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Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

ABSTRACT: Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10?¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R.?=?0.923, 95% CI 0.860-0.991; p?=?0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p?=?0.004; after eGFR adjustment: 0.89 [0.83-0.96], p?=?0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

SUBMITTER: Padmanabhan S

PROVIDER: S-EPMC2965757 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Padmanabhan Sandosh S Melander Olle O Johnson Toby T Di Blasio Anna Maria AM Lee Wai K WK Gentilini Davide D Hastie Claire E CE Menni Cristina C Monti Maria Cristina MC Delles Christian C Laing Stewart S Corso Barbara B Navis Gerjan G Kwakernaak Arjan J AJ van der Harst Pim P Bochud Murielle M Maillard Marc M Burnier Michel M Hedner Thomas T Kjeldsen Sverre S Wahlstrand Björn B Sjögren Marketa M Fava Cristiano C Montagnana Martina M Danese Elisa E Torffvit Ole O Hedblad Bo B Snieder Harold H Connell John M C JM Brown Morris M Samani Nilesh J NJ Farrall Martin M Cesana Giancarlo G Mancia Giuseppe G Signorini Stefano S Grassi Guido G Eyheramendy Susana S Wichmann H Erich HE Laan Maris M Strachan David P DP Sever Peter P Shields Denis Colm DC Stanton Alice A Vollenweider Peter P Teumer Alexander A Völzke Henry H Rettig Rainer R Newton-Cheh Christopher C Arora Pankaj P Zhang Feng F Soranzo Nicole N Spector Timothy D TD Lucas Gavin G Kathiresan Sekar S Siscovick David S DS Luan Jian'an J Loos Ruth J F RJ Wareham Nicholas J NJ Penninx Brenda W BW Nolte Ilja M IM McBride Martin M Miller William H WH Nicklin Stuart A SA Baker Andrew H AH Graham Delyth D McDonald Robert A RA Pell Jill P JP Sattar Naveed N Welsh Paul P Munroe Patricia P Caulfield Mark J MJ Zanchetti Alberto A Dominiczak Anna F AF

PLoS genetics 20101028 10

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identi ...[more]

PMID: 21082022

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Project description:BackgroundHypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively.MethodsGenome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data.ResultsThe median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms.ConclusionWe detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.

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Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

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Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

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