Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa.

As the common birthplace of all human populations, modern humans have lived longer on the African continent than in any other geographical region of the world. This long history, along with the evolutionary need to adapt to environmental challenges such as exposure to infectious agents, has led to greater genetic variation in Africans. The vast genetic variation in Africans also extends to genes involved in the absorption, distribution, metabolism and excretion of pharmaceuticals. Ongoing cataloging of these clinically relevant variants reveals huge allele-frequency differences within and between African populations. Here, we examine Africa's large burden of infectious disease, discuss key examples of known genetic variation modulating disease risk, and provide examples of clinically relevant variants critical for establishing dosing guidelines. We propose that a more systematic characterization of the genetic diversity of African ancestry populations is required if the current benefits of precision medicine are to be extended to these populations.

The need for an integrated approach for chronic disease research and care in Africa.

With the changing distribution of infectious diseases, and an increase in the burden of non-communicable diseases, low- and middle-income countries, including those in Africa, will need to expand their health care capacities to effectively respond to these epidemiological transitions. The interrelated risk factors for chronic infectious and non-communicable diseases and the need for long-term disease management, argue for combined strategies to understand their underlying causes and to design strategies for effective prevention and long-term care. Through multidisciplinary research and implementation partnerships, we advocate an integrated approach for research and healthcare for chronic diseases in Africa.

H3Africa multi-centre study of the prevalence and environmental and genetic determinants of type 2 diabetes in sub-Saharan Africa: study protocol.

The burden and aetiology of type 2 diabetes (T2D) and its microvascular complications may be influenced by varying behavioural and lifestyle environments as well as by genetic susceptibility. These aspects of the epidemiology of T2D have not been reliably clarified in sub-Saharan Africa (SSA), highlighting the need for context-specific epidemiological studies with the statistical resolution to inform potential preventative and therapeutic strategies. Therefore, as part of the Human Heredity and Health in Africa (H3Africa) initiative, we designed a multi-site study comprising case collections and population-based surveys at 11 sites in eight countries across SSA. The goal is to recruit up to 6000 T2D participants and 6000 control participants. We will collect questionnaire data, biophysical measurements and biological samples for chronic disease traits, risk factors and genetic data on all study participants. Through integrating epidemiological and genomic techniques, the study provides a framework for assessing the burden, spectrum and environmental and genetic risk factors for T2D and its complications across SSA. With established mechanisms for fieldwork, data and sample collection and management, data-sharing and consent for re-approaching participants, the study will be a resource for future research studies, including longitudinal studies, prospective case ascertainment of incident disease and interventional studies.

Pharmacogenomics, ancestry and clinical decision making for global populations.

Pharmacogenomically relevant markers of drug response and adverse drug reactions are known to vary in frequency across populations. We examined minor allele frequencies (MAFs), genetic diversity (FST) and population structure of 1156 genetic variants (including 42 clinically actionable variants) in 212 genes involved in drug absorption, distribution, metabolism and excretion (ADME) in 19 populations (n=1478). There was wide population differentiation in these ADME variants, reflected in the range of mean MAF (ΔMAF) and FST. The largest mean ΔMAF was observed in African ancestry populations (0.10) and the smallest mean ΔMAF in East Asian ancestry populations (0.04). MAFs ranged widely, for example, from 0.93 for single-nucleotide polymorphism (SNP) rs9923231, which influences warfarin dosing to 0.01 for SNP rs3918290 associated with capecitabine metabolism. ADME genetic variants show marked variation between and within continental groupings of populations. Enlarging the scope of pharmacogenomics research to include multiple global populations can improve the evidence base for clinical translation to benefit all peoples.

Circulating adiponectin is associated with renal function independent of age and serum lipids in west africans.

