at baseline. The results for women were similar with multivariable RR of 1.16 (1.06-1.27) at 30 years, 1.14 (1.05-1.24) at 50 years and 1.11 (0.99-1.24) at baseline. Conclusion: These findings suggest that high load of OPA previous in life may play a role in increasing the risk for AF in both men and women.

We conducted a two-sample Mendelian randomization study to investigate the causal associations of type 2 diabetes mellitus (T2DM) with risk of overall cancer and 22 site-specific cancers. Summary-level data for cancer were extracted from the Breast Cancer Association Consortium and UK Biobank. Genetic predisposition to T2DM was associated with higher odds of pancreatic, kidney, uterine, and cervical cancer and lower odds of esophageal cancer and melanoma but not associated with 16 other site-specific cancers or overall cancer. The odds ratios (ORs) were 1.13 (95% CI 1.04, 1.22), 1.08 (1.00, 1.17), 1.08 (1.01, 1.15), 1.07 (1.01, 1.15), 0.89 (0.81, 0.98), and 0.93 (0.89, 0.97) for pancreatic, kidney, uterine, cervical, and esophageal cancer and melanoma, respectively. The association between T2DM and pancreatic cancer was also observed in a meta-analysis of this and a previous Mendelian randomization study (OR 1.08; 95% CI 1.02, 1.14; P = 0.009). There was limited evidence supporting causal associations between fasting glucose and cancer. Genetically predicted fasting insulin levels were positively associated with cancers of the uterus, kidney, pancreas, and lung. The current study found causal detrimental effects of T2DM on several cancers. We suggest reinforcing the cancer screening in T2DM patients to enable the early detection of cancer.

We conducted a two-sample Mendelian randomisation study to investigate the causal associations of type 2 diabetes mellitus (T2DM) with risk of overall cancer and 22 site-specific cancers. Summary-level data for cancer were extracted from the Breast Cancer Association Consortium and UK Biobank. Genetic predisposition to T2DM was associated with higher odds of pancreatic, kidney, uterine and cervical cancer, lower odds of oesophageal cancer and melanoma, but not associated with 16 other site-specific cancers or overall cancer. The odds ratios (95% confidence interval) were 1.13 (1.04, 1.22), 1.08 (1.00, 1.17), 1.08 (1.01, 1.15), 1.07 (1.01, 1.15), 0.89 (0.81, 0.98), and 0.93 (0.89, 0.97) for pancreatic, kidney, uterine, cervical, and oesophageal cancer and melanoma, respectively. The association between T2DM and pancreatic cancer was also observed in a meta-analysis of this and a previous Mendelian randomisation study (odds ratio 1.08; 1.02, 1.14; p=0.009). There was limited evidence supporting causal associations between fasting glucose and cancer. Genetically predicted fasting insulin levels were positively associated with cancers of the uterus, kidney, pancreas and lung. The present study found causal detrimental effects of T2DM on several cancers. We suggested to reinforce the cancers screening in T2DM patients to enable the early detection of cancer.

ObjectivesTo use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels.DesignTwo-sample Mendelian randomization (MR) analysis.SettingSummary-level genetic association data.ParticipantsParticipants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants).Main outcomes and measuresLung ACE2 and TMPRSS2 expression and plasma ACE2 levels.ResultsThere were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4×10−4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes.ConclusionsThis study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification.Summary boxesWhat is already known on this topicSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic.Serine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor.Expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19.What this study addsWe used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels.Our findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression.We found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies.

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. We here assess the potential effect of statin therapy on cancer risk in Mendelian randomization analyses. We obtained genetic associations with the risk of overall and 22 site-specific cancers for 367,703 individuals in UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (OR per 1 standard deviation increase in LDL-cholesterol 1.32, 95% CI 1.13-1.53, p=0.0003), but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically-predicted LDL-cholesterol was not associated with overall cancer risk (OR 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk, but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

