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Importance: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE)., Objective: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism., Design, Setting, and Participants: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018., Exposures: A panel of several established cardiovascular risk factors., Main Outcomes and Measures: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI)., Results: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers., Conclusions and Relevance: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Background: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown.Objectives: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population.Methods: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed.Results: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy.Conclusions: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]

The apolipoprotein E(APOE) ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism, vascular disease and dementia. The impact of the full range of structural genetic variation in APOE for lipids, lipoproteins and apolipoproteins and for vascular disease in the general population is not known. We systematically sequenced APOE in 10,296 individuals from the Copenhagen City Heart Study and genotyped nine rare variants (frequency≥2/10,296) in 95,227 individuals from the Copenhagen General Population Study. The UK Biobank was used for validation of common APOE variants. Rare mutations in APOE , predicted to be deleterious, are present in 1 in 257 individuals in the general population. In the meta-analysis, multifactorially adjusted hazard ratios (95% confidence intervals) for ϵ44 and ϵ22 versus ϵ33 were 1.15 (1.04–1.26) and 1.02 (0.83–1.24) for ischemic cerebrovascular disease (ICVD), 1.11 (1.04–1.19) and 0.94 (0.83–1.08) for ischemic heart disease (IHD) and 1.03 (0.89–1.17) and 1.49 (1.20–1.87) for peripheral arterial disease (PAD). A multifactorially and ϵ2/ϵ3/ϵ4 adjusted weighted allele score on the continuous scale including all common and rare structural variants showed that for individuals with genetically predicted high plasma apoE and remnant cholesterol the risk for PAD was increased. APOE variants with high apoE, triglycerides, and remnant cholesterol are associated with PAD, whereas common APOE variants with high LDL cholesterol, triglycerides and remnant cholesterol are associated with IHD. APOE variants with low apoE are associated with increased risk of ICVD. These findings highlight that both rare and common structural variations in APOE play a role in vascular disease. [Display omitted] • The APOE ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism. • We sequenced APOE in 10,296 and genotyped rare variants in 95,227 individuals. • ϵ2-like variants are associated with peripheral arterial disease. • Variants with low apoE are associated with ischemic cerebrovascular disease. • Structural variations in APOE beyond the ϵ2 and ϵ4 alleles play a role. [ABSTRACT FROM AUTHOR]