Adiponectin, a protein secreted by adipose tissue, has been associated with renal dysfunction. However, these observations have not been adequately investigated in large epidemiological studies of healthy individuals in general and in African populations in particular. Hence, we designed this study to evaluate the relationship between adiponectin and renal function in a large group of nondiabetic West Africans. Total adiponectin was measured in 792 participants. MDRD and Cockroft-Gault (CG-) estimated GFR were used as indices of renal function. Linear and logistic regression models were used to determine the relationship between adiponectin and renal function. Adiponectin showed an inverse relationship with eGFR in univariate (Beta(MDRD) = -0.18, Beta(CG) = -0.26) and multivariate (Beta(MDRD) = -0.10, Beta(CG) = -0.09) regression analyses. The multivariate models that included age, sex, BMI, hypertension, smoking, HDL-C, LDL-C, triglycerides, and adiponectin explained 30% and 55.6% of the variance in GFR estimated by MDRD and CG methods, respectively. Adiponectin was also a strong predictor of moderate chronic kidney disease (defined as eGFR < 60 mL/min/1.73 m(2)). We demonstrate that adiponectin is associated with renal function in nondiabetic West Africans. The observed relationship is independent of age and serum lipids. Our findings suggest that adiponectin may have clinical utility as a biomarker of renal function.

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

AIMS/HYPOTHESIS: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. METHODS: We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs. RESULTS: Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci. CONCLUSIONS/INTERPRETATION: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.

Office based muscle biopsy using Vacora vacuum assisted biopsy system.

INTRODUCTION: Muscle biopsy is a minor surgical procedure that has been conducted over several decades in clinical practice. Over the years, the technique to implement this procedure has been modified to make it easier to perform and more tolerable for the patient. This study aimed to assess the feasibility of muscle biopsy as an office based procedure, by using a vacuum Assisted Biopsy System. METHOD: The procedure was successfully carried out on 57 individuals with/without diabetes, currently involved in the African American Diabetes Mellitus Study. One specimen was collected percutaneously from the vastus lateralis, under local anesthesia. A 16-gauge needle was used. RESULTS: Muscle biopsies were successfully carried out on all study participants. The study participants reported no complications after the procedure. CONCLUSION: The findings from our study show that muscle biopsy can be feasibly implemented as an office based procedure, involving minimal muscle invasion, less trauma, hospital stay time, and expenses.

Capacity-building in human genetics for developing countries: initiatives and perspectives in sub-Saharan Africa.

BACKGROUND: Stakeholders who are committed to bridge the gap in genetics services need to be aware of current initiatives in sub-Saharan Africa. METHODS: We reviewed selected experiences from African geneticists that led to specific recommendations. RESULTS: The initiation of prenatal diagnosis of sickle cell anaemia founded the first medical genetic service in Cameroon. There remains a need for international collaborative effort to overcome the lack of human, technical and financial resources around the practice of medical genetics in Africa. The African Society of Human Genetics, Wellcome Trust and NIH have recently proposed a model on how to fully engage Africa in genomics. It includes a 'Health and disease' phase I: use of the case-control design to study genetic and epidemiological determinants of 7 important diseases in Africa, and a 'Genetic variation' phase II: comprehensive documentation of genetic variations in 100 carefully selected ethnic groups across Africa. The strategy would require the development of: (1) clinical phenotyping centres, (2) molecular phenotyping centres, (3) genotyping and sequencing capability, (4) data centres, and (5) a bio-repository in Africa. CONCLUSIONS: Governments and international health agencies need to recognise that genetics is important to the global medical community. The initiatives of African geneticists need advocacy and encouragement from the international community.

Basal insulin resistance and secretion in Nigerians with type 2 diabetes mellitus.