ObjectivesTo investigate the casual role of body mass index, body fat composition and height in cancer.DesignTwo stage mendelian randomisation studySettingPrevious genome wide association studies and the UK BiobankParticipantsGenetic instrumental variables for body mass index (BMI), fat mass index (FMI), fat free mass index (FFMI) and height from previous genome wide association studies and UK Biobank. Cancer outcomes from 367 586 participants of European descent from the UK Biobank.Main outcome measuresOverall cancer risk and 22 site-specific cancers risk for genetic instrumental variables for BMI, FMI, FFMI and height.ResultsGenetically predicted BMI (per 1 kg/m2) was not associated with overall cancer risk (OR 0.99; 95% confidence interval (CI) 0-98-1.00, p=0.105). Elevated BMI was associated with increased risk of stomach cancer (OR 1.15, 95% (CI) 1.05-1.26; p=0.003) and melanoma (OR 0.96, 95% CI 0.92-1.00; p=0.044). For sex-specific cancers, BMI was positively associated with uterine cancer (OR 1.08, 95% CI 1.01-1.14; p=0.015) but inversely associated with breast (OR 0.95, 95% CI 0.92-0.98; p=0.001), prostate (OR 0.95, 95% CI 0.92-0.99; p=0.007) and testicular cancer (OR 0.89, 95% CI 0.81-0.98; p=0.017). Elevated FMI (per 1 kg/m2) was associated with gastrointestinal cancer (stomach cancer OR 4.23, 95% CI 1.18-15.13, p=0.027; colorectal cancer OR 1.94, 95% CI 1.23-3.07; p=0.004). Increased height (per 1 standard deviation, approximately 6.5cm) was associated with increased risk of overall cancer (OR 1.06; 95% 1.04-1.09; p = 2.97×10-8) and most site-specific cancers with the strongest estimates for kidney, non-Hodgkin lymphoma, colorectal, lung, melanoma and breast cancer.ConclusionsThere is little evidence for BMI as a casual risk factor for cancer. BMI may have a causal role for sex-specific cancers, although with inconsistent directions of effect, and FMI for gastrointestinal malignancies. Elevated height is a risk factor for overall cancer and multiple site cancers.

BackgroundA deeper understanding of the causal links from education level to health outcomes may shed a light for disease prevention at a novel and efficient perspective.MethodsWe conducted a wide-angled Mendelian randomization to disentangle the causal role of education level from intelligence for 31 health outcomes and explore to what extent body mass index and smoking mediate the associations. Univariable and multivariable Mendelian randomization analyses were performed.ResultsGenetically higher education level was associated with lower risk of major mental disorders and most somatic diseases independent of intelligence. The intelligence-adjusted odds ratios for each additional standard deviation of education (4.2 years) were 0.48 (0.37, 0.62) for suicide attempts, 0.50 (0.36, 0.68) for large artery stroke, 0.51 (0.42, 0.63) for heart failure, 0.52 (0.42, 0.65) for lung cancer, 0.45 (0.33,0.61) for rheumatoid arthritis, and 0.48 (0.43, 0.55) for type 2 diabetes. Higher education level adjusted for intelligence was additionally associated with lower risk of insomnia, major depressive disorder, stroke, coronary artery disease, breast cancer, ovarian cancer and gout but with higher risk of obsessive-compulsive disorder, anorexia nervosa, bipolar disorder and prostate cancer. Moreover, higher education level was associated with modifiable health-related risk factors in a favorable manner. Adjustment for body mass index and smoking attenuated the associations between education level and several outcomes, especially for type 2 diabetes and heart failure. High education level exerts causal protective effects on major somatic diseases.ConclusionsThese findings emphasize the importance of education to reduce the burden of common diseases.

Early‐adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual‐level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18–24 years and other breast cancer risk factors showed that weight gain from ages 18–24 to 35–44 or to 45–54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45–54: 0.96, 95% CI: 0.95–0.98) and with oestrogen‐receptor(ER)‐positive breast cancer (HR per 5 kg to ages 45–54: 0.96, 95% CI: 0.94–0.98). Weight gain from ages 25–34 was inversely associated with ER‐positive breast cancer only and weight gain from ages 35–44 was not associated with risk. None of these weight gains were associated with ER‐negative breast cancer. Weight loss was not consistently associated with overall or ER‐specific risk after adjusting for initial weight. Weight increase from early‐adulthood to ages 45–54 years is associated with a reduced premenopausal breast cancer risk independently of early‐adulthood weight. Biological explanations are needed to account for these two separate factors., What's new? Body weight in childhood and early adulthood plays a key role in determining premenopausal breast cancer risk but little is conclusively known about how subsequent weight changes affect this risk. Here the authors pooled results from existing studies on weight changes and breast cancer risk including more than 600,000 premenopausal women. The results show that weight gain >10–15 kg from early adulthood on lowers the risk of developing premenopausal breast cancer, providing further evidence of body weight as an important determinant of breast cancer risk.

Aims The causal role of adiposity for several cardiovascular diseases (CVDs) is unclear. Our primary aim was to apply the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 CVDs and arterial hypertension. We also assessed the roles of fat mass and fat-free mass on the same outcomes. Methods and results Single-nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instrumental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was significantly positively associated with eight outcomes, including and with decreasing magnitude of association: aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio (OR) per 1 kg/m2 increase in BMI ranged from 1.06 [95% confidence interval (CI) 1.02–1.11; P = 2.6 × 10−3] for pulmonary embolism to 1.13 (95% CI 1.05–1.21; P = 1.2 × 10−3) for aortic valve stenosis. There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes (P Conclusion This study provides evidence that higher BMI and particularly fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions.

Aims The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs). Methods and results Our primary genetic instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage. Conclusion This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.

