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

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.

Sociodemographic and behavioural risk factors for obesity among community-dwelling older adults in Ghana and Nigeria: A secondary analysis of data from the SIREN study.

OBJECTIVES: To explore the prevalence and risk factors of obesity among older adults from low- and middle-income countries (LMICs). METHODS: This is a secondary analysis of data obtained from the SIREN study through in-person interviews and measurements from healthy stroke-free older adults (≥60 years). Overweight/obesity was defined as body mass index ≥25 kg/m2. Abdominal obesity was defined as waist-to-hip ratio (WHR) of >0.90 for males and >0.85/females or waist circumference (WC) of >102 cm for males/>88 cm for females. Adjusted odds ratio (aORs) with 95% confidence interval (CIs) of the relationship between obesity and sociodemographic factors were assessed at P < 0.05. RESULTS: Overall, 47.5% of participants were overweight/obese, 76.6% had a larger than recommended WHR, and 54.4% had a larger than recommended WC. Abdominal obesity (WC; aOR: 9.43, CI: 6.99-12.50), being a Nigerian (aOR: 0.55; CI: 0.42-0.72), living in an urban setting (aOR: 1.92; CI: 1.49-2.46), earning >$100/month (aOR: 1.53; CI: 1.19-1.96), and having formal education (aOR: 1.42; CI: 1.08-1.87) were associated with overweight/obesity. CONCLUSION: Living in urban settings, earning a higher income, and having a formal education were associated with a higher odds of obesity among older adults from LMICs.

Differential associations between pre-diabetes, diabetes and stroke occurrence among West Africans.

BACKGROUND: There are limited data from Africa on the burden and associations between pre-diabetes (pre-DM), diabetes mellitus (DM) and stroke occurrence in a region experiencing a profound rise in stroke burden. PURPOSE: To characterize the associations between stroke and dysglycemic status among West Africans. METHODS: The Stroke Investigative Research and Educational Network (SIREN) is a multicenter, case-control study involving 15 sites in Ghana and Nigeria. Cases include adults aged ≥18 years with clinical and radiological evidence of an acute stroke. Controls were age-and-gender matched stroke-free adults. Detailed evaluations for vascular factors were performed. Pre-diabetes was defined as HBA1c of 5.7%-6.4% or Fasting blood glucose (FBG) 5.6-7.0 mmol/L and DM as HBA1c >6.5% or FBG>7.0 mmol/L. We used conditional logistic regression to estimate adjusted odds ratios (aOR) with 95% Confidence Interval. RESULTS: Among 2,935 stroke cases the mean age was 60.0 ± 14.2 years with 55.2% being males. By glycemic status, 931 (31.7%) were euglycemic, 633 (21.6%) had Pre-diabetes and 1371 (46.7%) had DM. Of the age- and sex-matched stroke-free controls 69.2% were euglycemic, 13.3% had pre-DM and 17.5% had DM. Pre-DM [aOR (95% CI): 3.68(2.61-5.21)] and DM [4.29 (3.19-5.74)] were independently associated with stroke. The aOR of Pre-DM for ischemic stroke 3.06 (2.01-4.64)] was lower than 4.82 (3.37-6.89) for DM. However, the aOR of Pre-DM for hemorrhagic stroke 6.81 (95% CI: 3.29 - 14.08)] was higher than 3.36 (1.94-5.86) for DM. Furthermore, the aOR of pre-DM for ischemic stroke subtypes were 9.64 (1.30-71.57) for cardio-embolic stroke, 3.64 (1.80-7.34) for small-vessel occlusive disease and 4.63 (0.80-26.65) for large-vessel disease. CONCLUSION: Pre-DM is strongly and independently associated with stroke in Africans. Improving glycemic control through screening, healthy lifestyle and pharmacotherapy at a population level may be strategic in reducing the rising burden of stroke in Africa.

Frequency & factors associated with recurrent stroke in Ghana and Nigeria.