AIM: The objective of this study was to estimate basal insulin resistance (IR) and insulin secretion (IS) in Nigerians with type 2 diabetes mellitus (T2DM). METHODS: The homeostasis model assessment (HOMA) method was used to estimate basal IR and IS in 146 Nigerians with T2DM and in 33 controls at the University of Nigeria Teaching Hospital (UNTH), Enugu, Nigeria. Correlations and multiple regression analysis between Box-Cox-transformed IR and log-transformed IS and anthropometric indices were carried out. RESULTS: IR and reduced IS were present, respectively, in 139 (95.5%) and 109 (74.7%) of the diabetic subjects and in 25 (75.8%) and 4 (12.1%) of the controls. In the diabetic subjects, age at diagnosis, duration of diabetes, waist circumference (WC), and body mass index (BMI) correlated significantly with IR (r = -0.2399, P = 0.0035; r = 0.1993, P = 0.0166; r = 0.2267, P = 0.0059; r = 0.2082, P = 0.0120; respectively), whereas duration of diabetes, WC, and BMI correlated significantly with IS (r = -0.2166, P = 0.0091; r = 0.3062, P = 0.0002; r = 0.2746, P = 0.0008; respectively). Age at diagnosis, WC, and duration of diabetes were significant predictors of IR (beta = -0.0161, P < 0.001; beta = 0.0121, P = 0.002; beta = 0.0138, P = 0.042; respectively), whereas duration of diabetes and WC significantly predicted IS (beta = -0.0159, P = 0.025; beta = 0.0155, P < 0.001). CONCLUSIONS: This study shows that both IR and reduced IS are major features of T2DM in Nigerians and that WC consistently correlated and predicted IR. WC measurement is simple and ideal in resource-poor settings for the detection of IR and abdominal obesity. The apparent rarity of coronary heart disease (CHD) in black Africans with T2DM despite a high prevalence of IR warrants further investigation.

Association of GNB3 C825T polymorphism with peak oxygen consumption.

The C825T single nucleotide polymorphism (SNP) in the guanine nucleotide-binding protein, beta polypeptide 3 ( GNB3) gene gives rise to a splice variant, GNB3s that has enhanced G protein activation and signal transduction activity. This variant has been reported to be associated with cardiovascular disease, diabetes and obesity. We studied this SNP in 95 healthy 18 to 30 year-old African American university students to determine its association with aerobic capacity and cardiorespiratory fitness as measured by peak oxygen consumption (VO (2)peak). We also tested the effect of heart rate variability (HRV) as an independent predictor of VO (2)peak. We tested the association of the SNP and HRV with VO (2)peak in a multivariate regression analysis with appropriate adjustments of covariates, under dominant and recessive models. We found a significant independent association of the 825T allele with VO (2)peak under the dominant model (beta-coef.=-0.101, P=0.0442). We also observed that HRV marginally influenced VO (2)peak. This finding suggests that GNB3 C825T polymorphism is associated with VO (2)peak which is influenced by autonomic modulation of heart rate in African Americans.

Beta cell function and response to treatment in Nigerians with Type 2 diabetes mellitus.

There are scant data from African populations on the association between beta-cell function and response to treatment with oral hypoglycaemic agents in Type 2 diabetes mellitus (T2DM). Fasting plasma C-peptide (FCP) and glucagon-stimulated C-peptide (GSCP) levels were measured in 116 Nigerians with T2DM at a university teaching hospital. After 9 months of follow-up and treatment, they were categorized into three groups based on response to treatment: (A) good control but not on maximum sulphonylurea (SU) therapy, (B) inadequate control but not on maximum SU therapy and (C) on maximum SU therapy+/-insulin or biguanide. Logistic regression models were used to investigate how well C-peptide levels predicted the subjects belonging to Group C who are likely to require insulin. The mean FCP and mean GSCP levels of Group C were significantly lower than in the other groups (p=0.024; p= <0.001 respectively). A GSCP cut-off value of < or =1.3 ng/mL predicted membership of Group C with 85% sensitivity and 89% specificity while a cut-off of < or =1.8 ng/mL was associated with 91% sensitivity and 66% specificity. In resource-poor settings where inadequate treatment are common, estimation of GSCP may be useful in predicting treatment response and should be weighed against the cost of inadequate therapy with higher morbidity and mortality.

Conceptualizing human variation.

What is the relationship between the patterns of biological and sociocultural variation in extant humans? Is this relationship accurately described, or best explained, by the term 'race' and the schema of 'racial' classification? What is the relationship between 'race', genetics and the demographic groups of society? Can extant humans be categorized into units that can scientifically be called 'races'? These questions underlie the discussions that address the explanations for the observed differences in many domains between named demographic groups across societies. These domains include disease incidence and prevalence and other variables studied by biologists and social scientists. Here, we offer a perspective on understanding human variation by exploring the meaning and use of the term 'race' and its relationship to a range of data. The quest is for a more useful approach with which to understand human biological variation, one that may provide better research designs and inform public policy.

