Dataset Information

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

ABSTRACT: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component.Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h (2) = 0.50 ± 0.05, p < 4 × 10(-35)), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD = 4.9, p < 1 × 10(-5)) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p < 3 × 10(-7); minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts.Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

SUBMITTER: Chittoor G

PROVIDER: S-EPMC4818944 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

Chittoor Geetha G Kent Jack W JW Almeida Marcio M Puppala Sobha S Farook Vidya S VS Cole Shelley A SA Haack Karin K Göring Harald H H HH MacCluer Jean W JW Curran Joanne E JE Carless Melanie A MA Johnson Matthew P MP Moses Eric K EK Almasy Laura L Mahaney Michael C MC Lehman Donna M DM Duggirala Ravindranath R Comuzzie Anthony G AG Blangero John J Voruganti Venkata Saroja VS

BMC genomics 20160402

<h4>Background</h4>The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans f ...[more]

PMID: 27039371

Similar Datasets

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.

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:Genome-wide association studies (GWAS) evaluate associations between genetic variants and a trait or disease of interest free of prior biological hypotheses. GWAS require stringent correction for multiple testing, with genome-wide significance typically defined as association p-value <5*10-8. This study presents a new tool that uses external information about genes to prioritize SNP associations (GenToS). For a given list of candidate genes, GenToS calculates an appropriate statistical significance threshold and then searches for trait-associated variants in summary statistics from human GWAS. It thereby allows for identifying trait-associated genetic variants that do not meet genome-wide significance. The program additionally tests for enrichment of significant candidate gene associations in the human GWAS data compared to the number expected by chance. As proof of principle, this report used external information from a comprehensive resource of genetically manipulated and systematically phenotyped mice. Based on selected murine phenotypes for which human GWAS data for corresponding traits were publicly available, several candidate gene input lists were derived. Using GenToS for the investigation of candidate genes underlying murine skeletal phenotypes in data from a large human discovery GWAS meta-analysis of bone mineral density resulted in the identification of significantly associated variants in 29 genes. Index variants in 28 of these loci were subsequently replicated in an independent GWAS replication step, highlighting that they are true positive associations. One signal, COL11A1, has not been discovered through GWAS so far and represents a novel human candidate gene for altered bone mineral density. The number of observed genes that contained significant SNP associations in human GWAS based on murine candidate gene input lists was much greater than the number expected by chance across several complex human traits (enrichment p-value as low as 10-10). GenToS can be used with any candidate gene list, any GWAS summary file, runs on a desktop computer and is freely available.

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.

Dataset Information

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

Publications

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets