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Padmanabhan, S.* ; Melander, O.* ; Johnson, T.* ; di Blasio, A.M.* ; Lee, W.K.* ; Gentilini, G.* ; 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.* ; Conell, J.M.C.* ; Brown, M.* ; Samani, N.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.F.* ; Wareham, N.J.* ; Penninx, B.W.* ; Nolte, I.M.* ; McBride, M.* ; Miller, W.H.* ; Nicklin, S.A.* ; Baker, A.H.* ; Graham, D.* ; Mc Donald, R.A.* ; Pell, J.P.* ; Sattar, N.* ; Welsh, P.* ; Munroe, P.* ; Caulfield, M.J.* ; Zanchetti, A.* ; Dominiczak, A.F.*

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

PLoS Genet. 6, 1-11:e1001177 (2010)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 casecontrol design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6610211). 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords TAMM-HORSFALL PROTEIN; CHRONIC KIDNEY-DISEASE; URINARY-EXCRETION; RISK-FACTORS; LOCI; NEPHROPATHY; FEASIBILITY; MUTATIONS; MORTALITY; BURDEN
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Journal PLoS Genetics
Quellenangaben Volume: 6, Issue: 10, Pages: 1-11, Article Number: e1001177 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place San Francisco
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)