Search

Hypertension treatment regimens used by African American adults in the Jackson Heart Study were evaluated at the first two clinical examinations (2415 treated hypertensive persons at examination I [exam I], 2000-2004; 2577 at examination II [exam II], 2005-2008). Blood pressure (BP) was below 140/90 mm Hg for 66% and 70% of treated participants at exam I and exam II, respectively. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure treatment targets were met for 56% and 61% at exam I and exam II, respectively. Persons with diabetes or chronic kidney disease were less likely to have BP at target, as were men compared with women. Thiazide diuretics were the most commonly used antihypertensive medication, and persons taking a thiazide were more likely to have their BP controlled than persons not taking them; thiazides were used significantly less among men than women. Although calcium channel blockers are often considered to be effective monotherapy for African Americans, persons using calcium channel blocker monotherapy were significantly less likely to be at target BP than persons using thiazide monotherapy.

Background Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. Objective To identify novel genetic variants associated with resting heart rate in African Americans. Methods Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci ( P ≤2.5×10 −8 ). Results Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10 −15 ). This SNP was approximately 350 kb downstream of GJA1 , a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6 , which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. Conclusions An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations., Author Summary This paper presents improved methodologies for the analysis of genome-wide association studies in admixed populations, which are populations that came about by the mixing of two or more distant continental populations over a few hundred years (e.g., African Americans or Latinos). Studies of admixed populations offer the promise of capturing additional genetic diversity compared to studies over homogeneous populations such as Europeans. In admixed populations, correlation between genetic variants exists both at a fine scale in the ancestral populations and at a coarse scale due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered either one or the other type of correlation, but not both. In this work we develop novel statistical methods that account for both types of genetic correlation, and we show that the combined approach attains greater statistical power than that achieved by applying either approach separately. We provide analysis of simulated and real data from major studies performed in African-American men and women to show the improvement obtained by our methods over the standard methods for analyzing association studies in admixed populations.

The study of recent natural selection in human populations has important applications to human history and medicine. Positive natural selection drives the increase in beneficial alleles and plays a role in explaining diversity across human populations. By discovering traits subject to positive selection, we can better understand the population level response to environmental pressures including infectious disease. Our study examines unusual population differentiation between three large data sets to detect natural selection. The populations examined, African Americans, Nigerians, and Gambians, are genetically close to one another (F ST < 0.01 for all pairs), allowing us to detect selection even with moderate changes in allele frequency. We also develop a tree-based method to pinpoint the population in which selection occurred, incorporating information across populations. Our genome-wide significant results corroborate loci previously reported to be under selection in Africans including HBB and CD36. At the HLA locus on chromosome 6, results suggest the existence of multiple, independent targets of population-specific selective pressure. In addition, we report a genome-wide significant (p = 1.36 × 10 -11) signal of selection in the prostate stem cell antigen (PSCA) gene. The most significantly differentiated marker in our analysis, rs2920283, is highly differentiated in both Africa and East Asia and has prior genome-wide significant associations to bladder and gastric cancers. © 2011 The American Society of Human Genetics.

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

Background African Americans have historically had high high-density lipoprotein cholesterol (HDL-C) compared with other races and ethnicities. Objective We sought to characterize whether there is a cross-sectional association between age and HDL-C in a contemporary community-based study of African Americans. Methods Cross-sectional data were modeled by logistic regression for predictors of HDL-C among African Americans, ages 35–74, participating in the baseline examination of a community-based study of cardiovascular disease in Jackson, Mississippi, during 2000–2004. After excluding persons taking lipid-lowering medications, hormone replacement therapy, oral contraceptives, or thyroid replacement, the analytical data set comprised 2420 persons (1370 women, 1050 men). Results HDL-C had a significant positive association with age after controlling for serum triglycerides, sex, waist circumference, percent dietary calories from carbohydrates, alcohol use, and leisure physical activity. Sex was a significant effect modifier of this relationship, whereby the increase in HDL-C with age was steeper for women than for men. Conclusions Cross-sectional analysis found a positive association of HDL-C with age while controlling for triglycerides. Careful evaluation of longitudinal data will be needed to confirm whether this is a true effect of aging, or a cohort or survivor effect.

The burden of cardiovascular risk associated with obesity disproportionately affects African Americans and little is known about ethnic/racial differences in the relationship of obesity to cardiometabolic risk. This report assesses whether obesity is similarly associated with cardiometabolic risk factors in African Americans and whites of European ancestry. Cross-sectional observational data from the Jackson Heart Study (JHS) and the Framingham Heart Study (FHS) were compared. This analysis uses participants aged 35–74 years with BMI >18.5 kg/m2, and free of prevalent cardiovascular disease (CVD), from the initial JHS clinical examination (2000–2004) and the FHS Offspring (1998–2001) and Third Generation (2002–2005) cohorts. Participants were evaluated for the presence of lipid abnormalities, hypertension, and diabetes. Overall, 4,030 JHS (mean age 54 years, 64% women) and 5,245 FHS (mean age 51 years, 54% women) participants were available for analysis. The prevalence of all risk factors except high triglycerides and low high-density lipoprotein (HDL) was substantially higher in JHS (all P < 0.001) and BMI was associated with increasing prevalence of most CVD risk factors within each race. For diabetes mellitus, hypertension, and low HDL, steeper relationships to BMI were observed in FHS than in JHS (P values

