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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). 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 analysis(3), 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 approach(4), 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 ancestry(5). 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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| 3. |
- Kotseva, K, et al.
(författare)
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Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry
- 2019
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Ingår i: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 26:8, s. 824-835
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine whether the Joint European Societies guidelines on secondary cardiovascular prevention are followed in everyday practice. Design A cross-sectional ESC-EORP survey (EUROASPIRE V) at 131 centres in 81 regions in 27 countries. Methods Patients (<80 years old) with verified coronary artery events or interventions were interviewed and examined ≥6 months later. Results A total of 8261 patients (females 26%) were interviewed. Nineteen per cent smoked and 55% of them were persistent smokers, 38% were obese (body mass index ≥30 kg/m2), 59% were centrally obese (waist circumference: men ≥102 cm; women ≥88 cm) while 66% were physically active <30 min 5 times/week. Forty-two per cent had a blood pressure ≥140/90 mmHg (≥140/85 if diabetic), 71% had low-density lipoprotein cholesterol ≥1.8 mmol/L (≥70 mg/dL) and 29% reported having diabetes. Cardioprotective medication was: anti-platelets 93%, beta-blockers 81%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75% and statins 80%. Conclusion A large majority of coronary patients have unhealthy lifestyles in terms of smoking, diet and sedentary behaviour, which adversely impacts major cardiovascular risk factors. A majority did not achieve their blood pressure, low-density lipoprotein cholesterol and glucose targets. Cardiovascular prevention requires modern preventive cardiology programmes delivered by interdisciplinary teams of healthcare professionals addressing all aspects of lifestyle and risk factor management, in order to reduce the risk of recurrent cardiovascular events.
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