BACKGROUND: Data on the burden and outcomes of recurrent strokes in sub-Saharan Africa are limited, impeding efforts at optimal recurrent stroke prevention. OBJECTIVE: To assess the prevalence, risk factor profile, stroke types and mortality from recurrent strokes in Ghana and Nigeria. METHODS: We analyzed data from 3553 stroke cases involved in the Stroke Investigative Research and Educational Networks (SIREN) study for proportion with recurrent strokes. Conditional logistic regression models were constructed to interrogate for risk factors of recurrent stroke compared with stroke-free controls. Generalized Linear models were used to assess correlates of recurrent strokes relative to index strokes. RESULTS: Among stroke cases, 335 (9.4%) were recurrent strokes, of which 79.9% were ischemic and 20.1% hemorrhagic. Those with recurrent stroke were significantly older than index stroke cases 62.2 ± 12.9 years vs 58.9 ± 14.0 years, p < 0.01 respectively. Topmost risk factors associated with recurrent stroke were hypertension adjusted odds ratio 50.7 (95%CI: 6.6-392.7), dyslipidemia 2.8 (1.3-6.2), diabetes mellitus 4.0 (2.1-7.7) and family history of cardiovascular disease (CVD) 2.1 (1.1-4.2). The relative risk (95%CI) of factors associated with recurrent stroke vs index stroke were age > 50 years (1.5: 1.1-2.0); Hausa ethnicity (1.5:1.1-2.1), Yoruba ethnicity with Akan as referent; table added salt (0.4:0.2-0.8) and current alcohol intake (0.6:0.4-0.9). In-patient mortality among those with recurrent stroke vs. primary stroke was 20.5% vs. 21.4%. CONCLUSION: Several modifiable lifestyle related factors may warrant additional emphasis as targets for reducing the burden of recurrent stroke in sub-Saharan Africa.

A Novel Afrocentric Stroke Risk Assessment Score: Models from the Siren Study.

BACKGROUND: Stroke risk can be quantified using risk factors whose effect sizes vary by geography and race. No stroke risk assessment tool exists to estimate aggregate stroke risk for indigenous African. OBJECTIVES: To develop Afrocentric risk-scoring models for stroke occurrence. MATERIALS AND METHODS: We evaluated 3533 radiologically confirmed West African stroke cases paired 1:1 with age-, and sex-matched stroke-free controls in the SIREN study. The 7,066 subjects were randomly split into a training and testing set at the ratio of 85:15. Conditional logistic regression models were constructed by including 17 putative factors linked to stroke occurrence using the training set. Significant risk factors were assigned constant and standardized statistical weights based on regression coefficients (ß) to develop an additive risk scoring system on a scale of 0-100%. Using the testing set, Receiver Operating Characteristics (ROC) curves were constructed to obtain a total score to serve as cut-off to discriminate between cases and controls. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at this cut-off. RESULTS: For stroke occurrence, we identified 15 traditional vascular factors. Cohen's kappa for validity was maximal at a total risk score of 56% using both statistical weighting approaches to risk quantification and in both datasets. The risk score had a predictive accuracy of 76% (95%CI: 74-79%), sensitivity of 80.3%, specificity of 63.0%, PPV of 68.5% and NPV of 76.2% in the test dataset. For ischemic strokes, 12 risk factors had predictive accuracy of 78% (95%CI: 74-81%). For hemorrhagic strokes, 7 factors had a predictive accuracy of 79% (95%CI: 73-84%). CONCLUSIONS: The SIREN models quantify aggregate stroke risk in indigenous West Africans with good accuracy. Prospective studies are needed to validate this instrument for stroke prevention.

Frequency and factors associated with post-stroke seizures in a large multicenter study in West Africa.

