Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry.

Background: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts. Methods: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. Results: Two genome-wide significant (P < 5 × 10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. Conclusion: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.

Genetic Association and Transferability for Urinary Albumin-Creatinine Ratio as a Marker of Kidney Disease in four Sub-Saharan African Populations and non-continental Individuals of African Ancestry.

BACKGROUND: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts. METHODS: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. RESULTS: Two genome-wide significant (P<5x10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. CONCLUSION: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes. METHODS: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. RESULTS: Two genome-wide significant (P<5x10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. CONCLUSION: This study contributes novel insights into the genetic architecture of kidney function in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations.

Undernutrition in children aged 0-59 months by region and over time: secondary analysis of the Burkina Faso 2012-2018 National Nutrition Surveys.

The global burden of undernutrition remains high, responsible for significant under-five mortality in resource-limited settings. Numerous sustainable development goals (SDGs) are linked to nutrition, and nationally representative nutrition surveillance is a key activity to track progress towards SDGs and guide efficient programmes. OBJECTIVES: The aim of this study is to look at spatial and temporal trends in undernutrition in children under 5 years age in Burkina Faso. SETTING: We used data from annual National Nutrition Surveys using Standardised Monitoring and Assessment of Relief and Transitions methodology (anthropometry, morbidity) over 7 years (2012-2018) in Burkina Faso. PARTICIPANTS: Children of under 5 years from households selected through systemic sampling at countrywide level. MAIN OUTCOME MEASURES: Prevalence of stunting (height-for-age z-score, <-2), underweight (weight-for-age z-score, <-2) and wasting (weight-for-height z-score, <-2) at regional and national. We used general linear mixed models, adjusted by age, survey year, sex, presence of fever and/or diarrhoea, and poverty index to quantify the risk of undernutrition over time and by region of residence. RESULTS: Between 2012 and 2018, decreases were observed overall in the prevalence of growth retardation (stunting) decreased from 33.0% (95% CI 32.3 to 33.8) in 2012 to 26.7% (95% CI 26.2 to 27.3) in 2018. Underweight reduced from 24.4% (95% CI 23.7 to 25.1) to 18.7% (95% CI 18.2 to 19.2) for the same period and wasting decreased from 10.8% (95% CI 10.3 to 11.3) in 2012 to 8.4% (95% CI 8.1 to 8.8) in 2018. However, there was substantial variation across the country, with increased risk of undernutrition in the regions of Sahel, East and Cascades primarily. High-risk regions were characterised by a lower poverty index and limited access to healthcare services. CONCLUSIONS: Our findings could inform national policymakers in refining and optimising resource allocation based on the identification of high-risk areas.

Men's motivations, barriers to and aspirations for their families' health in the first 1000 days in sub-Saharan Africa: a secondary qualitative analysis.

Introduction: The first 1000 days of life are a critical period of growth and development that have lasting implications for health, cognitive, educational and economic outcomes. In sub-Saharan Africa, gender and social norms are such that many men have little engagement with maternal and child health and nutrition during pregnancy and early childhood. This study explores how men perceive their role in three sites in sub-Saharan Africa. Methods: Secondary qualitative analysis of 10 focus group discussions with 76 men in Burkina Faso, Ghana and South Africa. Data were thematically analysed to explore men's perceptions of maternal and child health and nutrition. Results: Men considered themselves 'providers' and 'advisors' within their families, particularly of finances, food and medicines. They also indicated that this advice was out of care and concern for their families' health. There were similarities in how the men perceive their role. Differences between men living in rural and urban settings included health priorities, the advice and the manner in which it was provided. Across all settings, men wanted to be more involved with maternal and child health and nutrition. Challenges to doing so included stigma and proscribed social gender roles. Conclusion: Men want a greater engagement in improving maternal and child health and nutrition but felt that their ability to do so was limited by culture-specified gender roles, which are more focused on providing for and advising their families. Involving both men and women in intervention development alongside policymakers, health professionals and researchers is needed to improve maternal and child health and nutrition.

Genetic insights into smoking behaviours in 10,558 men of African ancestry from continental Africa and the UK.

