A Multitrait Genetic Study of Hemostatic Factors and Hemorrhagic Transformation after Stroke Treatment

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient\u27s prognosis. OBJECTIVES: to investigate the association between genetically determined natural hemostatic factors\u27 levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10 CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

[Background] Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient’s prognosis.[Objectives] To investigate the association between genetically determined natural hemostatic factors’ levels and increased risk of HT after r-tPA treatment.[Methods] Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.[Results] Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10−11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10−10; rs1421067 (CHD9), P = 1.81 × 10−14; and rs34780449, near ROBO1 gene, P = 1.64 × 10−8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10−14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [−0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).[Conclusion] We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. E.M. is supported by a Río Hortega Contract (CM18/00198) from the ISCIII. J.C.-M. is supported by an Agència de Gestió d’Ajuts Universitaris i de Recerca Contract (FI_DGR 2020, grant number 2020FI_B1 00157) cofinanced by the European Social Fund. C.G.-F. is supported by a Sara Borrell Contract (CD20/00043) from ISCIII and Fondo Europeo de Desarrollo Regional (ISCIII- FEDER). M.L. is supported by a Contratos Predoctorales de Formación en Investigación en Salud Contract from the ISCIII (FI19/00309).Peer reviewe

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

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(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.</p

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

Drug resistance and secondary treatment of ischaemic stroke: The genetic component of the response to acetylsalicylic acid and clopidogrel

Introduction: Cerebrovascular diseases are among the leading causes of death and disability in developed countries. Acetylsalicylic acid (ASA) and clopidogrel are the most widely used antiplatelet drugs for secondary prevention of recurrent thromboembolic events. However, there have been cases in which antiplatelet drugs did not inhibit platelet activity; this phenomenon is called resistance, and it may be modulated at the genetic level. Development: Following a literature search, we reviewed the current state of antiplatelet therapy and covered the different types of resistance to antiplatelet therapy, how it is measured, current problems and limitations, and any genetic factors that have been associated with resistance. We mainly used the Genome Wide Association Studies in the field of ASA and clopidogrel resistance. Conclusions: We observed an association between different genetic factors and antiplatelet drug resistance as measured by platelet activity. However, there is no evident association between these genetic factors and risk of new thromboembolic events. Resumen: Introducción: Las enfermedades cerebrovasculares están entre las principales causas de mortalidad y discapacidad en los países desarrollados. El ácido acetilsalicílico (AAS) y el clopidogrel son los tratamientos antiagregantes plaquetarios más utilizados para la profilaxis de nuevos eventos tromboembólicos. Sin embargo, se han observado casos en los que el tratamiento antiagregante no inhibe la actividad plaquetaria, un fenómeno llamado resistencia y que posiblemente puede estar modulado a nivel genético. Desarrollo: Tras una búsqueda bibliográfica se realizó una revisión sobre el estado actual del tratamiento antiagregante plaquetario. Se tratan los diferentes tipos de resistencia a la terapia antiagregante, de qué manera se mide, la problemática y limitaciones actuales, así como los factores genéticos que se han asociado a esta resistencia. Principalmente se analizan los estudios genéticos realizados en el campo de la resistencia a AAS y clopidogrel mediante Genome Wide Association. Conclusiones: Parece existir una asociación entre diferentes factores genéticos y la resistencia a los fármacos antiagregantes medida mediante la actividad plaquetaria; no obstante, no hay una asociación evidente entre estos factores genéticos y el riesgo de nuevos eventos tromboembólicos. Keywords: Stroke, Acetylsalicylic acid, Clopidogrel, Antiplatelet drugs, Resistance, Pharmacogenetics, Palabras clave: Ictus, Ácido acetilsalicílico, Clopidogrel, Antiagregantes, Resistencia, Farmacogenétic