Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans

\ua9 The Author(s) 2024. Background: African ancestry populations have the highest burden of stroke worldwide, yet the genetic basis of stroke in these populations is obscure. The Stroke Investigative Research and Educational Network (SIREN) is a multicenter study involving 16 sites in West Africa. We conducted the first-ever genome-wide association study (GWAS) of stroke in indigenous Africans. Methods: Cases were consecutively recruited consenting adults (aged > 18 years) with neuroimaging-confirmed ischemic stroke. Stroke-free controls were ascertained using a locally validated Questionnaire for Verifying Stroke-Free Status. DNA genotyping with the H3Africa array was performed, and following initial quality control, GWAS datasets were imputed into the NIH Trans-Omics for Precision Medicine (TOPMed) release2 from BioData Catalyst. Furthermore, we performed fine-mapping, trans-ethnic meta-analysis, and in silico functional characterization to identify likely causal variants with a functional interpretation. Results: We observed genome-wide significant (P-value < 5.0E−8) SNPs associations near AADACL2 and miRNA (MIR5186) genes in chromosome 3 after adjusting for hypertension, diabetes, dyslipidemia, and cardiac status in the base model as covariates. SNPs near the miRNA (MIR4458) gene in chromosome 5 were also associated with stroke (P-value < 1.0E−6). The putative genes near AADACL2, MIR5186, and MIR4458 genes were protective and novel. SNPs associations with stroke in chromosome 2 were more than 77 kb from the closest gene LINC01854 and SNPs in chromosome 7 were more than 116 kb to the closest gene LINC01446 (P-value < 1.0E−6). In addition, we observed SNPs in genes STXBP5-AS1 (chromosome 6), GALTN9 (chromosome 12), FANCA (chromosome 16), and DLGAP1 (chromosome 18) (P-value < 1.0E−6). Both genomic regions near genes AADACL2 and MIR4458 remained significant following fine mapping. Conclusions: Our findings identify potential roles of regulatory miRNA, intergenic non-coding DNA, and intronic non-coding RNA in the biology of ischemic stroke. These findings reveal new molecular targets that promise to help close the current gaps in accurate African ancestry-based genetic stroke’s risk prediction and development of new targeted interventions to prevent or treat stroke

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

The role of context in implementation research for non-communicable diseases: Answering the 'how-to' dilemma.

INTRODUCTION:Understanding context and how this can be systematically assessed and incorporated is crucial to successful implementation. We describe how context has been assessed (including exploration or evaluation) in Global Alliance for Chronic Diseases (GACD) implementation research projects focused on improving health in people with or at risk of chronic disease and how contextual lessons were incorporated into the intervention or the implementation process. METHODS:Using a web-based semi-structured questionnaire, we conducted a cross-sectional survey to collect quantitative and qualitative data across GACD projects (n = 20) focusing on hypertension, diabetes and lung diseases. The use of context-specific data from project planning to evaluation was analyzed using mixed methods and a multi-layered context framework across five levels; 1) individual and family, 2) community, 3) healthcare setting, 4) local or district level, and 5) state or national level. RESULTS:Project teams used both qualitative and mixed methods to assess multiple levels of context (avg. = 4). Methodological approaches to assess context were identified as formal and informal assessments, engagement of stakeholders, use of locally adapted resources and materials, and use of diverse data sources. Contextual lessons were incorporated directly into the intervention by informing or adapting the intervention, improving intervention participation or improving communication with participants/stakeholders. Provision of services, equipment or information, continuous engagement with stakeholders, feedback for personnel to address gaps, and promoting institutionalization were themes identified to describe how contextual lessons are incorporated into the implementation process. CONCLUSIONS:Context is regarded as critical and influenced the design and implementation of the GACD funded chronic disease interventions. There are different approaches to assess and incorporate context as demonstrated by this study and further research is required to systematically evaluate contextual approaches in terms of how they contribute to effectiveness or implementation outcomes

Factors associated with hypertension among stroke‐free indigenous Africans: Findings from the SIREN study

Abstract Hypertension is one of the most important risk factors for stroke and cardiovascular diseases (CVD) globally. Understanding risk factors for hypertension among individuals with matching characteristics with stroke patients may inform primordial/primary prevention of hypertension and stroke among them. This study identified the risk factors for hypertension among community‐dwelling stroke‐free population in Ghana and Nigeria. Data for 4267 community‐dwelling stroke‐free controls subjects in the Stroke Investigative Research and Education Network (SIREN) study in Nigeria and Ghana were used. Participants were comprehensively assessed for sociodemographic, lifestyle and metabolic factors using standard methods. Hypertension was defined as a previous diagnosis by a health professional or use of an anti‐hypertensive drug or mean systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg. Logistic regression analysis was used to estimate adjusted odds ratios (aOR) of hypertension and their 95% confidence intervals (CI) at p < .05. Overall, 56.7% of the participants were hypertensive with a higher proportion among respondents aged ≥60 years (53.0%). Factors including physical inactivity (aOR: 9.09; 95% CI: 4.03 to 20.53, p < .0001), diabetes (aOR: 2.70; CI: 1.91 to 3.82, p < .0001), being ≥60 years (aOR: 2.22; 95% CI: 1.78 to 2.77, p < .0001), and family history of CVD (aOR 2.02; CI: 1.59 to 2.56, p < .0001) were associated with increased aOR of hypertension. Lifestyle factors were associated with hypertension in the current population of community‐dwelling stroke‐free controls in west Africa. Community‐oriented interventions to address sedentary lifestyles may benefit this population and reduce/prevent hypertension and stroke among them

The role of context in implementation research for non-communicable diseases : Answering the 'how-to' dilemma

Introduction Understanding context and how this can be systematically assessed and incorporated is crucial to successful implementation. We describe how context has been assessed (including exploration or evaluation) in Global Alliance for Chronic Diseases (GACD) implementation research projects focused on improving health in people with or at risk of chronic disease and how contextual lessons were incorporated into the intervention or the implementation process. Methods Using a web-based semi-structured questionnaire, we conducted a cross-sectional survey to collect quantitative and qualitative data across GACD projects (n = 20) focusing on hypertension, diabetes and lung diseases. The use of context-specific data from project planning to evaluation was analyzed using mixed methods and a multi-layered context framework across five levels; 1) individual and family, 2) community, 3) healthcare setting, 4) local or district level, and 5) state or national level. Results Project teams used both qualitative and mixed methods to assess multiple levels of context (avg. = 4). Methodological approaches to assess context were identified as formal and informal assessments, engagement of stakeholders, use of locally adapted resources and materials, and use of diverse data sources. Contextual lessons were incorporated directly into the intervention by informing or adapting the intervention, improving intervention participation or improving communication with participants/stakeholders. Provision of services, equipment or information, continuous engagement with stakeholders, feedback for personnel to address gaps, and promoting institutionalization were themes identified to describe how contextual lessons are incorporated into the implementation process. Conclusions Context is regarded as critical and influenced the design and implementation of the GACD funded chronic disease interventions. There are different approaches to assess and incorporate context as demonstrated by this study and further research is required to systematically evaluate contextual approaches in terms of how they contribute to effectiveness or implementation outcomes

Behaviour change strategies for reducing blood pressure-related disease burden: Findings from a global implementation research programme

10.1186/s13012-015-0331-0Implementation Science10115