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Title: Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.
Authors: Padmanabhan, S.
Melander, O.
Johnson, T.
Di Blasio, A. M.
Lee, W. K.
Gentilini, D.
Hastie, C. E.
Menni, C.
Monti, M. C.
Delles, C.
Laing, S.
Corso, B.
Navis, G.
Kwakernaak, A. J.
van der Harst, P.
Bochud, M.
Maillard, M.
Burnier, M.
Hedner, T.
Kjeldsen, S.
Wahlstrand, B.
Sjögren, M.
Fava, C.
Montagnana, M.
Danese, E.
Torffvit, O.
Hedblad, B.
Snieder, H.
Connell, J. M.
Brown, M.
Samani, Nilesh J.
Farrall, M.
Cesana, G.
Mancia, G.
Signorini, S.
Grassi, G.
Eyheramendy, S.
Wichmann, H. E.
Laan, M.
Strachan, D. P.
Sever, P.
Shields, D. C.
Stanton, A.
Vollenweider, P.
Teumer, A.
Völzke, H.
Rettig, R.
Newton-Cheh, C.
Arora, P.
Zhang, F.
Soranzo, N.
Spector, T. D.
Lucas, G.
Kathiresan, S.
Siscovick, D. S.
Luan, J.
Loos, R. J.
Wareham, N. J.
Penninx, B. W.
Nolte, I. M.
McBride, M.
Miller, W. H.
Nicklin, S. A.
Baker, A. H.
Graham, D.
McDonald, R. A.
Pell, J. P.
Sattar, N.
Welsh, P.
Global BPgen Consortium
Munroe, P.
Caulfield, M. J.
Zanchetti, A.
Dominiczak, A. F.
First Published: 28-Oct-2010
Publisher: Public Library of Science
Citation: PLoS Genetics, 2010, 6 (10), pp. e1001177-e1001177
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.
DOI Link: 10.1371/journal.pgen.1001177
ISSN: 1553-7390
eISSN: 1553-7404
Type: Journal Article
Rights: Copyright: © 2010 Padmanabhan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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