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.

Corrigendum: Apolipoprotein E Genetic Variation and its Association With Cognitive Function in Rural-Dwelling Older South Africans.

[This corrects the article DOI: 10.3389/fgene.2021.689756.].

Apolipoprotein E Genetic Variation and Its Association With Cognitive Function in Rural-Dwelling Older South Africans.

Apolipoprotein E (APOE) 𝜀4 allele carrier status is well known for its association with an increased likelihood of developing Alzheimer's disease, but its independent role in cognitive function is unclear. APOE genetic variation is understudied in African populations; hence, this cross-sectional study in a rural South African community examined allele and genotype frequencies, and their associations with cognitive function. Cognitive function was assessed using two different screening methods to produce a total cognition score and four domain-specific cognition scores for verbal episodic memory, executive function, language, and visuospatial ability. Cognitive phenotype and APOE genotype data were used to determine whether APOE variation was significantly associated with cognitive function in this population. Observed allele frequencies for 1776 participants from the HAALSI study [age 40-80years (mean=56.19); 58.2% female] were 58.1% (𝜀3), 25.4% (𝜀4) and 16.5% (𝜀2). Allele distributions were similar to the African super population, but different from all non-African super populations from the 1,000 Genomes Project. The 𝜀3 homozygous genotype was most common (34.9%) and used as the base genotype for comparison in regression models. Four models were tested for each of the five cognitive phenotypes to explore association of APOE variation with cognitive function. In the first model assessing association with all genotypes for all individuals, marginally significant associations were observed for 𝜀2 homozygotes where executive function scored higher by ~0.5 standard deviations (p=0.037, SE=0.23), and for 𝜀3/𝜀4 heterozygotes where visuospatial ability scores were lower (p=0.046, SE=0.14). These did not survive correction for multiple testing. Regional African population differences were observed at the APOE locus. Marginally, significant associations between APOE genotype, and executive function and visuospatial ability indicate the need for larger studies to better examine these associations in African populations. Furthermore, longitudinal data could shed light on APOE genetic association with rate of change, or decline, in cognitive function.

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.

Adiposity Phenotypes and Subclinical Atherosclerosis in Adults from Sub-Saharan Africa: An H3Africa AWI-Gen Study.

Background: Obesity and adipose tissue distribution contribute to an increased risk of cardiovascular disease (CVD) by promoting atherosclerosis. This association has been poorly studied in sub-Saharan Africa (SSA) despite the rising prevalence of cardiovascular disease. Objectives: We determined the association between various adiposity phenotypes and carotid intima-media thickness (CIMT), a proxy of subclinical atherosclerosis, in a large SSA population. Methods: A population-based cross-sectional study was performed from 2013-2016 in Burkina Faso, Ghana, Kenya and South Africa. Body mass index (BMI), waist (WC), hip circumferences (HC), visceral (VAT) and subcutaneous adipose tissue (SCAT) using B-mode ultrasound were measured. Ultrasonography of left and right far wall CIMT of the common carotid artery was used as an indicator of subclinical atherosclerosis. Individual participant data meta-analyses were used to determine the associations between adiposity phenotypes and CIMT in the pooled sample while adjusted multivariable linear regression analyses were used for site specific analyses. Results: Data were obtained from 9,010 adults (50.3% women and a mean age of 50± 6years). Men had higher levels of visceral fat than women while women had higher BMI, waist and hip circumference and subcutaneous fat than men at all sites except Burkina Faso. In the pooled analyses, BMI (ß-value [95% CIs]: 19.5 [16.8, 22.3] µm) showed the strongest relationship with CIMT followed by VAT (5.86 [4.65, 7.07] µm), SCAT (5.00 [2.85, 7.15] µm), WC (1.27 [1.09, 1.44] µm) and HC (1.23 [1.04, 1.42] µm). Stronger associations were observed in men than in women. Conclusion: Obesity within SSA will likely result in higher levels of atherosclerosis and promote the occurrence of cardio- and cerebrovascular events, especially in males, unless addressed through primary prevention of obesity in both rural and urban communities across Africa. The inverse association of VAT with CIMT in Burkina Faso and Ghana requires further investigation. Highlights: All adiposity phenotypes were positively associated with common carotid intima-media thickness (CIMT) in the entire cohort (pooled analyses).BMI had the strongest association with CIMT compared to other phenotypes.The magnitude of association between adiposity phenotypes and CIMT was higher in men than in women.Subcutaneous adipose tissue was inversely associated with CIMT only in women.An unexpected finding was the inverse association of visceral adipose tissue with CIMT in Burkina Faso and Ghana.

