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

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Version: Final published version
Serval ID
serval:BIB_88EC5A692A5D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.
Journal
Plos Genetics
Author(s)
Padmanabhan Sandosh, Melander Olle, Johnson Toby, Di Blasio Anna Maria, Lee Wai K., Gentilini Davide, Hastie Claire E., Menni Cristina, Monti Maria Cristina, Delles Christian, Laing Stewart, Corso Barbara, Navis Gerjan, Kwakernaak Arjan J., Van der Harst Pim, Bochud Murielle, Maillard Marc, Burnier Michel, Hedner Thomas, Kjeldsen Sverre, Wahlstrand Björn, Sjögren Marketa, Fava Cristiano, Montagnana Martina, Danese Elisa, Torffvit Ole, Hedblad Bo, Snieder Harold, Connell John M.C., Brown Morris, Samani Nilesh J., Farrall Martin, Cesana Giancarlo, Mancia Giuseppe, Signorini Stefano, Grassi Guido, Eyheramendy Susana, Wichmann H. Erich , Laan Maris, Strachan David P., Sever Peter, Shields Denis Colm, Stanton Alice, Vollenweider Peter, Teumer Alexander, Völzke Henry, Rettig Rainer, Newton-Cheh Christopher, Arora Pankaj, Zhang Feng, Soranzo Nicole, Spector Timothy D., Lucas Gavin, Kathiresan Sekar, Siscovick David S., Luan Jian'an, Loos Ruth J.F., Wareham Nicholas J., Penninx Brenda W., Nolte Ilja M., McBride Martin, Miller William H., Nicklin Suart A., Baker Andrew H., Graham Delyth, McDonald Robert A., Pell Jill P., Sattar Naveed, Welsh Paul, Munroe Patricia, Caulfield Mark J., Zanchetti Alberto, Dominiczak Anna F.
Working group(s)
Global BPGen Consortium
ISSN
1553-7404[electronic], 1553-7390[linking]
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
6
Number
10
Pages
e1001177
Language
english
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.
Keywords
Colaus Study
Pubmed
Web of science
Open Access
Yes
Create date
18/11/2010 14:53
Last modification date
20/08/2019 14:48
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