Heritability of obesity-related traits among Nigerians, Jamaicans and US black people.

OBJECTIVE: The mean values for anthropometric traits vary across population groups and this variation is clearly determined for the most part by the environment. The familiarity of anthropometric traits also varies in reports from different populations, although this variation has not been shown to follow a consistent pattern. To examine whether heritability is influenced by socio-cultural factors, we conducted a cross-cultural study of populations of the African diaspora. PARTICIPANTS: Data were collected on 1868 family members from Nigeria, 623 from Jamaica and 2132 from metropolitan Chicago, IL, USA. MEASUREMENTS: Height and weight were measured and body mass index (kg/m(2)) calculated. Fat-free mass, fat mass and percentage body fat were estimated using bioelectrical impedance analysis. Plasma leptin concentrations were also measured. The proportion of variance attributable to additive genetic and non-shared environmental components was estimated with the maximum likelihood variance decomposition method. RESULTS: Mean values for all anthropometric traits increased along the socio-cultural gradient, and obesity increased from 5% in Nigeria to 23% in Jamaica and 39% in the USA. Within populations the relationships among traits both within individuals and within families were highly consistent. Heritability estimates for weight, body mass index, fat mass and percentage body fat were approximately 50% for all groups. Heritability for height was lower in Nigeria (62%) than in Jamaica (74%) or the US (87%). CONCLUSION: The familial patterns of body size and energy storage appear to be consistent in these genetically related populations across a wide range of environmental conditions.

Distribution and functional consequences of nucleotide polymorphisms in the 3'-untranslated region of the human Sep15 gene.

Selenium has been shown to prevent cancer in a variety of animal model systems. Both epidemiological studies and supplementation trials have supported its efficacy in humans. However, the mechanism by which selenium suppresses tumor development remains unknown. Selenium is present in known human selenoproteins as the amino acid selenocysteine (Sec). Sec is inserted cotranslationally in response to UGA codons within selenoprotein mRNAs in a process requiring a sequence within the 3'-untranslated region (UTR), referred to as a Sec insertion sequence (SECIS) element. Recently, a human Mr 15,000 selenoprotein (Sep15) was identified that contains an in-frame UGA codon and a SECIS element in the 3'-UTR. Examination of the available cDNA sequences for this protein revealed two polymorphisms located at position 811 (C/T) and at position 1125 (G/A) located within the 3'-UTR. Here, we demonstrate significant differences in Sep15 allele frequencies by ethnicity and that the identity of the nucleotides at the polymorphic sites influences SECIS function in a selenium-dependent manner. This, together with genetic data indicating loss of heterozygosity at the Sep15 locus in certain human tumor types, suggests that Sep15 may be involved in cancer development, risk, or both.

The beta 3-adrenergic receptor gene and obesity in a population sample of African Americans.

OBJECTIVE: To examine the role of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and the beta 3-adrenergic receptor gene locus in obesity-related traits in African Americans. SUBJECTS: A total of 687 individuals representing 193 African American families who were residents of metropolitan Chicago. MEASUREMENTS: Genotyping of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and three microsatellite markers flanking the beta 3-adrenergic receptor gene (ADRB3) locus and measuring various obesity-related traits, including body mass index (BMI), fat-free mass, fat mass, percentage fat mass, waist circumference and serum lipid levels. RESULTS: The prevalence of obesity (defined as body mass index > or = 30 kg/m(2)) in the population was 27.3% and 51.2% in men and women, respectively. The frequency of the Arg64 allele was 10.0%. Multivariate regression analyses confirmed the existence of a significant contribution of familial variance to each of the five obesity-related traits noted above. Likelihood ratio statistics computed in a multivariate regression analysis failed to demonstrate a significant association between the Arg64 allele and any of the five obesity-related traits. Single and multipoint analyses using extended Haseman--Elston regression analyses failed to demonstrate suggestive evidence of linkage of three microsatellite markers that flank the beta 3-adrenergic receptor gene to BMI, percentage body fat, waist circumference or serum leptin levels. CONCLUSION: Given the contribution of familial variance to obesity-related traits in this population, neither the null finding for the Arg64 allele nor the lack of evidence of linkage of the ADRB3 locus to obesity-related traits could be attributed to lack of transmissibility of the traits suggesting that neither the Arg64 variant of the beta 3-adrenergic receptor gene nor another genetic variant in or near the ADRB3 locus contribute significantly to familial aggregation of obesity-related traits in African Americans. International Journal of Obesity (2001) 25, 54-60