BACKGROUND: Post-stroke seizures (PSS) are associated with significant morbidity and mortality across the globe. There is a paucity of data on PSS in Africa. PURPOSE: To assess the frequency and factors associated with PSS by stroke types across 15 hospitals in Nigeria and Ghana. METHODS: We analyzed data on all stroke cases recruited into the Stroke Investigative Research and Educational Network (SIREN). We included adults aged ≥18 years with radiologically confirmed ischemic stroke (IS) or intracerebral hemorrhage (ICH). PSS were defined as acute symptomatic seizures occurring at stroke onset and/or during acute hospitalization up until discharge. We used logistic regression to estimate adjusted odds ratios (aOR) with 95% Confidence Interval. RESULTS: Among 3344 stroke patients, 499 (14.9%) had PSS (95% CI: 13.7-16.2%). The mean duration of admission in days for those with PSS vs no PSS was 17.4 ± 28.6 vs 15.9 ± 24.7, p = 0.72. There were 294(14.1%) PSS among 2091 ischemic strokes and 159(17.7%) among 897 with ICH, p = 0.01. The factors associated with PSS occurrence were age < 50 years, aOR of 1.59 (1.08-2.33), National Institute of Health Stroke Score (NIHSS), 1.29 (1.16-1.42) for each 5 units rise and white cell count 1.07 (1.01-1.13) for each 10^3 mm3 rise. Factors associated with PSS in ischemic were NIHSS score, aOR of 1.17 (1.04-1.31) and infarct volume of 10-30 cm3 aOR of 2.17(1.37-3.45). Among ICH, associated factors were alcohol use 5.91 (2.11-16.55) and lobar bleeds 2.22 (1.03-4.82). CONCLUSION: The burden of PSS among this sample of west Africans is substantial and may contribute to poor outcomes of stroke in this region. Further longitudinal studies are required to understand the impact on morbidity and mortality arising from PSS in Africa.

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

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.

Unraveling the risk factors for spontaneous intracerebral hemorrhage among West Africans.

OBJECTIVE: To characterize risk factors for spontaneous intracerebral hemorrhage (sICH) occurrence and severity among West Africans. METHODS: The Stroke Investigative Research and Educational Network (SIREN) study is a multicenter case-control study involving 15 sites in Ghana and Nigeria. Patients were adults ≥18 years old with CT-confirmed sICH with age-, sex-, and ethnicity-matched stroke-free community controls. Standard instruments were used to assess vascular, lifestyle, and psychosocial factors. Factors associated with sICH and its severity were assessed using conditional logistic regression to estimate odds ratios (ORs) and population-attributable risks (PARs) with 95% confidence intervals (CIs) for factors. RESULTS: Of 2,944 adjudicated stroke cases, 854 were intracerebral hemorrhage (ICH). Mean age of patients with ICH was 54.7 ± 13.9 years, with a male preponderance (63.1%), and 77.3% were nonlobar. Etiologic subtypes of sICH included hypertension (80.9%), structural vascular anomalies (4.0%), cerebral amyloid angiopathy (0.7%), systemic illnesses (0.5%), medication-related (0.4%), and undetermined (13.7%). Eight factors independently associated with sICH occurrence by decreasing order of PAR with their adjusted OR (95% CI) were hypertension, 66.63 (20.78-213.72); dyslipidemia, 2.95 (1.84-4.74); meat consumption, 1.55 (1.01-2.38); family history of CVD, 2.22 (1.41-3.50); nonconsumption of green vegetables, 3.61 (2.07-6.31); diabetes mellitus, 2.11 (1.29-3.46); stress, 1.68 (1.03-2.77); and current tobacco use, 14.27 (2.09-97.47). Factors associated with severe sICH using an NIH Stroke Scale score >15 with adjusted OR (95% CI) were nonconsumption of leafy green vegetables, 2.03 (1.43-2.88); systolic blood pressure for each mm Hg rise, 1.01 (1.00-1.01); presence of midline shift, 1.54 (1.11-2.13); lobar ICH, 1.72 (1.16-2.55); and supratentorial bleeds, 2.17 (1.06-4.46). CONCLUSIONS: Population-level control of the dominant factors will substantially mitigate the burden of sICH in West Africa.

Stroke in Indigenous Africans, African Americans, and European Americans: Interplay of Racial and Geographic Factors.

BACKGROUND AND PURPOSE: The relative contributions of racial and geographic factors to higher risk of stroke in people of African ancestry have not been unraveled. We compared stroke type and contributions of vascular risk factors among indigenous Africans (IA), African Americans (AA), and European Americans (EA). METHODS: SIREN (Stroke Investigative Research and Educational Network) is a large multinational case-control study in West Africa-the ancestral home of 71% AA-whereas REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a cohort study including AA and EA in the United States. Using harmonized assessments and standard definitions, we compared data on stroke type and established risk factors for stroke in acute stroke cases aged ≥55 years in both studies. RESULTS: There were 811 IA, 452 AA, and 665 EA stroke subjects, with mean age of 68.0±9.3, 73.0±8.3, and 76.0±8.3 years, respectively (P<0.0001). Hemorrhagic stroke was more frequent among IA (27%) compared with AA (8%) and EA (5.4%; P<0.001). Lacunar strokes were more prevalent in IA (47.1%), followed by AA (35.1%) and then EA (21.0%; P<0.0001). The frequency of hypertension in decreasing order was IA (92.8%), followed by AA (82.5%) and then EA (64.2%; P<0.0001) and similarly for diabetes mellitus IA (38.3%), AA (36.8%), and EA (21.0%; P<0.0001). Premorbid sedentary lifestyle was similar in AA (37.7%) and EA (34.0%) but lower frequency in IA (8.0%). CONCLUSIONS: Environmental risk factors such as sedentary lifestyle may contribute to the higher proportion of ischemic stroke in AA compared with IA, whereas racial factors may contribute to the higher proportion of hypertension and diabetes mellitus among stroke subjects of African ancestry.

Exploring Overlaps Between the Genomic and Environmental Determinants of LVH and Stroke: A Multicenter Study in West Africa.

BACKGROUND: Whether left ventricular hypertrophy (LVH) is determined by similar genomic and environmental risk factors with stroke, or is simply an intermediate stroke marker, is unknown. OBJECTIVES: We present a research plan and preliminary findings to explore the overlap in the genomic and environmental determinants of LVH and stroke among Africans participating in the SIREN (Stroke Investigative Research and Education Network) study. METHODS: SIREN is a transnational, multicenter study involving acute stroke patients and age-, ethnicity-, and sex-matched control subjects recruited from 9 sites in Ghana and Nigeria. Genomic and environmental risk factors and other relevant phenotypes for stroke and LVH are being collected and compared using standard techniques. RESULTS: This preliminary analysis included only 725 stroke patients (mean age 59.1 ± 13.2 years; 54.3% male). Fifty-five percent of the stroke subjects had LVH with greater proportion among women (51.6% vs. 48.4%; p < 0.001). Those with LVH were younger (57.9 ± 12.8 vs. 60.6 ± 13.4; p = 0.006) and had higher mean systolic and diastolic blood pressure (167.1/99.5 mm Hg vs 151.7/90.6 mm Hg; p < 0.001). Uncontrolled blood pressure at presentation was prevalent in subjects with LVH (76.2% vs. 57.7%; p < 0.001). Significant independent predictors of LVH were age <45 years (adjusted odds ratio [AOR]: 1.91; 95% confidence interval [CI]: 1.14 to 3.19), female sex (AOR: 2.01; 95% CI: 1.44 to 2.81), and diastolic blood pressure > 90 mm Hg (AOR: 2.10; 95% CI: 1.39 to 3.19; p < 0.001). CONCLUSIONS: The prevalence of LVH was high among stroke patients especially the younger ones, suggesting a genetic component to LVH. Hypertension was a major modifiable risk factor for stroke as well as LVH. It is envisaged that the SIREN project will elucidate polygenic overlap (if present) between LVH and stroke among Africans, thereby defining the role of LVH as a putative intermediate cardiovascular phenotype and therapeutic target to inform interventions to reduce stroke risk in populations of African ancestry.

Organ Donation Among Tiers of Health Workers: Expanding Resources to Optimize Organ Availability in a Developing Country.

UNLABELLED: The global increase in end organ failure but disproportional shortage of organ donation calls for attention. Expanding the organ pool by assessing and improving health workers' attitude at all levels of care may be a worthwhile initiative. METHODS: A questionnaire-based cross sectional study involving tertiary, secondary, and primary health institutions in Southwestern Nigeria was conducted. RESULTS: Age range was 18 to 62 (36.7 ± 9.2) years. Only 13.5%, 11.7%, and 11.2% from primary, secondary, and tertiary health centers, respectively, would definitely donate despite high level of awareness (>90%) at each level of care. Participants from primary health care are of low income (P < 0.05), and this cohort is less likely to be aware of organ donation (P < 0.05). At each level of care, permission by religion to donate organs influenced positive attitudes (willingness to donate, readiness to counsel families of potential donors, and signing of organ donation cards) toward organ donation. Good knowledge of organ donation only significantly influenced readiness to counsel donors (P < 0.05) and not willingness to donate (P > 0.05). At each level of health care, young health care workers (P < 0.05) and women (P > 0.05) would be willing to donate, whereas men show positive attitude in signing of organ donor cards (P < 0.05) and counseling of families of potential donors (P > 0.05). CONCLUSIONS: Knowledge and willingness to donate organs among health care levels were not different. Considering the potential advantage of community placement of other tiers of health care (primary and secondary) in Nigeria, integrating them would be strategically beneficial to organ donation.

