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

Home Assessment of Indoor Microbiome (HAIM) in Relation to Lower Respiratory Tract Infections among Under-Five Children in Ibadan, Nigeria: The Study Protocol

The association between household air pollution and lower respiratory tract infections (LRTI) among children under five years of age has been well documented; however, the extent to which the microbiome within the indoor environment contributes to this association is uncertain. The home assessment of indoor microbiome (HAIM) study seeks to assess the abundance of indoor microbiota (IM) in the homes of under-five children (U-5Cs) with and without LRTI. HAIM is a hospital- and community-based study involving 200 cases and 200 controls recruited from three children's hospitals in Ibadan, Nigeria. Cases will be hospital-based patients with LRTI confirmed by a pediatrician, while controls will be community-based participants, matched to cases on the basis of sex, geographical location, and age (±3 months) without LRTI. The abundance of IM in houses of cases and controls will be investigated using active and passive air sampling techniques and analyzed by qualitative detection of bacterial 16SrRNA gene (V3-V4), fungal ITS1 region, and viral RNA sequencing. HAIM is expected to elucidate the relationship between exposure to IM and incidence of LRTI among U-5Cs and ultimately provide evidence base for strategic interventions to curtail the burgeoning burden of LRTI on the subcontinent

Childhood lower respiratory tract infections linked to residential airborne bacterial and fungal microbiota

Residential microbial composition likely contributes to the development of lower respiratory tract infections (LRTI) among children, but the association is poorly understood. We aimed to study the relationship between the indoor airborne dust bacterial and fungal microbiota and childhood LRTI in Ibadan, Nigeria. Ninety-eight children under the age of five years hospitalized with LRTI were recruited and matched by age (±3 months), sex, and geographical location to 99 community-based controls without LRTI. Participants’ homes were visited and sampled over a 14-day period for airborne house dust using electrostatic dustfall collectors (EDC). In airborne dust samples, the composition of bacterial and fungal communities was characterized by a meta-barcoding approach using amplicons targeting simultaneously the bacterial 16S rRNA gene and the internal-transcribed-spacer (ITS) region-1 of fungi in association with the SILVA and UNITE database respectively. A 100-unit change in house dust bacterial, but not fungal, richness (OR 1.06; 95%CI 1.03–1.10) and a 1-unit change in Shannon diversity (OR 1.92; 95%CI 1.28–3.01) were both independently associated with childhood LRTI after adjusting for other indoor environmental risk factors. Beta-diversity analysis showed that bacterial (PERMANOVA p < 0.001, R2 = 0.036) and fungal (PERMANOVA p < 0.001, R2 = 0.028) community composition differed significantly between homes of cases and controls. Pair-wise differential abundance analysis using both DESEq2 and MaAsLin2 consistently identified the bacterial phyla Deinococcota (Benjamini-Hochberg (BH) adjusted p-value <0.001) and Bacteriodota (BH-adjusted p-value = 0.004) to be negatively associated with LRTI. Within the fungal microbiota, phylum Ascomycota abundance (BH adjusted p-value <0.001) was observed to be directly associated with LRTI, while Basidiomycota abundance (BH adjusted p-value <0.001) was negatively associated with LRTI. Our study suggests that early-life exposure to certain airborne bacterial and fungal communities is associated with LRTI among children under the age of five years

Secondhand smoke exposure is independently associated with stroke among non-smoking adults in West Africa

Background Stroke is a leading cause of disability and mortality worldwide, but little is known about the contribution of secondhand smoke exposure (SHSE) to stroke epidemiology among indigenous Africans. Objective To evaluate the association of SHSE with stroke among indigenous Africans. Methods We analyzed the relationship of SHSE with stroke among 2990 case-control pairs of adults who had never smoked (identified in the SIREN study) using conditional logistic regression at a two-sided P \u3c 0.05. Results Multivariable-adjusted odds ratio and 95% confidence interval; 1.25 (1.04, 1.50; P = 0.02) revealed SHSE was positively associated with stroke independent of stroke subtypes. Conclusion Culturally relevant primary prevention strategies targeted at SHSE might be promising in preventing stroke among Africans

Determinants of metabolic syndrome and its prognostic implications among stroke patients in Africa: Findings from the Stroke Investigative Research and Educational Network (SIREN) study