Smoking is a leading risk factor for many of the top ten causes of death worldwide. Of the 1.3 billion smokers globally, 80% live in low- and middle-income countries, where the number of deaths due to tobacco use is expected to double in the next decade according to the World Health Organization. Genetic studies have helped to identify biological pathways for smoking behaviours, but have mostly focussed on individuals of European ancestry or living in either North America or Europe. We performed a genome-wide association study of two smoking behaviour traits in 10,558 men of African ancestry living in five African countries and the UK. Eight independent variants were associated with either smoking initiation or cessation at P-value < 5 × 10-6, four being monomorphic or rare in European populations. Gene prioritisation strategy highlighted five genes, including SEMA6D, previously described as associated with several smoking behaviour traits. These results confirm the importance of analysing underrepresented populations in genetic epidemiology, and the urgent need for larger genomic studies to boost discovery power to better understand smoking behaviours, as well as many other traits.

Apolipoprotein L1 High-Risk Genotypes and Albuminuria in Sub-Saharan African Populations.

BACKGROUND AND OBJECTIVES: Recessive inheritance of African-specific APOL1 kidney risk variants is associated with higher risk of nondiabetic kidney disease, progression to kidney failure, and early-onset albuminuria that precedes eGFR decline. The effect of APOL1 risk variants on kidney disease in continental Africans is understudied. Objectives of this study were to determine APOL1 risk allele prevalence and associations between APOL1 genotypes and kidney disease in West, East, and South Africa. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional population-based study in four African countries included 10,769 participants largely aged 40-60 years with sociodemographic and health information, anthropometry data, and blood and urine tests for biomarkers of kidney disease. APOL1 risk alleles were imputed from the H3Africa genotyping array, APOL1 risk allele and genotype frequencies were determined, and genetic associations were assessed for kidney disease. Kidney disease was defined as the presence of eGFR <60 ml/min per 1.73 m2, albuminuria, or a composite end point including eGFR <60 ml/min per 1.73 m2 and/or albuminuria. RESULTS: High G1 allele frequencies occurred in South and West Africa (approximately 7%-13%). G2 allele frequencies were highest in South Africa (15%-24%), followed by West Africa (9%-12%). Associations between APOL1 risk variants and albuminuria were significant for recessive (odds ratio, 1.63; 95% confidence interval, 1.25 to 2.12) and additive (odds ratio, 1.39; 95% confidence interval, 1.09 to 1.76) models. Associations were stronger for APOL1 G1/G1 genotypes versus G0/G0 (odds ratio, 3.87; 95% confidence interval, 2.16 to 6.93) compared with either G2/G2 (odds ratio, 1.65; 95% confidence interval, 1.09 to 2.51) or G1/G2 (odds ratio, 1.24; 95% confidence interval, 0.83 to 1.87). No association between APOL1 risk variants and eGFR <60 ml/min per 1.73 m2 was observed. CONCLUSIONS: APOL1 G1 and G2 alleles and high-risk genotype frequencies differed between and within West and South Africa and were almost absent from East Africa. APOL1 risk variants were associated with albuminuria but not eGFR <60 ml/min per 1.73 m2. There may be differential effects of homozygous G1 and G2 genotypes on albuminuria that require further investigation. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_05_16_CJN14321121.mp3.

Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits.

Genetic associations for lipid traits have identified hundreds of variants with clear differences across European, Asian and African studies. Based on a sub-Saharan-African GWAS for lipid traits in the population cross-sectional AWI-Gen cohort (N = 10,603) we report a novel LDL-C association in the GATB region (P-value=1.56 × 10-8). Meta-analysis with four other African cohorts (N = 23,718) provides supporting evidence for the LDL-C association with the GATB/FHIP1A region and identifies a novel triglyceride association signal close to the FHIT gene (P-value =2.66 × 10-8). Our data enable fine-mapping of several well-known lipid-trait loci including LDLR, PMFBP1 and LPA. The transferability of signals detected in two large global studies (GLGC and PAGE) consistently improves with an increase in the size of the African replication cohort. Polygenic risk score analysis shows increased predictive accuracy for LDL-C levels with the narrowing of genetic distance between the discovery dataset and our cohort. Novel discovery is enhanced with the inclusion of African data.

Genetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans.