In search of susceptibility genes for type 2 diabetes in West Africa: the design and results of the first phase of the AADM study.

PURPOSE: The purpose of this study is to map type 2 diabetes susceptibility genes in West African ancestral populations of African-Americans, through an international collaboration between West African and US investigators. DESIGN AND METHODS: Affected sib-pairs (ASP) along with unaffected spouse controls are being enrolled and examined in West Africa, with two sites established in Ghana (Accra and Kumasi) and three in Nigeria (Enugu, Ibadan, and Lagos). Eligible participants are invited to study clinics to obtain detailed epidemiologic, family, and medical history information. Blood samples are drawn from each participant to measure glucose, insulin, C-peptide, total cholesterol, LDL, HDL, triglycerides, albumin, creatinine, urea, uric acid, total calcium and to detect autoantibodies to glutamic acid decarboxylase (GAD). DNA is isolated from frozen white blood cells obtained from 20 ml of EDTA whole blood samples. RESULTS: With full informed consent, 162 individuals from 78 families have been enrolled and examined since the Africa America Diabetes Mellitus (AADM) study began in June of 1997. Logistics of field examinations and specimen shipping have been successfully established. At the end of the third year of field activity (September 2000) the AADM study will have enrolled and performed comprehensive examination on 400 ASP with type 2 diabetes, for a minimum of 800 cases and 200 controls from Ghana and Nigeria. At the current participation rate, the goal of 400 sib-pairs and 200 controls will be met before the scheduled closing date. CONCLUSIONS: The AADM study will create a comprehensive epidemiologic and genetic resource that will facilitate a powerful genome-wide search for West African susceptibility genes to type 2 diabetes.

Comparability of resting energy expenditure in Nigerians and U.S. blacks.

OBJECTIVE: To determine the influence of environmental factors on resting energy expenditure (REE) and its relationship to adiposity in two populations of West African origin, Nigerians and U.S. blacks. RESEARCH METHODS AND PROCEDURES: REE and body composition were measured in a cross-sectional sample of 89 Nigerian adults (39 women and 50 men), and 181 U.S. black adults (117 women and 65 men). Both groups represent randomly selected population samples. REE was measured by indirect calorimetry after an overnight fast in both sites using the same instrument. Body composition was estimated using bioelectrical impedance analysis (BIA) in 72 Nigerians and 156 U.S. participants. Multivariate regression analysis was used to determine the significant predictors of REE. The analyses were repeated in a set of 17 Nigerians and 28 U.S. blacks in whom body composition was measured using deuterium dilution. RESULTS: U.S. black adults were significantly heavier and had both more fat-free mass (FFM) and body fat than Nigerians. FFM was the only significant determinant of REE in both population groups, whether body composition was measured using BIA or deuterium dilution. The relationship between REE and body composition did not differ by site. There was no relationship between REE and adiposity. DISCUSSION: Differences in current environmental settings did not impact REE. The differences observed in mean levels of body fat between Nigerians and U.S. blacks were not the result of differences in REE adjusted for body composition.

Abdominal adiposity and clustering of multiple metabolic syndrome in White, Black and Hispanic americans.

