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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 ancestry1,2. 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 < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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Cardiac surgery in North America and coronavirus disease 2019 (COVID-19): Regional variability in burden and impactObjective: The coronavirus disease 2019 (COVID-19) pandemic has resulted in an increase in hospital resource utilization and the need to defer nonurgent cardiac surgery procedures. The present study aims to report the regional variations of North American adult cardiac surgical case volume and case mix through the first wave of the COVID-19 pandemic. Methods: A survey was sent to recruit participating adult cardiac surgery centers in North America. Data in regard to changes in institutional and regional cardiac surgical case volume and mix were analyzed. Results: Our study comprises 67 adult cardiac surgery institutions with diverse geographic distribution across North America, representing annualized case volumes of 60,452 in 2019. Nonurgent surgery was stopped during the month of March 2020 in the majority of centers (96%), resulting in a decline to 45% of baseline with significant regional variation. Hospitals with a high burden of hospitalized patients with COVID-19 demonstrated similar trends of decline in total volume as centers in low burden areas. As a proportion of total surgical volume, there was a relative increase of coronary artery bypass grafting surgery (high +7.2% vs low +4.2%, P =.550), extracorporeal membrane oxygenation (high +2.5% vs low 0.4%, P =.328), and heart transplantation (high +2.7% vs low 0.4%, P =.090), and decline in valvular cases (high –7.6% vs low –2.6%, P =.195). Conclusions: The present study demonstrates the impact of COVID-19 on North American cardiac surgery institutions as well as helps associate region and COVID-19 burden with the impact on cardiac surgery volumes and case mix.
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The genomics of heart failure: design and rationale of the HERMES consortiumAims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