Atherosclerosis precedes the onset of clinical manifestations of cardiovascular diseases (CVDs). We used carotid intima-media thickness (cIMT) to investigate genetic susceptibility to atherosclerosis in 7894 unrelated adults (3963 women, 3931 men; 40 to 60 years) resident in four sub-Saharan African countries. cIMT was measured by ultrasound and genotyping was performed on the H3Africa SNP Array. Two new African-specific genome-wide significant loci for mean-max cIMT, SIRPA (p = 4.7E-08), and FBXL17 (p = 2.5E-08), were identified. Sex-stratified analysis revealed associations with one male-specific locus, SNX29 (p = 6.3E-09), and two female-specific loci, LARP6 (p = 2.4E-09) and PROK1 (p = 1.0E-08). We replicate previous cIMT associations with different lead SNPs in linkage disequilibrium with SNPs primarily identified in European populations. Our study find significant enrichment for genes involved in oestrogen response from female-specific signals. The genes identified show biological relevance to atherosclerosis and/or CVDs, sex-differences and transferability of signals from non-African studies.

Patterns of child mortality in rural area of Burkina Faso: evidence from the Nanoro health and demographic surveillance system (HDSS).

BACKGROUND: Half of global child deaths occur in sub-Saharan Africa. Understanding child mortality patterns and risk factors will help inform interventions to reduce this heavy toll. The Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso was described previously, but patterns and potential drivers of heterogeneity in child mortality in the district had not been studied. Similar studies in other districts indicated proximity to health facilities as a risk factor, usually without distinction between facility types. METHODS: Using Nanoro HDSS data from 2009 to 2013, we estimated the association between under-5 mortality and proximity to inpatient and outpatient health facilities, seasonality of death, age group, and standard demographic risk factors. RESULTS: Living in homes 40-60 min and > 60 min travel time from an inpatient facility was associated with 1.52 (95% CI: 1.13-2.06) and 1.74 (95% CI: 1.27-2.40) greater hazard of under-5 mortality, respectively, than living in homes < 20 min from an inpatient facility. No such association was found for outpatient facilities. The wet season (July-November) was associated with 1.28 (95% CI: 1.07, 1.53) higher under-5 mortality than the dry season (December-June), likely reflecting the malaria season. CONCLUSIONS: Our results emphasize the importance of geographical proximity to health care, distinguish between inpatient and outpatient facilities, and also show a seasonal effect, probably driven by malaria.

Prevalence and socio-demographic correlates of tobacco and alcohol use in four sub-Saharan African countries: a cross-sectional study of middle-aged adults.

BACKGROUND: Substance misuse is a global public health problem. In addition to social and economic concerns, consumption of tobacco and alcohol is associated with susceptibility to cardiovascular, respiratory, and infectious diseases, cancers, and risk of transition to substance use disorders. African data suggest regional differences in the prevalence and patterns of substance use, but a number of key questions remain. This cross-sectional population-based study of middle-aged adults aims to examine prevalence and socio-demographic correlates of substance use in four sub-Saharan African countries, in rural and urban settings. METHODS: Participants aged between 40 and 60 years were recruited from six research centres as part of the Africa Wits-INDEPTH partnership for Genomic Research study. Data on patterns of tobacco and alcohol consumption was captured, and the latter further assessed using the CAGE (cut-annoyed-guilty-eye) questionnaire. RESULTS: Data from 10,703 participants suggested that more men (68.4%) than women (33.3%) were current substance users. The prevalence of current smoking was significantly higher in men than in women (34.5% vs 2.1%, p < 0.001). Smokeless tobacco was used more by women than men (14.4% vs 5.3%, p < 0.001). Current smoking was associated with alcohol consumption in men, and smoking cessation in men was associated with being a former drinker, having higher socio-economic status, and if married or cohabiting. Current alcohol consumption was higher in men, compared to women (60.3% vs 29.3%), and highest in men from Soweto (70.8%) and women from Nanoro (59.8%). The overall prevalence of problematic alcohol consumption among men was 18.9%, and women 7.3%. Men were significantly more likely to develop problematic drinking patterns, and this was more common in those who were divorced or widowed, and in current smokers. CONCLUSIONS: Regional variation in the patterns and prevalence of substance use was observed across study sites, and in rural and urban settings. The high levels of substance use recorded in this study are of concern due to the increased risk of associated morbidities. Further longitudinal data will be valuable in determining trends in substance misuse in Africa.