BACKGROUND AND PURPOSE: To clarify the causal associations of interleukin-1 receptor antagonist (IL-1ra) and interleukin-2 receptor alpha subunit (IL-2rα) with the risk of amyotrophic lateral sclerosis (ALS). METHODS: A two-sample Mendelian randomization study design was employed. Single-nucleotide polymorphisms associated with IL-1ra (n = 2) and IL-2rα (n = 1) at the genome-wide significance level were used as unbiased instrumental variables. Summary-level data for ALS were obtained from Project MinE, an international collaboration consortium with 12 577 ALS cases and 23 475 controls of European descent. RESULTS: Genetic predisposition to higher levels of IL-1ra was significantly associated with lower odds of ALS. For a 1-SD increase of circulating IL-1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46-0.88; P = 0.005). There was a borderline inverse association between IL-2rα levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83-1.00; P = 0.058). CONCLUSIONS: Interleukin-1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin-1 inhibitors may lower the risk of this always fatal disease. The role of IL-2rα levels in ALS needs further verification in causal inference studies with larger sample sizes.

Aims/hypothesis Epidemiological data on the associations of circulating fatty acid levels with type 2 diabetes are inconsistent. We conducted a two-sample Mendelian randomisation study to explore the causal associations of plasma levels of ten fatty acids with type 2 diabetes and glycaemic traits. Methods Thirteen SNPs associated with circulating levels of ten individual fatty acids at the genome-wide significance level (p −8) were selected as instrumental variables for the exposures. For the outcomes, summary-level data were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium for type 2 diabetes (898,130 individuals) and from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for the glycaemic traits (up to 46,186 non-diabetic individuals). The inverse-variance weighted method was used for analyses. Results Genetic predisposition to higher plasma levels of eight of the ten fatty acids were statistically significantly associated with lower or higher odds of type 2 diabetes. The OR per one SD increment of each fatty acid was 0.93 (95% CI 0.90, 0.96; p = 2.21 × 10−5) for α-linolenic acid, 0.96 (95% CI 0.94, 0.98; p = 1.85 × 10−4) for linoleic acid, 0.86 (95% CI 0.81, 0.91; p = 6.68 × 10−7) for palmitoleic acid, 0.87 (95% CI 0.81, 0.93; p = 2.21 × 10−5) for oleic acid, 1.08 (95% CI 1.03, 1.12; p = 0.002) for eicosapentaenoic acid, 1.04 (95% CI 1.02, 1.07; p = 0.001) for docosapentaenoic acid, 1.03 (95% CI 1.02, 1.05; p = 2.51 × 10−5) for arachidonic acid and 1.09 (95% CI 1.03, 1.15; p = 0.003) for stearic acid. The same eight fatty acids were also associated with fasting glucose levels and HOMA-B. The associations, except that for palmitoleic acid, were driven by variants in FADS1/2. Conclusions/interpretation Genetic predisposition to higher circulating levels of eight out of ten fatty acids was associated with type 2 diabetes, fasting glucose and islet beta cell function. However, the associations, except that for palmitoleic acid, were driven by variants in FADS1/2, which encode enzymes with a key role in fatty acid metabolism.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

BackgroundTumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer.MethodsSingle-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia.FindingsGenetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94).InterpretationThis study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.

OBJECTIVE: We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with low- and high-density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A-I and B (apoA-I and apoB) at the level of genomewide significance (p

Supplemental Digital Content is available in the text., Background: Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within the FADS1 gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS. FADS1 encodes a rate-limiting enzyme for ω-3 and ω-6 fatty acid metabolism. The aim of this study was to decipher the local transcriptomic and lipidomic consequences of rs174547 in tricuspid aortic valves from patients with AS. Methods: Expression quantitative trait loci study was performed using data from Illumina Human610-Quad BeadChip, Infinium Global Screening Arrays, and Affymetrix Human Transcriptome 2.0 arrays in calcified and noncalcified aortic valve tissue from 58 patients with AS (mean age, 74.2; SD, 5.9). Fatty acid content was assessed in aortic valves from 25 patients with AS using gas chromatography. Δ5 and Δ6 desaturase activity was assessed by the product-to-precursor ratio. Results: The minor C-allele of rs174547, corresponding to the protective genotype for AS, was associated with higher FADS2 mRNA levels in calcified valve tissue, whereas FADS1 mRNA and other transcripts in proximity of the single nucleotide polymorphism were unaltered. In contrast, the FADS1 Δ5-desaturase activity and the FADS2 Δ6-desaturase activity were decreased. Finally, docosahexaenoic acid was decreased in calcified tissue compared with non-calcified tissue and C-allele carriers exhibited increased docosahexaenoic acid levels. Overall desaturase activity measured with ω-3 fatty acids was higher in C-allele carriers. Conclusions: The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.