Background— Electrocardiographic QT interval prolongation is a risk factor for sudden cardiac death and drug-induced arrhythmia. The clinical correlates and heritability of QT interval duration in blacks have not been well studied despite their higher risk for sudden cardiac death compared with non-Hispanic whites. We sought to investigate potential correlates of the QT interval and estimate its heritability in the Jackson Heart Study. Methods and Results— The Jackson Heart Study comprises a sample of blacks residing in Jackson, Miss, of whom 5302 individuals with data at the baseline examination were available for study. Jackson Heart Study participants on QT-altering medications, with bundle-branch block, paced rhythm, atrial fibrillation/flutter, or other arrhythmias were excluded, resulting in a sample of 4660 individuals eligible for analyses. The relation between QT and potential covariates was tested using multivariable stepwise linear regression. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routine in a subset of 1297 Jackson Heart Study participants in 292 families; the remaining sample included unrelated individuals. In stepwise multivariable linear regression analysis, covariates significantly associated with QT interval duration included R-R interval, sex, QRS duration, age, serum potassium, hypertension, body mass index, coronary heart disease, diuretic use, and Sokolow-Lyon voltage ( P ≤0.01 for all). The heritability of QT interval duration in the age-, sex-, and R-R interval–adjusted model and in the fully adjusted model was 0.41 (SE, 0.07) and 0.40 (SE, 0.07; P −11 for both), respectively. Conclusions— There is substantial heritability of adjusted QT interval in blacks, supporting the need for further investigation to identify its genetic determinants.

Background Chronic kidney disease (CKD) leads to end-stage renal disease and is a growing epidemic throughout the world. In the United States, African Americans have an incidence of end-stage renal disease 4 times that of whites. Study Design Cross-sectional to examine the prevalence and awareness of CKD in African Americans. Setting & Participants Observational cohort in the Jackson Heart Study (JHS). Predictor CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2, the presence of albuminuria, or dialysis therapy. Outcomes & Measurements Data from the JHS were analyzed. Medical history, including disease awareness and drug therapy, anthropometric measurements, and serum and urine samples, were obtained from JHS participants at the baseline visit. Associations between CKD prevalence and awareness and selected demographic, socioeconomic, health care access, and disease status parameters were assessed by using logistic regression models. Results The prevalence of CKD in the JHS was 20%; CKD awareness was only 15.8%. Older participants had a greater prevalence, but also were more aware of CKD. Hypertension, diabetes, cardiovascular disease, hypercholesterolemia, hypertriglyceridemia, increasing age and waist circumference, and being single or less physically active were associated with CKD. Only advancing CKD stage was associated with awareness. Limitations Cross-sectional assessment, single urine measurement. Conclusions The JHS has a high prevalence and low awareness of CKD, especially in those with less severe disease status. This emphasizes the need for earlier diagnosis and increased education of health care providers and the general population.

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped acrossor= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR 30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish., Author Summary Chronic kidney disease (CKD) is an increasing global public health problem and disproportionately affects populations of African ancestry. Many studies have shown that genetic variants are associated with the development of CKD; however, similar studies are lacking in African ancestry populations. The CARe consortium consists of more than 8,000 individuals of African ancestry; genome-wide association analysis for renal-related phenotypes was conducted. In cross-ethnicity analyses, we found that 23 of 24 previously identified SNPs in European ancestry populations have the same effect direction in our samples of African ancestry. We also identified 3 suggestive genetic variants associated with measurement of kidney function. We then tested these genes in zebrafish knockdown models and demonstrated that kcnq1 is involved in kidney development in zebrafish. These results highlight the similarity of genetic variants across ethnicities and show that cross-species modeling in zebrafish is feasible for genes associated with chronic human disease.

Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 x 10(-6) and 3.61 x 10(-6) in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.

Background Socioeconomic status (SES) is recognized as a key social environmental factor because it has implications for access to resources that help individuals care for themselves and others. Few studies have examined the association of SES with chronic kidney disease (CKD) in high-risk populations. Study Design Single-site longitudinal population-based cohort. Setting & Participants Data for this study were drawn from the baseline examination of the Jackson Heart Study. The analytic cohort consisted of 3,430 African American men and women living in the tricounty region of the Jackson, MS, metropolitan area with complete data to determine CKD status. Predictor High SES (defined as having a family income at least 3.5 times the poverty level or having at least 1 undergraduate degree). Outcomes & Measurements CKD (defined as the presence of albuminuria or decreased estimated glomerular filtration rate [ 2 ]). Associations were explored using bivariable analyses and multivariable logistic regression analyses adjusting for CKD and cardiovascular disease risk factors, as well as demographic factors. Results The prevalence of CKD in the Jackson Heart Study was 20% (865 of 3,430 participants). Proportions of the Jackson Heart Study cohort with albuminuria and decreased estimated glomerular filtration rate were 12.5% (429 of 3,430 participants) and 10.1% (347 of 3,430 participants), respectively. High SES was associated inversely with CKD. The odds of having CKD were 41% lower for affluent participants than their less affluent counterparts. There were no statistically significant interactions between sex and education or income, although subgroup analysis showed that high income was associated with CKD in men (OR, 0.47; 95% CI, 0.23-0.97), but not women (OR, 0.64; 95% CI, 0.40-1.03). Limitations Models were estimated using cross-sectional data. Conclusion CKD is associated with SES. Additional research is needed to elucidate the impact of wealth and social contexts in which individuals are embedded and the mediating effects of sociocultural factors.

Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase (LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p = 2.7×10−6) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations., Author Summary Single-base changes in DNA can affect biochemical measures, such as blood cholesterol or lipid levels. Such changes or “variants” can be associated with a trait either because they cause the trait or because they are linked to other causal variants. In either case, the associated variant(s) may be useful in predicting the trait. The chromosomes in which DNA is packaged cross over and recombine with each other in each generation, so that in historically separate populations, such as Africans and Europeans, the patterns of genetic linkage between variants differ. In the current study, we analyzed a large group of African Americans, testing genetic variants that had been associated with cholesterol and lipid levels in European-derived populations to assess their predictive value on two different genetic backgrounds within the same cohort. The ability of some variants to predict cholesterol or lipid traits was strongly dependent on genetic background, indicating that they may be tightly linked to other causal variant(s) in European populations and may not, themselves, be directly responsible for trait variability. We conclude that the predictive value of specific variants for risk assessment can differ critically across populations.

Despite the high prevalence of cardiovascular disease documented among the African-American population, there has been little emphasis on the role of dyslipidemia as a prominent risk factor in this large subpopulation. Questions of medication efficacy also have been raised. Together, these factors may have affected awareness, diagnosis, and treatment rates.Dyslipidemia was defined as the presence of either hypercholesterolemia or hypertriglyceridemia using National Cholesterol Education Program III criteria and the fasting lipid measurements, self-reported treatment history, and medication survey available from 5302 Jackson Heart Study participants. Dyslipidemia was more common in men (compared with women) aged less than 50 years and increased with age in both genders. Hypercholesterolemia prevalence rates approached 50% in women aged more than 65 years. The lifestyle-related attributes found to be related to prevalence were being overweight and less physically active, and all disease status variables exhibited significant (P.05) associations. Awareness of hypercholesterolemia is approximately 55% or more in both men and women aged more than 35 years. Treatment rates lag far behind awareness, particularly in younger adult men, and less than 50% of women and men aged less than 65 years were treated for hypercholesterolemia.Higher rates of identification and effective treatment of dyslipidemia are clearly needed in this, and probably other African-American communities. Despite the less than optimal treatment, the identification and importance of the known cardiovascular disease states and risk factors in these analyses suggest the adoption of National Cholesterol Education Program III "high-risk strategy" algorithms in treatment recommendations and decisions by providers is occurring.

African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established.We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval.The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P.001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P.001). Hypokalemia was associated with diuretic use (78%; P.001).SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y.

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P

The prevalence of obesity (body mass index (BMI) ≥30 kg/m2) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (ρ = −0.042, P = 1.6×10−7). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = −3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = −4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI., Author Summary Obesity is about 1.5-fold more prevalent in African Americans than European Americans. To determine whether genetic background may contribute to this observed disparity, we scanned the genomes of African Americans, searching for genomic regions where obese individuals have a difference from the average proportion of African ancestry. By examining genetic data from more than 15,000 African Americans, we show that the proportion of European ancestry is inversely correlated with BMI. In obese individuals, we detect two loci with increased African ancestry on chromosome X (Xq13.1 and Xq25) and one locus with increased European ancestry on chromosome 5 (5q13.3). The 5q13.3 and Xq25 regions both contain genes that are known to be involved in appetite regulation. Our results suggest that genetic factors may contribute to the difference in obesity prevalence between African Americans and European Americans. Further studies of the regions may identify the causative variants affecting susceptibility to obesity.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant., Author Summary Many African Americans have white blood cell counts (WBC) that are persistently below the normal range for people of European descent, a condition called “benign ethnic neutropenia.” Because most African Americans have both African and European ancestors, selected genetic variants can be analyzed to assign probable African or European origin to each region of each such person's chromosomes. Previously, we found a region on chromosome 1 where increased local African ancestry completely accounted for differences in WBC between African and European Americans, suggesting the presence of an African-derived variant causing low WBC. Here, we show that low neutrophil count is predominantly responsible for low WBC; that a dominant, European-derived allele contributes to high neutrophil count; and that the frequency of this allele differs in Africans and Europeans by >91%. Across the chromosome 1 locus, only the well-characterized “Duffy” polymorphism was this differentiated. Neutrophil count was more strongly associated to the Duffy variant than to ancestry, suggesting that the variant itself causes benign ethnic neutropenia. The African, or “null,” form of this variant abolishes expression of the “Duffy Antigen Receptor for Chemokines” on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration.