Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.

Prolonged mechanical ventilation after cardiac surgery: substudy of the Transfusion Requirements in Cardiac Surgery III trial.

Purpose: Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications.

Methods: Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included.

Transferability of genetic risk scores in African populations.

The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores.

Review and update of the concept of embolic stroke of undetermined source.

Ischaemic strokes have traditionally been classified according to the TOAST criteria, in which strokes with unclear aetiology are classified as cryptogenic strokes. However, the definition of cryptogenic stroke did not meet the operational criteria necessary to define patient populations for randomized treatment trials. To address this problem, the concept of embolic stroke of undetermined source (ESUS) was developed and published in 2014.

Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study.

Background: Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD.

Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study.

Background: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding.

DNA methylation changes in cord blood and the developmental origins of health and disease - a systematic review and replication study.

Background: Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance.

Methods: We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age.

Association of Clonal Hematopoiesis of Indeterminate Potential with Worse Kidney Function and Anemia in Two Cohorts of Patients with Advanced Chronic Kidney Disease.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in CKD is unknown.

Methods: We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.

Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.

Background: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes.

Methods And Findings: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate).

Normalized Subendocardial Myocardial Attenuation on Coronary Computed Tomography Angiography Predicts Postoperative Adverse Cardiovascular Events: Coronary CTA VISION Substudy.

Background: Abnormalities in computed tomography myocardial perfusion has been associated with coronary artery disease and major adverse cardiovascular events (MACE). We sought to investigate if subendocardial attenuation using coronary computed tomography angiography predicts MACE 30 days postelective noncardiac surgery.

Methods: Using a 17-segment model, coronary computed tomography angiography images were analyzed for subendocardial and transmural attenuation and the corresponding blood pool.

GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia.

Background: Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial (MT) function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation.

Methods: We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called 'automatic mitochondrial copy (AutoMitoC).

Rare genetic causes of obesity: Diagnosis and management in clinical care.

Rare genetic forms of obesity are linked to impaired energy balance (i.e., eating behaviour and energy expenditure) involving hypothalamic pathways.

Mitochondrial DNA Copy Number as a Marker and Mediator of Stroke Prognosis: Observational and Mendelian Randomization Analyses.

Background And Objectives: Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies.

Methods: First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month poststroke outcomes in 3,498 cases of acute, first stroke from 25 countries from the international, multicenter case-control study Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE).

Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial.

Aims/hypothesis: Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care.

Methods: In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline.

Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories.

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesize that rare variant burden over a large number of genes can be combined into a predictive rare variant genetic risk score (RVGRS).

Epigenetic Age and the Risk of Incident Atrial Fibrillation.

Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging.

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study.

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI.

Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients.

The prognostic significance of grade of ischemia in the ECG in patients with ST-elevation myocardial infarction: A substudy of the randomized trial of primary PCI with or without routine manual thrombectomy (TOTAL trial).

Background: The importance of the grade of ischemia (GI) ECG classification in the risk assessment of patients with STEMI has been shown previously. Grade 3 ischemia (G3I) is defined as ST-elevation with distortion of the terminal portion of the QRS complex in two or more adjacent leads, while Grade 2 ischemia (G2I) is defined as ST-elevation without QRS distortion. Our aim was to evaluate the prognostic impact of the GI classification on the outcome in patients with STEMI.

Clustering of obesity-related characteristics: A latent class analysis from the Canadian Longitudinal Study on Aging.

Measures of obesity, including body mass index (BMI) and waist circumference (WC), do not fully capture the complexity of obesity-related health risks. This study identified distinct classes of obesity-related characteristics and evaluated their associations with BMI, WC, and percent body fat (%BF) using cross-sectional data from 30,096 participants aged 45-85 in the Canadian Longitudinal Study on Aging (2011-2015). Sixteen obesity-related variables, including behavioural, metabolic, physical health, and mental health/social factors, were included in a latent class analysis to identify distinct classes of participants.

The effects of dietary nitrate supplementation on endurance exercise performance and cardiorespiratory measures in healthy adults: a systematic review and meta-analysis.

Background: Nitrate supplementation is thought to improve performance in endurance sports.

Objective: To meta-analyze studies evaluating the effect of nitrate supplementation on endurance sports performance among adults.

Data Sources: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science and CINAHL without language restrictions.