Aims/hypothesis The aim of this study was to use Mendelian randomisation (MR) to identify the causal risk factors for type 2 diabetes. Methods We first conducted a review of meta-analyses and review articles to pinpoint possible risk factors for type 2 diabetes. Around 170 possible risk factors were identified of which 97 risk factors with available genetic instrumental variables were included in MR analyses. To reveal more risk factors that were not included in our MR analyses, we conducted a review of published MR studies of type 2 diabetes. For our MR analyses, we used summary-level data from the DIAbetes Genetics Replication And Meta-analysis consortium (74,124 type 2 diabetes cases and 824,006 controls of European ancestry). Potential causal associations were replicated using the FinnGen consortium (11,006 type 2 diabetes cases and 82,655 controls of European ancestry). The inverse-variance weighted method was used as the main analysis. Multivariable MR analysis was used to assess whether the observed associations with type 2 diabetes were mediated by BMI. We used the Benjamini–Hochberg method that controls false discovery rate for multiple testing. Results We found evidence of causal associations between 34 exposures (19 risk factors and 15 protective factors) and type 2 diabetes. Insomnia was identified as a novel risk factor (OR 1.17 [95% CI 1.11, 1.23]). The other 18 risk factors were depression, systolic BP, smoking initiation, lifetime smoking, coffee (caffeine) consumption, plasma isoleucine, valine and leucine, liver alanine aminotransferase, childhood and adulthood BMI, body fat percentage, visceral fat mass, resting heart rate, and four plasma fatty acids. The 15 exposures associated with a decreased risk of type 2 diabetes were plasma alanine, HDL- and total cholesterol, age at menarche, testosterone levels, sex hormone binding globulin levels (adjusted for BMI), birthweight, adulthood height, lean body mass (for women), four plasma fatty acids, circulating 25-hydroxyvitamin D and education years. Eight associations remained after adjustment for adulthood BMI. We additionally identified 21 suggestive risk factors (p Conclusions/interpretation The present study verified several previously reported risk factors and identified novel potential risk factors for type 2 diabetes. Prevention strategies for type 2 diabetes should be considered from multiple perspectives on obesity, mental health, sleep quality, education level, birthweight and smoking. Graphical abstract

Background: The causal role of interleukins (ILs) for cardiovascular disease has not been fully elucidated. Weconducted a Mendelian randomization study to investigate the associations of circulating ILs with coronary artery disease (CAD), atrial fibrillation (AF), and ischemic stroke. Methods and results: Single-nucleotide polymorphisms associated with IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-2 receptor subunit alpha, IL-6, IL-16, IL-17 and IL-18 were identified from genome-wide association studies. Summary-level data of the outcomes were obtained from three large consortia. Genetic predisposition to higher IL-1ra levels were significantly associated with CAD. The odds ratio was 1.36 (95% confidence interval (CI), 1.14-1.63; P= 5.37 x 10(-4)) per one standard deviation increase in IL-1ra levels. Genetically higher IL-6 levels, predicted by a variant in the IL6R gene and corresponding to reduced IL-6 bio-function, were significantly inversely associated with CAD and AF. The odds ratios per one standard deviation increase in IL-6 levels were 0.64 (95%CI, 0.54-0.76; P = 2.22 x 10(-7)) for CAD and 0.70 (95%CI, 0.62-0.80; P = 1.34 x 10(-7)) for AF. There was a suggestive positive association of IL-1ra with cardioembolic stroke and suggestive inverse associations of IL-6 with any ischemic stroke, cardioembolic stroke, and small vessel stroke, and of IL-16 with CAD. The other ILs were not associated with any outcome. Conclusions: These results strengthen the evidence that IL-6 inhibition may offer a therapeutic approach for prevention of CAD, AF, and ischemic stroke. In contrast, IL-1 inhibition through raised IL-1ra levels may confer increased risk of CAD and cardioembolic stroke. The role of IL-16 for CAD warrants further investigation. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Lipoprotein(a) (Lp[a]) is a circulating lipoprotein with proatherogenic, proinflammatory, and possibly prothrombotic properties. Circulating Lp(a) levels are largely genetically determined, in particular, by the LPA gene. As such, genetic variants at the LPA locus can serve as instrumental variables for investigating the clinical effects of circulating Lp(a) levels. Mendelian randomization (MR) studies have shown that elevated Lp(a) levels are associated with a higher risk of coronary artery disease1–3 and aortic valve stenosis.2–4 Evidence on the causal role of elevated Lp(a) levels for other atherosclerotic and specific valvular diseases is limited, although there are MR data supporting a positive association between genetically predicted Lp(a) levels and peripheral artery disease.2,3 Whether Lp(a) is causally related to thrombotic disease and cerebrovascular disease remains unclear.2,3,5 In this study, we used the UK Biobank cohort to perform an MR investigation into the causal effects of circulating Lp(a) levels on atherosclerotic, cerebrovascular, thrombotic, and valvular diseases. Because a recent MR study provided evidence of an inverse association of Lp(a) levels with Alzheimer disease,5 we additionally explored whether genetically predicted Lp(a) levels are associated with Alzheimer disease and dementia.

