Background: As the second leading cause of death and the leading cause of adult-onset disability, stroke is a major public health concern particularly pertinent in Sub-Saharan Africa (SSA), where nearly 80% of all global stroke mortalities occur, and stroke burden is projected to increase in the coming decades. However, traditional and emerging risk factors for stroke in SSA have not been well characterized, thus limiting efforts at curbing its devastating toll. The Stroke Investigative Research and Education Network (SIREN) project is aimed at comprehensively evaluating the key environmental and genomic risk factors for stroke (and its subtypes) in SSA while simultaneously building capacities in phenomics, biobanking, genomics, biostatistics, and bioinformatics for brain research. Methods: SIREN is a transnational, multicentre, hospital and community-based study involving 3,000 cases and 3,000 controls recruited from 8 sites in Ghana and Nigeria. Cases will be hospital-based patients with first stroke within 10 days of onset in whom neurovascular imaging will be performed. Etiological and topographical stroke subtypes will be documented for all cases. Controls will be hospital- and community-based participants, matched to cases on the basis of gender, ethnicity, and age (±5 years). Information will be collected on known and proposed emerging risk factors for stroke. Study Significance: SIREN is the largest study of stroke in Africa to date. It is anticipated that it will shed light on the phenotypic characteristics and risk factors of stroke and ultimately provide evidence base for strategic interventions to curtail the burgeoning burden of stroke on the sub-continent.

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.

Background: We conducted the first-of-its kind randomized stroke trial in Africa to test whether a THRIVES (Tailored Hospital-based Risk reduction to Impede Vascular Events after Stroke) intervention improved blood pressure (BP) control among patients with stroke. Methods and Results: Intervention comprised a patient global risk factor control report card, personalized phone text-messaging, and educational video. Four hundred patients recruited from 4 distinct medical facilities in Nigeria, aged ≥18 years with stroke-onset within one-year, were randomized to THRIVES intervention and control group. The control group also received text messages, and both groups received modest financial incentives. The primary outcome was mean change in systolic BP (SBP) at 12 months. There were 36.5% females, 72.3% with ischemic stroke; mean age was 57.2±11.7 years; 93.5% had hypertension and mean SBP was 138.33 (23.64) mm Hg. At 12 months, there was no significant difference in SBP reduction from baseline in the THRIVES versus control group (2.32 versus 2.01 mm Hg, P =0.82). In an exploratory analysis of subjects with baseline BP >140/90 mm Hg (n=168), THRIVES showed a significant mean SBP (diastolic BP) decrease of 11.7 (7.0) mm Hg while control group showed a significant mean SBP (diastolic BP) decrease of 11.2 (7.9) mm Hg at 12 months. Conclusions: THRIVES intervention did not significantly reduce SBP compared with controls. However, there was similar significant decrease in mean BP in both treatment arms in the subgroup with baseline hypertension. As text-messaging and a modest financial incentive were the common elements between both treatment arms, further research is required to establish whether these measures alone can improve BP control among stroke survivors. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01900756.

Accurate epidemiological surveillance of the burden of stroke is direly needed to facilitate the development and evaluation of effective interventions in Africa. The authors therefore conducted a systematic review of the methodology of stroke epidemiological studies conducted in Africa from 1970 to 2017 using gold standard criteria obtained from landmark epidemiological publications. Of 1330 articles extracted, only 50 articles were eligible for review grouped under incidence, prevalence, case-fatality, health-related quality of life, and disability-adjusted life-years studies. Because of various challenges, no study fulfilled the criteria for an excellent stroke incidence study.The relatively few stroke epidemiology studies in Africa have significant methodological flaws. Innovative approaches leveraging available information and communication technology infrastructure are recommended to facilitate rigorous epidemiological studies for accurate stroke surveillance in Africa.