Background The prognostic implications of metabolic syndrome (METS) among African stroke patients are poorly understood. This study aimed to investigate the determinants of METS and its prognostic implications among Africans with newly diagnosed stroke in the SIREN study. Methods We included stroke cases (adults aged \u3e18 years with CT/MRI confirmed stroke). The validated tools comprehensively evaluated vascular, lifestyle, and psychosocial factors. We used logistic regression to estimate adjusted odds ratios (OR) with 95% CIs for the association between METS and risk factors. We also computed the prediction power of the domain of covariates in a sequential manner using the area under the receiver operating curve (ROC) curve. Results Among 3998 stroke subjects enrolled in the study, 76.8% had METS by at least one of the clinical definitions. Factors associated with METS were age \u3e 50 years (OR- 1.46, CI-1.19-1.80), male gender (OR 4.06, CI- 3.28-5.03), income \u3e100USD (OR1.42, CI-1.17-1.71), stress (OR1.46, CI-1.14-1.87), family history of diabetes mellitus (OR1.38, CI-1.06-1.78), and cardiac disease (OR1.42, CI-1.18-1.65). Stroke severity was higher among those with METS (SLS = 5.8 ± 4.3) compared with those without METS (6.2 ± 4.5) at p = 0.037. METS was associated with higher odds (aOR 1.31, CI-1.08-1.58) of one-month fatality after adjusting for stroke severity, age \u3e 50 years, and average monthly income \u3e100USD. Conclusion METS is very common among African stroke patients and is associated with stroke severity and worse one-month fatality. Lifestyle interventions may prevent METS and attenuate its impact on stroke occurrence and outcomes

Home Assessment of Indoor Microbiome (HAIM) in Relation to Lower Respiratory Tract Infections among Under-Five Children in Ibadan, Nigeria: The Study Protocol

The association between household air pollution and lower respiratory tract infections (LRTI) among children under five years of age has been well documented; however, the extent to which the microbiome within the indoor environment contributes to this association is uncertain. The home assessment of indoor microbiome (HAIM) study seeks to assess the abundance of indoor microbiota (IM) in the homes of under-five children (U-5Cs) with and without LRTI. HAIM is a hospital- and community-based study involving 200 cases and 200 controls recruited from three children's hospitals in Ibadan, Nigeria. Cases will be hospital-based patients with LRTI confirmed by a pediatrician, while controls will be community-based participants, matched to cases on the basis of sex, geographical location, and age (±3 months) without LRTI. The abundance of IM in houses of cases and controls will be investigated using active and passive air sampling techniques and analyzed by qualitative detection of bacterial 16SrRNA gene (V3-V4), fungal ITS1 region, and viral RNA sequencing. HAIM is expected to elucidate the relationship between exposure to IM and incidence of LRTI among U-5Cs and ultimately provide evidence base for strategic interventions to curtail the burgeoning burden of LRTI on the subcontinent

Dominant modifiable risk factors for stroke in Ghana and Nigeria (SIREN): a case-control study

Summary: Background: Sub-Saharan Africa has the highest incidence, prevalence, and fatality from stroke globally. Yet, only little information about context-specific risk factors for prioritising interventions to reduce the stroke burden in sub-Saharan Africa is available. We aimed to identify and characterise the effect of the top modifiable risk factors for stroke in sub-Saharan Africa. Methods: The Stroke Investigative Research and Educational Network (SIREN) study is a multicentre, case-control study done at 15 sites in Nigeria and Ghana. Cases were adults (aged ≥18 years) with stroke confirmed by CT or MRI. Controls were age-matched and gender-matched stroke-free adults (aged ≥18 years) recruited from the communities in catchment areas of cases. Comprehensive assessment for vascular, lifestyle, and psychosocial factors was done using standard instruments. We used conditional logistic regression to estimate odds ratios (ORs) and population-attributable risks (PARs) with 95% CIs. Findings: Between Aug 28, 2014, and June 15, 2017, we enrolled 2118 case-control pairs (1192 [56%] men) with mean ages of 59·0 years (SD 13·8) for cases and 57·8 years (13·7) for controls. 1430 (68%) had ischaemic stoke, 682 (32%) had haemorrhagic stroke, and six (<1%) had discrete ischaemic and haemorrhagic lesions. 98·2% (95% CI 97·2–99·0) of adjusted PAR of stroke was associated with 11 potentially modifiable risk factors with ORs and PARs in descending order of PAR of 19·36 (95% CI 12·11–30·93) and 90·8% (95% CI 87·9–93·7) for hypertension, 1·85 (1·44–2·38) and 35·8% (25·3–46·2) for dyslipidaemia, 1·59 (1·19–2·13) and 31·1% (13·3–48·9) for regular meat consumption, 1·48 (1·13–1·94) and 26·5% (12·9–40·2) for elevated waist-to-hip ratio, 2·58 (1·98–3·37) and 22·1% (17·8–26·4) for diabetes, 2·43 (1·81–3·26) and 18·2% (14·1–22·3) for low green leafy vegetable consumption, 1·89 (1·40–2·54) and 11·6% (6·6–16·7) for stress, 2·14 (1·34–3·43) and 5·3% (3·3–7·3) for added salt at the table, 1·65 (1·09–2·49) and 4·3% (0·6–7·9) for cardiac disease, 2·13 (1·12–4·05) and 2·4% (0·7–4·1) for physical inactivity, and 4·42 (1·75–11·16) and 2·3% (1·5–3·1) for current cigarette smoking. Ten of these factors were associated with ischaemic stroke and six with haemorrhagic stroke occurrence. Interpretation: Implementation of interventions targeting these leading risk factors at the population level should substantially curtail the burden of stroke among Africans. Funding: National Institutes of Health