Purpose Observational studies have suggested that polyunsaturated fatty acids (PUFAs) may decrease Alzheimer’s disease (AD) risk. In the present study, we examined this hypothesis using a Mendelian randomization analysis. Methods We used summary statistics data for single-nucleotide polymorphisms associated with plasma levels of n-6 PUFAs (linoleic acid, arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid), and the corresponding data for AD from a genome-wide association meta-analysis of 63,926 individuals (21,982 diagnosed AD cases, 41,944 controls). Results None of the genetically predicted PUFAs was significantly associated with AD risk; odds ratios (95% confidence interval) per 1 SD increase in PUFA levels were 0.98 (0.93, 1.03) for linoleic acid, 1.01 (0.98, 1.05) for arachidonic acid, 0.96 (0.88, 1.06) for alpha-linolenic acid, 1.03 (0.93, 1.13) for eicosapentaenoic acid, 1.03 (0.97, 1.09) for docosapentaenoic acid, and 1.01 (0.81, 1.25) for docosahexaenoic acid. Conclusions This study did not support the hypothesis that PUFAs decrease AD risk.

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p &lt, 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45, p = 0.11), 2.11 (1.16, 3.83, p = 0.02), 10.89 (2.44, 48.59, p = 0.002) and 0.30 (0.17, 0.53, p = 2 &times, 10&minus, 5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00, p = 0.05), 0.75 (0.59, 0.97, p = 0.03), 0.41 (0.20, 0.88, p = 0.02) and 1.49 (1.04, 2.14, p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

Background: Although both season and fat mass affect serum 25-hydroxyvitamin D (S‑25OHD), these factors are often ignored when assessing vitamin D status. We aimed to investigate the impact of season and fat mass on the association of S‑25OHD with fracture risk. Methods: We enrolled 5003 women, mean age 68 years, with body composition scans and blood collection in a population-based cohort. Fracture information was obtained from Swedish clinical databases. Proportional hazards regression, stratified by season and fat mass, was used to determine hazard ratios (HR) of fracture according to S-25OHD. Our secondary exposures were serum 1,25‑dihydroxycholecalciferol, the most active vitamin D metabolite and plasma parathyroid hormone (P-PTH). Findings: During an average of 9.2 years of follow-up, 1080 women had a fracture. Compared with women with S‑25OHD >60 nmol/L during sunny months (May through October), those with S‑25OHD

OBJECTIVE: To investigate whether overall obesity (as measured by BMI) and abdominal obesity (as measured by waist-to-hip ratio adjusted for BMI) are associated with gout risk and serum urate concentrations using Mendelian randomization. METHODS: Single nucleotide polymorphisms associated with BMI (n = 97) and waist-to-hip ratio adjusted for BMI (n = 49) were analysed for association with gout risk in 2115 gout cases and 67 259 controls, and with serum urate concentrations in 110 347 individuals from the Global Urate Genetics Consortium. RESULTS: Genetically higher BMI, but not waist-to-hip ratio adjusted for BMI, was positively associated with risk of gout and serum urate concentrations. Each standard deviation (about 4.6 kg/m(2)) increase in genetically predicted BMI was associated with an odds ratio of gout of 2.24 (95% CI 1.70, 2.95; P = 8.4 × 10(–9)) and with a 0.30 mg/dl (95% CI 0.25, 0.35; P = 1.6 × 10(–36)) increase in serum urate concentrations. CONCLUSION: These findings provide support that overall obesity may be a risk factor for gout and is associated with higher serum urate concentrations.

Controversy exists on the association between alcohol consumption and risk of heart failure (HF). We carried out a meta-analysis to summarize available prospective data on alcohol consumption and HF.We searched PubMed for relevant studies published until January 1, 2017. Relative risk (RR) estimates from individual studies were pooled in a random-effects meta-analysis.A total of 13 prospective studies, with 13,738 HF cases and 355,804 participants, were included in the meta-analysis. Light alcohol drinking (0.1-7 drinks/week) was inversely associated with risk of HF (RR, 0.86; 95% confidence interval, 0.81-0.90). There was no statistically significant association between moderate (7.1-14 drinks/week), high (14.1-28 drinks/week), or heavy (28 drinks/week) alcohol consumption and HF risk. Former drinking was associated with an increased risk of HF compared with never or occasional drinking (RR, 1.22; 95% confidence interval, 1.11-1.33).This meta-analysis found that light alcohol drinking was associated with a lower risk of HF. Former drinking was associated with a higher risk of HF.

BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.