The changing epidemiology of hepatitis B and C infections in Nanoro, rural Burkina Faso: a random sampling survey.

BACKGROUND: This study sought to provide up-to-date hepatitis B (HBV) and C (HCV) seroprevalence in rural Burkina Faso decade after hepatitis B vaccine was introduced in the national immunization scheduled for children. METHODS: In 2018, a community-based, random sampling strategy with probability proportional to population size was conducted in Nanoro to investigate the prevalence of viral hepatitis in children and their mothers. Sociodemographic, vaccination history and risk factors were assessed by interview and health books. HBsAg rapid tests were done by finger prick and Dried Blood Spots (DBS) were collected for hepatitis seromarkers by chemiluminescence enzyme immunoassay. Positive samples underwent confirmatory PCR and phylogenetic analysis. RESULTS: Data were presented on 240 mother-child pairs. HBsAg Prevalence was 0.8% in children and 6.3% in mothers. Hepatitis B core antibody positivity was 89.2% in mothers, 59.2% in children and was associated with age, sex and scarification. Hepatitis B surface antibodies prevalence was 37.5% in children and 5.8% in mothers. Good vaccination coverage was limited by home delivery. Phylogenetic analysis of HBV strains based on full genome sequences (n = 7) and s-fragment sequences (n = 6) revealed genotype A, E, and recombinant A3/E. Viral genome homology was reported in one mother-child pair. Anti-HCV prevalence was 5.4% in mothers, 2.1% in children and strains belonged to genotype 2. CONCLUSIONS: In Nanoro, HBsAg prevalence was low in children, intermediate in mothers and mother-to-child transmission persists. Home delivery was a limiting factor of Hepatitis B vaccination coverage. HBV genotype E was predominant and genotype A3/E is reported for the first time in Burkina Faso.

Novel and Known Gene-Smoking Interactions With cIMT Identified as Potential Drivers for Atherosclerosis Risk in West-African Populations of the AWI-Gen Study.

INTRODUCTION: Atherosclerosis is a key contributor to the burden of cardiovascular diseases (CVDs) and many epidemiological studies have reported on the effect of smoking on carotid intima-media thickness (cIMT) and its subsequent effect on CVD risk. Gene-environment interaction studies have contributed towards understanding some of the missing heritability of genome-wide association studies. Gene-smoking interactions on cIMT have been studied in non-African populations (European, Latino-American, and African American) but no comparable African research has been reported. Our aim was to investigate smoking-SNP interactions on cIMT in two West African populations by genome-wide analysis. MATERIALS AND METHODS: Only male participants from Burkina Faso (Nanoro = 993) and Ghana (Navrongo = 783) were included, as smoking was extremely rare among women. Phenotype and genotype data underwent stringent QC and genotype imputation was performed using the Sanger African Imputation Panel. Smoking prevalence among men was 13.3% in Nanoro and 42.5% in Navrongo. We analyzed gene-smoking interactions with PLINK after adjusting for covariates: age and 6 PCs (Model 1); age, BMI, blood pressure, fasting glucose, cholesterol levels, MVPA, and 6 PCs (Model 2). All analyses were performed at site level and for the combined data set. RESULTS: In Nanoro, we identified new gene-smoking interaction variants for cIMT within the previously described RCBTB1 region (rs112017404, rs144170770, and rs4941649) (Model 1: p = 1.35E-07; Model 2: p = 3.08E-08). In the combined sample, two novel intergenic interacting variants were identified, rs1192824 in the regulatory region of TBC1D8 (p = 5.90E-09) and rs77461169 (p = 4.48E-06) located in an upstream region of open chromatin. In silico functional analysis suggests the involvement of genes implicated in biological processes related to cell or biological adhesion and regulatory processes in gene-smoking interactions with cIMT (as evidenced by chromatin interactions and eQTLs). DISCUSSION: This is the first gene-smoking interaction study for cIMT, as a risk factor for atherosclerosis, in sub-Saharan African populations. In addition to replicating previously known signals for RCBTB1, we identified two novel genomic regions (TBC1D8, near BCHE) involved in this gene-environment interaction.