PURPOSE: The aim of this study was to evaluate the association of abdominal adiposity assessed by waist circumference (WC) with clustering of multiple metabolic syndromes (MMS) in White, Black and Hispanic Americans. MMS was defined as the occurrence of two or more of either hypertension, type 2 diabetes mellitus, dyslipidemia, hypertriglyceridemia or hyperinsulinemia. METHODS: The number of MMS and fasting insulin (a surrogate measure of MMS) were each used as dependent variables in gender-specific multiple linear regression models, adjusting for age, smoking and alcohol intake. The contribution of WC to interethnic differences in clustering of MMS and fasting insulin concentration was assessed in gender-specific linear regression models. The risk of MMS due to large waist was estimated by comparing odds ratio for men with WC >/= 102 cm with those with WC < 102, and women with WC >/= 88 cm with women with WC < 88 cm in the logistic regression model adjusting for age, smoking and alcohol intake. RESULTS: WC was positively and independently associated with clustering of MMS and increased fasting insulin concentration adjusting for age, smoking and alcohol intake in the three ethnic groups (p < 0.01). Black ethnicity was associated with clustering of MMS and fasting insulin concentration (p < 0.01). Hispanic ethnicity was also associated with clustering of MMS in men and associated with fasting insulin concentration in both men and women (p < 0.01). In both men and women, the risk of MMS clustering was strongly associated with increased WC in all ethnic groups independent of BMI. CONCLUSION: WC appears to be a marker for multiple metabolic syndromes in these ethnic groups. The results of this investigation lend support to the view that waist measurement should be considered as a clinical variable for assessing the risk of cardiovascular diseases.

Lack of association between a biallelic polymorphism in the adducin gene and blood pressure in whites and African Americans.

Population-based candidate gene association analyses are becoming increasingly popular as a result of a greater number of genes and gene polymorphisms having been identified for which some functional information is available. Because many biochemical and physiologic systems impact blood pressure regulation and hypertension susceptibility, many of these identified genes and polymorphisms are candidates for population-level association studies involving blood pressure levels or hypertension status. Recent studies have suggested that the alpha-adducin gene may harbor polymorphisms that influence blood pressure level. Therefore, we embarked on a study to test one such polymorphism in two large US samples: one from an urban African American population (Maywood, IL) and another from a rural white population (Tecumseh, MI). We used both family-based association tests and tests that consider the impact of additional measured factors beyond adducin gene variation on blood pressure levels. We found no evidence for a significant effect of the chosen adducin polymorphism on blood pressure variation in either sample. We also found no association between Adducin genotypes and antihypertensive use. These facts, together with similar findings in companion studies, suggest that the alpha-adducin gene polymorphism does not have a pronounced effect on blood pressure variation in the populations studied. This does not suggest, however, that the alpha-adducin gene does not have a role in blood pressure regulation and hypertension susceptibility.

Heritability of angiotensin-converting enzyme and angiotensinogen: A comparison of US blacks and Nigerians.

Angiotensinogen (AGT) and angiotensin I-converting enzyme (ACE) are heritable traits, but whether the environmental context influences heritability has not been examined. Known genetic factors explain only a portion of variation in AGT and ACE, and levels of both proteins are influenced by the environment. The African diaspora provides an opportunity to compare these traits in genetically related populations in contrasting environments. As part of a study of the genetics of hypertension, we examined families that included 1449 Nigerians and 1147 African Americans. Body mass index (weight [kg]/height [m](2)) was 21 kg/m(2) in Nigeria and 29 kg/m(2) in the United States, which is consistent with a large environmental contrast. AGT was considerably higher among African Americans (1919 versus 1396, P<0.01), whereas ACE was higher in Nigerians (630 versus 517, P<0.01). A household effect was observed among the Nigerian families (spouse correlations 0.30 for AGT, 0.18 for ACE), and correlations among first-degree relatives were large (0.42 to 0. 51 and 0.36 to 0.38 for AGT and ACE, respectively). Among African Americans, the familial aggregations of AGT and ACE were very limited, and the familial correlation for AGT was not different from zero. Heritability was 77% for AGT and 67% for ACE in Nigeria and 18% for AGT and ACE in the United States. The familial patterns of body mass index and blood pressure were similar among both family sets. In conclusion, less familial aggregation was observed for AGT and ACE in the United States than in Nigeria, most likely reflecting a greater random individual environmental effect on these traits. Variation in heritability of traits could influence the power of epidemiological studies to identify genetic effects.