Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights From Genetic and Experimental Models.

Background: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial.

Methods: Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA.

Importance of Clinical, Laboratory, and Genetic Risk Factors for Incident CAD.

Background: Prior work suggests modifiable cardiovascular risk factors (CRFs) account for 80% to 90% of the risk for incident myocardial infarction. The contributions of genetic and other novel CRFs have not been simultaneously assessed in contemporary data sets.

Methods: In the United Kingdom Biobank, CRFs were identified and Cox proportional hazards models with traditional CRFs (hypertension, diabetes, dyslipidemia, waist-to-hip ratio, diet, exercise, alcohol, and socioeconomic deprivation) and contemporary/genetic CRFs (Lp(a) [lipoprotein(a)], hsCRP [high-sensitivity C-reactive protein], familial hypercholesterolemia variants, and polygenic risk score for coronary artery disease) were constructed for coronary artery disease.

Multi-population GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality. Although many genetic risk factors have been identified, a substantial portion of the heritability remains unexplained. Here we employ genome wide association study (GWAS) VTE across 9 international cohorts of the Global Biobank Meta-analysis Initiative (GBMI) to address this question, along with in vivo functional validation.

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci.

Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.

Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease. Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain-containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMCs), is significantly associated with BP-related traits.

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation.

Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score.

Background: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD.

Methods: Participants were of European ancestry from the UK Biobank without prevalent CAD.

Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation.

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related.

Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

Objective: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist.

Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries.

Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke.