| Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. | |
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MedLine Citation:
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PMID: 21082022 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sandosh Padmanabhan; Olle Melander; Toby Johnson; Anna Maria Di Blasio; Wai K Lee; Davide Gentilini; Claire E Hastie; Cristina Menni; Maria Cristina Monti; Christian Delles; Stewart Laing; Barbara Corso; Gerjan Navis; Arjan J Kwakernaak; Pim van der Harst; Murielle Bochud; Marc Maillard; Michel Burnier; Thomas Hedner; Sverre Kjeldsen; Björn Wahlstrand; Marketa Sjögren; Cristiano Fava; Martina Montagnana; Elisa Danese; Ole Torffvit; Bo Hedblad; Harold Snieder; John M C Connell; Morris Brown; Nilesh J Samani; Martin Farrall; Giancarlo Cesana; Giuseppe Mancia; Stefano Signorini; Guido Grassi; Susana Eyheramendy; H Erich Wichmann; Maris Laan; David P Strachan; Peter Sever; Denis Colm Shields; Alice Stanton; Peter Vollenweider; Alexander Teumer; Henry Völzke; Rainer Rettig; Christopher Newton-Cheh; Pankaj Arora; Feng Zhang; Nicole Soranzo; Timothy D Spector; Gavin Lucas; Sekar Kathiresan; David S Siscovick; Jian'an Luan; Ruth J F Loos; Nicholas J Wareham; Brenda W Penninx; Ilja M Nolte; Martin McBride; William H Miller; Stuart A Nicklin; Andrew H Baker; Delyth Graham; Robert A McDonald; Jill P Pell; Naveed Sattar; Paul Welsh; ; Patricia Munroe; Mark J Caulfield; Alberto Zanchetti; Anna F Dominiczak |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-28 |
Journal Detail:
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Title: PLoS genetics Volume: 6 ISSN: 1553-7404 ISO Abbreviation: PLoS Genet. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-11-18 Completed Date: 2011-03-07 Revised Date: 2011-03-11 |
Medline Journal Info:
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Nlm Unique ID: 101239074 Medline TA: PLoS Genet Country: United States |
Other Details:
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Languages: eng Pagination: e1001177 Citation Subset: IM |
Affiliation:
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Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aged Alleles Blood Pressure* Chromosomes, Human, Pair 16 / genetics Female Gene Frequency Genetic Predisposition to Disease Genome-Wide Association Study / methods*, statistics & numerical data Genotype Glomerular Filtration Rate Humans Hypertension / genetics*, physiopathology Linear Models Male Meta-Analysis as Topic Middle Aged Multivariate Analysis Polymorphism, Single Nucleotide Proportional Hazards Models Risk Factors Survival Analysis Uromodulin / blood, genetics* |
| Grant Support | |
ID/Acronym/Agency:
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CH/98001//British Heart Foundation; FS/05/095/19937//British Heart Foundation; RG/07/005/23633//British Heart Foundation; SP/08/005/25115//British Heart Foundation |
| Chemical | |
Reg. No./Substance:
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0/UMOD protein, human; 0/Uromodulin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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