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Evolutionary context for the association of ?-globin, serum uric acid, and hypertension in African Americans.

ABSTRACT: BACKGROUND:Hyperuricemia and associated cardio-metabolic disorders are more prevalent in African Americans than in European Americans. We used genome-wide admixture mapping and association testing to identify loci with ancestry effects on serum uric acid levels. METHODS:We analyzed 1,976 African Americans from Washington, D.C, including 1,322 individuals from 328 pedigrees and 654 unrelated individuals, enrolled in the Howard University Family Study. We performed admixture mapping and genome-wide association testing using ~800 k autosomal single-nucleotide polymorphisms (SNPs). We performed fine mapping by dense genotyping. We assessed functionality by a combination of bioinformatic annotation, reporter gene assays, and gel shift experiments. We also analyzed 12,641 individuals enrolled in the National Health and Nutrition Examination Survey. RESULTS:We detected a genome-wide significant locus on chromosome 11p15.4 at which serum uric acid levels increased with increasing African ancestry, independent of kidney function. Fine-mapping identified two independent signals in the ?-globin locus. The ancestral allele at SNP rs2855126, located upstream of the hemoglobin, gamma A gene HBG1, was associated with increased serum uric acid levels and higher expression of a reporter gene relative to the derived allele. Hyperuricemia was associated with increased risk of hypertension in 3,767 African Americans (Odds Ratio = 2.48, p = 2.71 × 10(-19)). CONCLUSIONS:Given that increased expression of ?-globin leads to increased levels of fetal hemoglobin which confers protection against malaria, we hypothesize that evolution in Africa of protection against malaria may have occurred at the cost of increased serum uric acid levels, contributing to the high rates of hyperuricemia and associated cardio-metabolic disorders observed in African Americans.

SUBMITTER: Shriner D

PROVIDER: S-EPMC4684912 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Project description:BackgroundUric acid is the primary byproduct of purine metabolism. Hyperuricemia is associated with body mass index (BMI), sex, and multiple complex diseases including gout, hypertension (HTN), renal disease, and type 2 diabetes (T2D). Multiple genome-wide association studies (GWAS) in individuals of European ancestry (EA) have reported associations between serum uric acid levels (SUAL) and specific genomic loci. The purposes of this study were: 1) to replicate major signals reported in EA populations; and 2) to use the weak LD pattern in African ancestry population to better localize (fine-map) reported loci and 3) to explore the identification of novel findings cognizant of the moderate sample size.MethodsAfrican American (AA) participants (n = 1,017) from the Howard University Family Study were included in this study. Genotyping was performed using the Affymetrix® Genome-wide Human SNP Array 6.0. Imputation was performed using MACH and the HapMap reference panels for CEU and YRI. A total of 2,400,542 single nucleotide polymorphisms (SNPs) were assessed for association with serum uric acid under the additive genetic model with adjustment for age, sex, BMI, glomerular filtration rate, HTN, T2D, and the top two principal components identified in the assessment of admixture and population stratification.ResultsFour variants in the gene SLC2A9 achieved genome-wide significance for association with SUAL (p-values ranging from 8.88 × 10(-9) to 1.38 × 10(-9)). Fine-mapping of the SLC2A9 signals identified a 263 kb interval of linkage disequilibrium in the HapMap CEU sample. This interval was reduced to 37 kb in our AA and the HapMap YRI samples.ConclusionsThe most strongly associated locus for SUAL in EA populations was also the most strongly associated locus in this AA sample. This finding provides evidence for the role of SLC2A9 in uric acid metabolism across human populations. Additionally, our findings demonstrate the utility of following-up EA populations GWAS signals in African-ancestry populations with weaker linkage disequilibrium.

Project description:OBJECTIVE:To examine whether partial replacement of a diet typical of the average American diet with Dietary Approaches to Stop Hypertension (DASH)-related foods in the home environment lowers the serum uric acid (UA) level in individuals with hypertension. METHODS:We conducted an ancillary study of a randomized trial of African American adults with controlled hypertension from an urban clinic. Participants were assigned to either a control group or an intervention (DASH-Plus) group. DASH-Plus participants received coach-directed dietary advice, assistance with purchasing DASH-related foods ($30/week), and home delivery of food via a community supermarket. Participants in the control group received a DASH diet brochure and a debit card account ($30/week) to purchase foods. Serum UA levels were measured at baseline and after 8 weeks. RESULTS:Of the original 123 randomized participants, 117 had available serum UA measurements. Seventy percent of the participants were women, the mean ± SD age was 59 ± 9.5 years, and the mean ± SD serum UA level was 6.4 ± 1.7 mg/dl. The DASH-Plus diet did not reduce serum UA levels compared with the control diet (difference in difference -0.01 mg/dl [95% confidence interval -0.39, 0.38]). However, there was a significant trend toward a greater reduction in the serum UA level in participants with higher baseline serum UA levels (P for trend = 0.008). Baseline changes in the serum UA level were inversely associated with changes in systolic blood pressure (P = 0.002), diastolic blood pressure (P = 0.001), and urinary sodium excretion (P = 0.05). CONCLUSION:Overall, in African American individuals, partial replacement of a typical diet with DASH foods did not lower serum UA levels compared with a control diet. However, there was a significant trend toward a greater reduction in serum UA levels in subjects with higher baseline serum UA levels. Furthermore, changes in serum UA levels were associated with known correlates, suggesting heterogeneity of effects in the treatment and control arms. Future pragmatic studies of consumption of the DASH diet to lower serum UA levels should optimize replacement strategies and enroll individuals with hyperuricemia or gout.

Project description:Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease (CVD). The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association (GWA) analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257, and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p < 1.3 × 10(-7)). The minor alleles of these SNPs had frequencies of 36.2, 36.2, and 38.2%, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3-7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight, and waist circumference (p < 1.4 × 10(-3)) and suggestive associations with albumin-creatinine ratio and total antioxidant status (TAS). The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p < 1.9 × 10(-6)) for joint linkage/association (JLA) was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors.

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Evolutionary context for the association of ?-globin, serum uric acid, and hypertension in African Americans.

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