BackgroundNut consumption has been found to be inversely associated with cardiovascular disease mortality, but the association between nut consumption and incidence of specific cardiovascular diseases is unclear. We examined the association between nut consumption and incidence of seven cardiovascular diseases.MethodsThis prospective study included 61 364 Swedish adults who had completed a Food Frequency Questionnaire and were followed up for 17 years through linkage with the Swedish National Patient and Death Registers.ResultsNut consumption was inversely associated with risk of myocardial infarction, heart failure, atrial fibrillation and abdominal aortic aneurysm in the age-adjusted and sex-adjusted analysis. However, adjustment for multiple risk factors attenuated these associations and only a linear, dose–response, association with atrial fibrillation (ptrend=0.004) and a non-linear association (pnon-linearity=0.003) with heart failure remained. Compared with no consumption of nuts, the multivariable HRs (95% CI) of atrial fibrillation across categories of nut consumption were 0.97 (0.93 to 1.02) for 1–3 times/month, 0.88 (0.79 to 0.99) for 1–2 times/week and 0.82 (0.68 to 0.99) for ≥3 times/week. For heart failure, the corresponding HRs (95% CI) were 0.87 (0.80 to 0.94), 0.80 (0.67 to 0.97) and 0.98 (0.76 to 1.27). Nut consumption was not associated with risk of aortic valve stenosis, ischaemic stroke or intracerebral haemorrhage.ConclusionsThese findings suggest that nut consumption or factors associated with this nutritional behaviour may play a role in reducing the risk of atrial fibrillation and possibly heart failure.Trial registration numberNCT01127711 and NCT01127698; Results.

Background and Purpose— Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). Methods— Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance–weighted MR was used to obtain the causal estimates. Inverse-variance–weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. Results— A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04–1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10–1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67–0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. Conclusions— LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

There is considerable discussion of the importance for increased serum 25-hydroxyvitamin D (S-25OHD) concentration associated with adequacy for bone health. Accordingly, whether long-term high S-25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S-25OHD concentrations and BMD. Five single-nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict 1 standard deviation increase in S-25OHD concentration. Summary statistics data for the associations of the S-25OHD-associated SNPs with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD were obtained from the Genetic Factors for Osteoporosis (GEFOS) Consortium (32,965 individuals) and ultrasound-derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs were associated with BMD at Bonferroni-corrected significance level, but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted 1 standard deviation increment of S-25OHD was not associated with higher femoral neck BMD (SD change in BMD 0.02; 95% confidence interval [CI] -0.03 to 0.07; p = 0.37), lumbar spine BMD (SD change in BMD 0.02; 95% CI -0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD -0.03; 95% CI -0.05 to -0.01; p = 0.02). This study does not support a causal association between long-term elevated S-25OHD concentrations and higher BMD in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence-based cut-off points for vitamin D inadequacy rather than a general recommendation to increase S-25OHD. © 2018 American Society for Bone and Mineral Research.

OBJECTIVES: To investigate associations between time updated information of milk and fermented milk consumption and risk of total stroke. METHODS: We included 79,613 Swedish adults (35,892 women and 43,721 men), 45–83 years of age, without stroke at baseline in 1997 (SIMPLER, simpler4health.se). The participants completed a validated 96-item food frequency questionnaire including questions about milk and soured milk and yogurt consumption at baseline and in 2009. Incident and previous stroke cases were identified by linkage with the Swedish National Patient and Cause of Death Registers. Associations between milk and fermented milk intake and incident total stroke were assessed by restricted cubic spline Cox regression. We included the baseline covariates sex and educational level, and time updated exposures and covariates (age, smoking, total energy intake, body mass index, physical activity, living alone, coffee, vitamin- and mineral supplements, alcohol consumption, hypertension, hypercholesterolemia, diabetes mellitus, coronary heart disease, weighted Charlson Comorbidity Index, and intakes of fermented milk (in analyses of milk), milk (in analyses of fermented milk), fruits and vegetables, processed meat, soft drink, juice, total fat, and saturated fat) from 2009. RESULTS: The average intake in 1997 was 260 grams (g)/day (d) for milk and 160 g/d for fermented milk (200 g corresponds to 1 glass). During a mean follow-up of 17.7 years (maximum follow-up of 22 years), 9736 total stroke cases were identified. P-values for non-linearity were 0.010 for milk and 0.721 for fermented milk. Compared with zero intake the Hazard ratio (HR) for milk intake was 0.95 (95% Confidence Interval (CI) 0.91, 0.99) for 200 g/d, 0.94 (95% CI 0.89, 1.00) for 400 g/d, and 0.97 (95% CI (0.91, 1.02) for 600 g/d. For fermented milk intake the HR was 0.99 (95% CI 0.95, 1.04) for 200 g/day, 1.00 (0.95% CI 0.95, 1.05) for 400 g/d, and 1.01 (95% CI 0.95, 1.07) for 600 g/d compared with zero intake. CONCLUSIONS: A low to moderate, but not higher, milk consumption (1–2 glasses/d) seem to have a protective effect on total stroke, compared to zero intake. Consumption of fermented milk was not associated with total stroke. FUNDING SOURCES: SIMPLER is funded by Vetenskapsrådet. The current work is funded by Forte.