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.

Classical Cardiovascular Risk Factors and HIV are Associated With Carotid Intima-Media Thickness in Adults From Sub-Saharan Africa: Findings From H3Africa AWI-Gen Study.

Background Studies on the determinants of carotid intima-media thickness ( CIMT ), a marker of sub-clinical atherosclerosis, mostly come from white, Asian, and diasporan black populations. We present CIMT data from sub-Saharan Africa, which is experiencing a rising burden of cardiovascular diseases and infectious diseases. Methods and Results The H3 (Human Hereditary and Health) in Africa's AWI-Gen (African-Wits-INDEPTH partnership for Genomic) study is a cross-sectional study conducted in adults aged 40 to 60 years from Burkina Faso, Kenya, Ghana, and South Africa. Cardiovascular disease risk and ultrasonography of the CIMT of right and left common carotids were measured. Multivariable linear and mixed-effect multilevel regression modeling was applied to determine factors related to CIMT. Data included 8872 adults (50.8% men), mean age of 50±6 years with age- and sex-adjusted mean (±SE) CIMT of 640±123µm. Participants from Ghana and Burkina Faso had higher CIMT compared with other sites. Age (ß = 6.77, 95%CI [6.34-7.19]), body mass index (17.6[12.5-22.8]), systolic blood pressure (7.52[6.21-8.83]), low-density lipoprotein cholesterol (5.08[2.10-8.06]) and men (10.3[4.75- 15.9]) were associated with higher CIMT. Smoking was associated with higher CIMT in men. High-density lipoprotein cholesterol (-12.2 [-17.9- -6.41]), alcohol consumption (-13.5 [-19.1--7.91]) and HIV (-8.86 [-15.7--2.03]) were inversely associated with CIMT. Conclusions Given the rising prevalence of cardiovascular diseases risk factors in sub-Saharan Africa, atherosclerotic diseases may become a major pan-African epidemic unless preventive measures are taken particularly for prevention of hypertension, obesity, and smoking. HIV -specific studies are needed to fully understand the association between HIV and CIMT in sub-Saharan Africa.

Genomic and environmental risk factors for cardiometabolic diseases in Africa: methods used for Phase 1 of the AWI-Gen population cross-sectional study.

There is an alarming tide of cardiovascular and metabolic disease (CMD) sweeping across Africa. This may be a result of an increasingly urbanized lifestyle characterized by the growing consumption of processed and calorie-dense food, combined with physical inactivity and more sedentary behaviour. While the link between lifestyle and public health has been extensively studied in Caucasian and African American populations, few studies have been conducted in Africa. This paper describes the detailed methods for Phase 1 of the AWI-Gen study that were used to capture phenotype data and assess the associated risk factors and end points for CMD in persons over the age of 40 years in sub-Saharan Africa (SSA). We developed a population-based cross-sectional study of disease burden and phenotype in Africans, across six centres in SSA. These centres are in West Africa (Nanoro, Burkina Faso, and Navrongo, Ghana), in East Africa (Nairobi, Kenya) and in South Africa (Agincourt, Dikgale and Soweto). A total of 10,702 individuals between the ages of 40 and 60 years were recruited into the study across the six centres, plus an additional 1021 participants over the age of 60 years from the Agincourt centre. We collected socio-demographic, anthropometric, medical history, diet, physical activity, fat distribution and alcohol/tobacco consumption data from participants. Blood samples were collected for disease-related biomarker assays, and genomic DNA extraction for genome-wide association studies. Urine samples were collected to assess kidney function. The study provides base-line data for the development of a series of cohorts with a second wave of data collection in Phase 2 of the study. These data will provide valuable insights into the genetic and environmental influences on CMD on the African continent.

Regional and sex-specific variation in BMI distribution in four sub-Saharan African countries: The H3Africa AWI-Gen study.

