Proteomic insights into the pathophysiology of hypertension-associated albuminuria: Pilot study in a South African cohort.

BACKGROUND: Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify potential proteins and pathways involved in hypertension-associated albuminuria by assessing urinary proteomic profiles in black South African participants with combined hypertension and albuminuria compared to those who have neither condition. METHODS: The study included 24 South African cases with both hypertension and albuminuria and 49 control participants who had neither condition. Protein was extracted from urine samples and analysed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Data were generated using data-independent acquisition (DIA) and processed using Spectronaut™ 15. Statistical and functional data annotation were performed on Perseus and Cytoscape to identify and annotate differentially abundant proteins. Machine learning was applied to the dataset using the OmicLearn platform. RESULTS: Overall, a mean of 1,225 and 915 proteins were quantified in the control and case groups, respectively. Three hundred and thirty-two differentially abundant proteins were constructed into a network. Pathways associated with these differentially abundant proteins included the immune system (q-value [false discovery rate] = 1.4 × 10- 45), innate immune system (q = 1.1 × 10- 32), extracellular matrix (ECM) organisation (q = 0.03) and activation of matrix metalloproteinases (q = 0.04). Proteins with high disease scores (76-100% confidence) for both hypertension and chronic kidney disease included angiotensinogen (AGT), albumin (ALB), apolipoprotein L1 (APOL1), and uromodulin (UMOD). A machine learning approach was able to identify a set of 20 proteins, differentiating between cases and controls. CONCLUSIONS: The urinary proteomic data combined with the machine learning approach was able to classify disease status and identify proteins and pathways associated with hypertension-associated albuminuria.

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.

Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations.

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 × 10-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 × 10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta = 9.36 × 10-10), chromosome 10 at PLCE1 (rs7099485, pmeta = 1.48 × 10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta = 1.47 × 10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.

Genome-wide association study of population-standardised cognitive performance phenotypes in a rural South African community.

Cognitive function is an indicator for global physical and mental health, and cognitive impairment has been associated with poorer life outcomes and earlier mortality. A standard cognition test, adapted to a rural-dwelling African community, and the Oxford Cognition Screen-Plus were used to capture cognitive performance as five continuous traits (total cognition score, verbal episodic memory, executive function, language, and visuospatial ability) for 2,246 adults in this population of South Africans. A novel common variant, rs73485231, reached genome-wide significance for association with episodic memory using data for ~14 million markers imputed from the H3Africa genotyping array data. Window-based replication of previously implicated variants and regions of interest support the discovery of African-specific associated variants despite the small population size and low allele frequency. This African genome-wide association study identifies suggestive associations with general cognition and domain-specific cognitive pathways and lays the groundwork for further genomic studies on cognition in Africa.

Genome-wide Association Study Meta-analysis of Blood Pressure Traits and Hypertension in Sub-Saharan African Populations: An AWI-Gen Study.

Most hypertension-related genome-wide association studies (GWAS) focus on non-African populations, despite hypertension (a major risk factor for cardiovascular disease) being highly prevalent in Africa. The AWI-Gen study GWAS meta-analysis for blood pressure-related traits (systolic and diastolic blood pressure, pulse pressure, mean-arterial pressure and hypertension) from three sub-Saharan African geographic regions (N=10,775), identified two genome-wide significant signals (p<5E-08): systolic blood pressure near P2RY1 (rs77846204; intergenic variant, p=4.25E-08) and pulse pressure near Linc01256 (rs80141533; intergenic variant, p=4.25E-08). No genome-wide signals were detected for the AWI-Gen GWAS meta-analysis with previous African-ancestry GWASs (UK Biobank (African), Uganda Genome Resource). Suggestive signals (p<5E-06) were observed for all traits, with 29 displaying pleiotropic effects and several replicating known associations. Polygenic risk scores developed from studies on different ancestries had limited transferability, with multi-ancestry models providing better prediction. This study provides insights into the genetics and physiology of blood pressure variation in African populations.

Exome-based mutation screening in South African children with primary congenital glaucoma.

OBJECTIVES: To identify pathogenic variants in a cohort of 23 black South African children with sporadic primary congenital glaucoma (PCG) using an exome-based approach. METHODS: Children with PCG were recruited from two Paediatric Ophthalmology Clinics in Johannesburg, South Africa. Whole exome sequencing was performed on genomic DNA. Of the 23 children, 19 were male and 19 had bilateral PCG. A variant prioritization strategy was employed whereby variants in known PCG genes (CYP1B1, LTBP2 and TEK) were evaluated first, followed by the identification of putative disease-causing variants in other genes related to eye diseases and phenotypes. RESULTS: Validated pathogenic variants in the CYP1B1 gene (c.1169 G>A; p.Arg390His) and TEK gene (c.922 G>A; p.Gly308Arg) were identified in one child each. No LTBP2 mutations were identified in this cohort. In silico predictions identified potentially damaging rare variants in genes previously associated with eye development phenotypes or glaucoma in a further 12 children. CONCLUSIONS: This study demonstrates the value of whole exome sequencing in identifying disease-causing variants in African children with PCG. It is the first report of a TEK disease-causing variant in an African PCG patient. Potential causative variants detected in PCG candidate genes warrant further investigation.