Objective:To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes.Methods:MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNP-stroke associations were derived from METASTROKE and the Stroke Genetics Network (n = 18,476 ischemic stroke cases and 37,296 controls).Results:Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16–1.40, p = 3.3 × 10−7) and small vessel stroke (OR 1.21, 95% CI 1.10–1.33, p = 8.9 × 10−5) but not cardioembolic stroke (OR 1.06, 95% CI 0.97–1.15, p = 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype.Conclusions:This study provides support that T2D may be causally associated with large artery stroke.

Background Alcohol consumption and cigarette smoking are modifiable lifestyle factors with important impact on public health. It is unclear whether these factors influence the risk of aortic valve stenosis (AVS). Objective To investigate the associations of alcohol consumption and smoking, including smoking intensity and time since cessation, with AVS incidence in two prospective cohorts. Methods This analysis was based on data from the Swedish Mammography Cohort and the Cohort of Swedish Men, comprising 69 365 adults without cardiovascular disease at baseline. Participants were followed for AVS incidence and death by linkage to the Swedish National Patient and Causes of Death Registers. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression. Results Over a mean follow-up of 15.3 years, 1249 cases of AVS (494 in women and 755 in men) were recorded. Compared with never drinkers of alcohol (lifelong abstainers), the risk of AVS was significantly lower in current light drinkers (1–6 drinks per week [1 drink = 12 g alcohol]; multivariable HR 0.82; 95% CI: 0.68–0.99). The risk of AVS increased with increasing smoking intensity. Compared with never smokers, the HR was 1.46 (95% CI: 1.16–1.85) in current smokers of ≥30 pack-years. Former smokers who had quit smoking 10 or more years previously had similar risk for AVS as never smokers. Conclusions This study suggests that current light alcohol consumption is associated with a lower risk of AVS, and indicates that the association between smoking and AVS risk is reversible.

Aims The aim of this study was to examine the association of overall and abdominal obesity with aortic valve stenosis (AVS) incidence in two prospective cohorts. Methods and results We used data from the Cohort of Swedish Men and the Swedish Mammography Cohort, involving 71 817 men and women who were free of cardiovascular disease and had reported their anthropometric measures in 1997. Aortic valve stenosis cases were ascertained through linkage with nationwide registers on hospitalization and causes of death. Data were analysed using Cox proportional hazards regression. During a mean follow-up of 15.3 years, 1297 incident AVS cases (771 in men; 526 in women) were ascertained. Both overall and abdominal obesity, measured as body mass index (BMI) and waist circumference, respectively, was associated with AVS incidence, with similar associations in men and women. Compared with BMI 18.5–22.5 kg/m2, the multivariable hazard ratios were 1.24 (95% confidence interval [CI] 1.05–1.48) for overweight (BMI 25.0–29.9 kg/m2) and 1.81 (95% CI 1.47–2.23) for obesity (BMI ≥30 kg/m2). The hazard ratio for substantially increased waist circumference (men: ≥102 cm; women: ≥88 cm) compared with normal waist circumference (men

Summary Background & aims Whether high intakes of fish and long-chain omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of atrial fibrillation (AF) remains uncertain. Thus, we aimed to evaluate the associations of total fish, types of fish, and omega-3 PUFA intake with AF incidence in a large prospective study. Methods We used data from the Cohort of Swedish Men and the Swedish Mammography Cohort to examine the associations of fish consumption and long-chain omega-3 PUFA intake with AF incidence. At baseline, information on fish and omega-3 PUFA intakes was available from 72,984 men and women, aged 45–83 years, without cardiac disease. Cases of AF were identified through linkage with the Swedish National Patient Register. Multivariable-adjusted relative risks were estimated with the use of Cox proportional hazards models. Results Over a follow-up period of 12 years, 6095 participants (3595 men and 2500 women) developed AF. Intakes of total fish, fatty fish (herring/mackerel and salmon/whitefish/char), and long-chain omega-3 PUFAs were not associated with AF incidence after adjustment for other risk factors. However, high consumption of lean fish (cod/saithe/fish fingers) was associated with a lower risk; multivariable relative risk of AF for ≥3 servings/week compared with never consumption was 0.79 (95% confidence interval, 0.65–0.95). Conclusions These findings do not support a beneficial association of fatty fish or omega-3 PUFA intake with incident AF. The association between lean fish consumption and AF risk warrants further investigation.