Awareness of stroke risk factors and warning signs in Nigerian adolescents compared with adults.

BACKGROUND: Stroke, a significant health problem affecting adults, is increasing among younger age groups, particularly because of changing lifestyles. The aim of the study was to compare the awareness of stroke risk factors and warning signs among students and teachers in selected secondary schools in Osun State, Nigeria. METHODS: This was a cross-sectional survey involving 703 (589 students and 114 teachers) respondents in selected secondary schools in Osun, Nigeria. Information on the awareness of stroke risk factors and warning signs was collected with the aid of a structured questionnaire. RESULTS: Hypertension (69.4%) was the most commonly identified stroke risk factor, with more teachers (79.8%) identifying correctly than the students (67.4%). Weakness (51.9%) was the most commonly identified warning sign of stroke with more students (53.8%) identifying correctly than the teachers (42.1%). There were significant differences in the awareness of some risk factors (age, obesity, family history, alcohol use, diet, transient ischemic attack, and hyperlipidemia) and warning signs (dizziness, weakness, and vision problems) between students and teachers. Predictors for adequate awareness of risk factors were being a teacher, not being obese and being hypertensive, whereas predictors for adequate awareness of warning signs were stroke in the family and being hypertensive. CONCLUSIONS: There was inadequate awareness of risk factors and warning signs among the respondents with students having better awareness of warning signs and teachers having better awareness of risk factors. Stroke campaigns should emphasize stroke risk factors particularly among adolescents and warning signs in adults. The use of media, particularly television, is recommended.

A review of stroke admissions at a tertiary hospital in rural Southwestern Nigeria.

BACKGROUND: Stroke is a common neurological disorder and is the third leading cause of death and a major cause of long-term disability. The disease is expected to increase in low- and middle-income countries like Nigeria. There is no information on stroke in rural Nigeria. OBJECTIVES: To review the clinical patterns, risk-factors, and outcome of stroke in a tertiary hospital in rural Nigeria and examine the rural-urban variation of stroke hospitalization in Nigeria. MATERIALS AND METHODS: We carried out a retrospective study of patients who had a clinical diagnosis of stroke at the Federal Medical Centre, Ido-Ekiti, South-western Nigeria between November 2006 and October 2009. RESULTS: A total of 101 patients who had stroke were admitted during this review period, accounting for 4.5% of medical admission and 1.3% of total hospital admission. Women accounted 52.5% of cases, with a male to female ratio of 1 : 1.1. Their mean age was 68 ± 12 years. Stroke occurrences increased with age, as almost half (49.5%) of the cases were aged ≥70 years and majority (84.2%) of them were in low socioeconomic class. The mean hospital stay for stroke treatment was 12 ± 9 days, Glasgow coma score on admission was 11 ± 4. Ischemic stroke was 64.4%; hemorrhagic stroke, 34.7%; and indeterminate, 1.0%. Hypertension (85.2%), diabetes mellitus (23.8%), and tobacco smoking (22.8%) were the common identifiable risk factors for stroke. Of all the patients, 69% had ≥2 risk factors for stroke. Thirty-day case fatality was 23.8%; it increases with age and was higher among men than women (29.2 vs 18.9%) and in patients with diagnosis of hemorrhagic stroke (34.3 vs 18.5%). The numbers of identifiable risk factors of stroke has no effect on the 30-day case fatality. When compared with stroke in urban areas of Nigeria, we found no differences in frequency of hospitalization (1.3 vs 0.9 - 4%) and the major risk factor (hypertension). Hemorrhagic stroke was more common in urban than in the rural community (45.2 - 51 vs 34.7%) and the 30-day case fatality was lower in the rural community (23.8 vs 37.6 - 41.2%). CONCLUSION: Stroke is also a common neurological condition in rural Nigeria, in view of the fact that almost 70% of the patients had ≥2 risk factors of stroke. We recommend that, sustainable, community-friendly intervention programmes are incorporated into the health care system for the early prevention, recognition, and modification of the risk factors in persons prone to the disease.