H3AGWAS: a portable workflow for genome wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) are a powerful method to detect associations between variants and phenotypes. A GWAS requires several complex computations with large data sets, and many steps may need to be repeated with varying parameters. Manual running of these analyses can be tedious, error-prone and hard to reproduce. RESULTS: The H3AGWAS workflow from the Pan-African Bioinformatics Network for H3Africa is a powerful, scalable and portable workflow implementing pre-association analysis, implementation of various association testing methods and post-association analysis of results. CONCLUSIONS: The workflow is scalable-laptop to cluster to cloud (e.g., SLURM, AWS Batch, Azure). All required software is containerised and can run under Docker or Singularity.

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.

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.

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.

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.

The Use of 'Omics for Diagnosing and Predicting Progression of Chronic Kidney Disease: A Scoping Review.

Globally, chronic kidney disease (CKD) contributes substantial morbidity and mortality. Recently, various 'omics platforms have provided insight into the molecular basis of kidney dysfunction. This scoping review is a synthesis of the current literature on the use of different 'omics platforms to identify biomarkers that could be used to detect early-stage CKD, predict disease progression, and identify pathways leading to CKD. This review includes 123 articles published from January 2007 to May 2021, following a structured selection process. The most common type of 'omic platform was proteomics, appearing in 55 of the studies and two of these included a metabolomics component. Most studies (n = 91) reported on CKD associated with diabetes mellitus. Thirteen studies that provided information on the biomarkers associated with CKD and explored potential pathways involved in CKD are discussed. The biomarkers that are associated with risk or early detection of CKD are SNPs in the MYH9/APOL1 and UMOD genes, the proteomic CKD273 biomarker panel and metabolite pantothenic acid. Pantothenic acid and the CKD273 biomarker panel were also involved in predicting CKD progression. Retinoic acid pathway genes, UMOD, and pantothenic acid provided insight into potential pathways leading to CKD. The biomarkers were mainly used to detect CKD and predict progression in high-income, European ancestry populations, highlighting the need for representative 'omics research in other populations with disparate socio-economic strata, including Africans, since disease etiologies may differ across ethnic groups. To assess the transferability of findings, it is essential to do research in diverse populations.

G6PD distribution in sub-Saharan Africa and potential risks of using chloroquine/hydroxychloroquine based treatments for COVID-19.

Chloroquine/hydroxychloroquine have been proposed as potential treatments for COVID-19. These drugs have warning labels for use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Analysis of whole genome sequence data of 458 individuals from sub-Saharan Africa showed significant G6PD variation across the continent. We identified nine variants, of which four are potentially deleterious to G6PD function, and one (rs1050828) that is known to cause G6PD deficiency. We supplemented data for the rs1050828 variant with genotype array data from over 11,000 Africans. Although this variant is common in Africans overall, large allele frequency differences exist between sub-populations. African sub-populations in the same country can show significant differences in allele frequency (e.g. 16.0% in Tsonga vs 0.8% in Xhosa, both in South Africa, p = 2.4 × 10-3). The high prevalence of variants in the G6PD gene found in this analysis suggests that it may be a significant interaction factor in clinical trials of chloroquine and hydroxychloroquine for treatment of COVID-19 in Africans.

Performing post-genome-wide association study analysis: overview, challenges and recommendations.

Genome-wide association studies (GWAS) provide  huge information on statistically significant single-nucleotide polymorphisms (SNPs) associated with various human complex traits and diseases. By performing GWAS studies, scientists have successfully identified the association of hundreds of thousands to  millions of SNPs to a single phenotype. Moreover, the association of some SNPs with rare diseases has been intensively tested. However, classic GWAS studies have not yet provided solid, knowledgeable insight into functional and biological mechanisms underlying phenotypes or mechanisms of diseases. Therefore, several post-GWAS (pGWAS) methods have been recommended. Currently, there is no simple scientific document to provide a quick guide for performing pGWAS analysis. pGWAS is a crucial step for a better understanding of the biological machinery beyond the SNPs. Here, we provide an overview to performing pGWAS analysis and demonstrate the challenges behind each method. Furthermore, we direct readers to key articles for each pGWAS method and present the overall issues in pGWAS analysis.  Finally, we include a custom pGWAS pipeline to guide new users when performing their research.