The potential cardioprotective effect of light-to-moderate alcohol consumption is disputed, and the association between heavy drinking and heart failure (HF) risk is unclear. We examined the association between alcohol consumption and risk of myocardial infarction (MI) and HF in two prospective cohorts.We analyzed data from the Cohort of Swedish Men (40,590 men) and the Swedish Mammography Cohort (34,022 women). Participants were free of ischemic heart disease and HF at baseline. MI and HF cases were ascertained by linkage with the Swedish National Patient Register. Cox proportional hazards regression model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).During follow-up (1998-2010), we ascertained 3678 and 1905 cases of MI and HF, respectively, in men and 1500 and 1328 cases of MI and HF, respectively, in women. Alcohol consumption was inversely associated with MI in both men and women (P trend0.001); compared with light drinkers, the multivariable HRs were 0.70 (95% CI, 0.56-0.87) in men who consumed28 drinks/week and 0.32 (95% CI, 0.15-0.67) in women who consumed 15-21 drinks/week. Alcohol consumption was not inversely associated with HF risk. However, in men, the risk of HF was higher in never, former, and heavy drinkers (28 drinks/week; HR=1.45; 95% CI, 1.09-1.93) compared with light drinkers.Alcohol consumption has divergent associations with MI and HF, with an inverse association observed for MI but not HF. Heavy drinking was associated with an increased HF risk in men.

Whether diet influences the risk of biliary tract cancer (BTC) is unknown. We examined the associations of two healthy dietary patterns, including a modified Dietary Approach to Stop Hypertension (mDASH) diet and a modified Mediterranean (mMED) diet, with the incidence of BTC in a population-based prospective study.The study population comprised 76,014 Swedish adults who were 45-83 years of age and cancer-free at baseline. The mDASH and mMED diets were calculated from self-reported dietary data collected by a validated food-frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI) adjusted for potential confounders.Over 1,010,777 person-years (mean 13.3 years) of follow-up, 140 extrahepatic BTC cases (including 77 gallbladder cancers) and 23 intrahepatic BTC cases were ascertained by linkage with the Swedish Cancer Register. Adherence to the mDASH and mMED diets was statistically significantly inversely associated with risk of extrahepatic BTC (PAdherence to a healthy diet may play a role in reducing the risk of extrahepatic BTC.

BACKGROUND Physical activity is associated with lower risk of coronary and cerebrovascular disease but its potential role in prevention of aortic valve stenosis (AVS) is unclear. Methods and Results: We investigated whether physical activity influences AVS risk in a cohort of 69,288 adults. During a mean follow-up of 15.3 years, 1,238 AVS cases were diagnosed. No associations were observed between AVS and walking/bicycling (≥1 h/day vs. almost never: hazard ratio 0.92, 95% CI 0.74-1.15) or exercise (≥4 hs/week vs.

Impaired left atrial dynamics and its improvement by guided physical activity reveal left atrial strain as a novel early indicator of reversible cardiac dysfunction in rheumatoid arthritis.

Observational studies have found that coffee consumption is inversely associated with risk of incident gout but inconsistently with serum uric acid concentrations.1–3 The causality of the associations is, however, uncertain since observational studies are susceptible to confounding and reverse causation bias. Genetic variants with an explicit impact on a modifiable exposure, such as a biomarker or habitual behaviour like coffee consumption, can be used as instrumental variables (proxies) for the exposure to improve causal inference.4 This method, known as Mendelian randomisation, builds on Mendel’s second law and the fact that genetic variants are randomly assorted during meiosis. Therefore, results from Mendelian randomisation studies are less prone to bias due to confounding and reverse causality. We used the Mendelian randomisation approach to examine whether coffee consumption is associated with gout and whether the association may be mediated by serum uric acid concentrations. A genome-wide association study from the Coffee and Caffeine Genetics Consortium identified 10 single-nucleotide polymorphisms (SNPs), at eight loci, associated with coffee …

Background & Aims Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. Methods We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. Results During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25–2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06–1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04–1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09–1.31) and EHBDC (HR 1.11; 95% CI 1.01–1.22) in Asian women only. Conclusion We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. Lay summary Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate PIn-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate (FDR)

Identification of causative risk factors amenable for modification is essential for the prevention and treatment of osteoporosis. Observational studies have identified associations between several potentially modifiable risk factors and osteoporosis. However, observational studies are susceptible to confounding, reverse causation bias, and measurement error, all of which limit their ability to provide causal estimates of the effect of exposures on outcomes, thereby reducing their ability to inform prevention and treatment strategies against bone loss and fractures. In addition, not all risk factors are suitable for an analysis in a randomized clinical trial. Mendelian randomization is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable exposures (e.g., biomarkers, adiposity measures, dietary factors, and behaviors) to determine the causal relationships between exposures and health outcomes. This technique has been used to provide evidence of causal associations of serum estradiol concentrations, smoking, body mass index, and type 2 diabetes with bone mineral density and the lack of associations of serum thyroid stimulating hormone, urate, C-reactive protein, and 25‑hydroxyvitamin D concentrations with bone mineral density in generally healthy populations. This review will briefly explain the concept of Mendelian randomization, the advantages and potential limitations of this study design, and give examples of how Mendelian randomization has been used to investigate questions relevant to osteoporosis.