BACKGROUND: African populations are characterised by diversity at many levels including: demographic history, genetic ancestry, language, wealth, socio-political landscape, culture and behaviour. Several of these have a profound impact on body fat mass. Obesity, a key risk factor for cardiovascular and metabolic diseases, in the wake of the epidemiological and health transitions across the continent, requires detailed analysis together with other major risk factors. OBJECTIVE: To compare regional and sex-specific body mass index (BMI) distributions, using a cross-sectional study design, in adults aged 40-60 years across six study sites in four sub-Saharan African (SSA) countries and to compare the determinants of BMI at each. METHODS: Anthropometric measurements were standardised across sites and BMI calculated. Median BMI and prevalence of underweight, lean, overweight and obesity were compared between the sexes and across sites. Data from multivariable linear regression models for the principal determinants of BMI were summarised from the site-specific studies. RESULTS: BMI was calculated in 10,702 participants (55% female) and was significantly higher in women than men at nearly all sites. The highest prevalence of obesity was observed at the three South African sites (42.3-66.6% in women and 2.81-17.5% in men) and the lowest in West Africa (1.25-4.22% in women and 1.19-2.20% in men). Across sites, higher socio-economic status and educational level were associated with higher BMI. Being married and increased dietary intake were associated with higher BMI in some communities, whilst smoking and alcohol intake were associated with lower BMI, as was HIV infection in the regions where it was prevalent. CONCLUSION: In SSA there is a marked variation in the prevalence of obesity both regionally and between men and women. Our data suggest that the drive for social upliftment within Africa will be associated with rising levels of obesity, which will require the initiation of targeted sex-specific intervention programmes across specific African communities.

Establishing an academic biobank in a resource-challenged environment.

Past practices of informal sample collections and spreadsheets for data and sample management fall short of best-practice models for biobanking, and are neither cost effective nor efficient to adequately serve the needs of large research studies. The biobank of the Sydney Brenner Institute for Molecular Bioscience serves as a bioresource for institutional, national and international research collaborations. It provides high-quality human biospecimens from African populations, secure data and sample curation and storage, as well as monitored sample handling and management processes, to promote both non-communicable and infectious-disease research. Best-practice guidelines have been adapted to align with a low-resource setting and have been instrumental in the development of a quality-management system, including standard operating procedures and a quality-control regimen. Here, we provide a summary of 10 important considerations for initiating and establishing an academic research biobank in a low-resource setting. These include addressing ethical, legal, technical, accreditation and/or certification concerns and financial sustainability.

Regional and Sex Differences in the Prevalence and Awareness of Hypertension: An H3Africa AWI-Gen Study Across 6 Sites in Sub-Saharan Africa.

BACKGROUND: There is a high prevalence of hypertension and related cardiovascular diseases in sub-Saharan Africa, yet few large studies exploring hypertension in Africa are available. The actual burden of disease is poorly understood and awareness and treatment to control it is often suboptimal. OBJECTIVES: The study sought to report the prevalence of measured hypertension and to assess awareness and control of blood pressure among older adults in rural and urban settings in 6 sites located in West, East, and Southern Africa. In addition, we examined regional, sex, and age differences related to hypertension. METHODS: A population-based cross-sectional study was performed at 6 sites in 4 African countries: Burkina Faso (Nanoro), Ghana (Navrongo), Kenya (Nairobi), and South Africa (Agincourt, Dikgale, Soweto). Blood pressure measurements were taken using standardized procedures on 10,696 adults 40 to 60 years of age. Hypertension was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or taking antihypertensive medication. RESULTS: The mean prevalence of hypertension ranged from 15.1% in Nanoro to 54.1% in Soweto. All 3 of the South African sites had a mean prevalence of hypertension of over 40.0%, significantly higher than in Nairobi (25.6%) and Navrongo (24.5%). Prevalence increased with age in both sexes and at all sites. A significantly higher prevalence of hypertension was observed in women in Agincourt, Dikgale, and Nairobi, whereas in Nanoro this trend was reversed. Within the hypertensive group the average proportion of participants who were aware of their blood pressure status was only 39.4% for men and 53.8% for women, and varied widely across sites. CONCLUSIONS: Our study demonstrates that the prevalence of hypertension and the level of disease awareness differ not only between but also within sub-Saharan African countries. Each nation must tailor their regional hypertension awareness and screening programs to match the characteristics of their local populations.