G6PD variant distribution in sub-Saharan Africa and potential risks of using chloroquine/hydroxychloroquine based treatments for COVID-19.

Chloroquine/hydroxychloroquine have been proposed as potential treatments for COVID-19. These drugs have warning labels for use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Analysis of whole-genome sequence data of 458 individuals from sub-Saharan Africa showed significant G6PD variation across the continent. We identified nine variants, of which four are potentially deleterious to G6PD function, and one (rs1050828) that is known to cause G6PD deficiency. We supplemented data for the rs1050828 variant with genotype array data from over 11,000 Africans. Although this variant is common in Africans overall, large allele frequency differences exist between sub-populations. African sub-populations in the same country can show significant differences in allele frequency (e.g. 16.0% in Tsonga vs 0.8% in Xhosa, both in South Africa, ρ=2.4×10 -3 ). The high prevalence of variants in the G6PD gene found in this analysis suggests that it may be a significant interaction factor in clinical trials of chloroquine and hydrochloroquine for treatment of COVID-19 in Africans.

Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism.

The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.

Kidney damage and associated risk factors in rural and urban sub-Saharan Africa (AWI-Gen): a cross-sectional population study.

BACKGROUND: Rapid epidemiological health transitions occurring in vulnerable populations in Africa that have an existing burden of infectious and non-communicable diseases predict an increased risk and consequent prevalence of kidney disease. However, few studies have characterised the true burden of kidney damage and associated risk factors in Africans. We investigated the prevalence of markers for kidney damage and known risk factors in rural and urban settings in sub-Saharan Africa. METHODS: In this cross-sectional population study (Africa Wits-International Network for the Demographic Evaluation of Populations and their Health Partnership for Genomic Studies [AWI-Gen]), we recruited unrelated adult participants aged 40-60 years from four rural community research sites (Nanoro, Burkina Faso; Navrongo, Ghana; Agincourt and Dikgale, South Africa), and two urban community research sites (Nairobi, Kenya; and Soweto, South Africa). Participants were identified and selected using random sampling frames already in use at each site. Participants completed a lifestyle and medical history questionnaire, had anthropometric and blood pressure measurements taken, and blood and urine samples were collected. Markers of kidney damage were defined as low estimated glomerular filtration rate (eGFR; <60 mL/min per 1·73 m2), presence of albuminuria (urine albumin creatinine ratio >3 mg/mmol); or chronic kidney disease (low eGFR or albuminuria, or both). We calculated age-adjusted prevalence of chronic kidney disease, low eGFR, and albuminuria by site and sex and used logistic regression models to assess risk factors of kidney damage. FINDINGS: Between August, 2013, and August, 2016, we recruited 10 702 participants, of whom 8110 were analysable. 4120 (50·8%) of analysable participants were male, with a mean age of 49·9 years (SD 5·8). Age-standardised population prevalence was 2·4% (95% CI 2·1-2·8) for low eGFR, 9·2% (8·4-10·0) for albuminuria, and 10·7% (9·9-11·7) for chronic kidney disease, with higher prevalences in South African sites than in west African sites (14·0% [11·9-16·4] in Agincourt vs 6·6% [5·5-7·9] in Nanoro). Women had a higher prevalence of chronic kidney disease (12·0% [10·8-13·2] vs 9·5% [8·3-10·8]) and low eGFR (3·0% [2·6-3·6] vs 1·7% [1·3-2·3]) than did men, with no sex-specific differences for albuminuria (9·9% [8·8-11·0] vs 8·4% [7·3-9·7]). Risk factors for kidney damage were older age (relative risk 1·04, 95% CI 1·03-1·05; p<0·0001), hypertension (1·97, 1·68-2·30; p<0·0001), diabetes (2·22, 1·76-2·78; p<0·0001), and HIV (1·65, 1·36-1·99; p<0·0001); whereas male sex was protective (0·85, 0·73-0·98; p=0·02). INTERPRETATION: Regional differences in prevalence and risks of chronic kidney disease in sub-Saharan Africa relate in part to varying stages of sociodemographic and epidemiological health transitions across the area. Public health policy should focus on integrated strategies for screening, prevention, and risk factor management in the broader non-communicable disease and infectious diseases framework. FUNDING: National Human Genome Research Institute, Office of the Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, the Office of AIDS Research, and National Institute of Diabetes and Digestive and Kidney Diseases, all of the National Institutes of Health, and the South African Department of Science and Technology.