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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)
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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 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter TAMM-HORSFALL PROTEIN; CHRONIC KIDNEY-DISEASE; URINARY-EXCRETION; RISK-FACTORS; LOCI; NEPHROPATHY; FEASIBILITY; MUTATIONS; MORTALITY; BURDEN
Sprache englisch
Veröffentlichungsjahr 2010
HGF-Berichtsjahr 2010
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 6, Heft: 10, Seiten: 1-11, Artikelnummer: e1001177 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort San Francisco
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
POF Topic(s) 30503 - Chronic Diseases of the Lung and Allergies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503900-001
PubMed ID 2965757
DOI 10.1371/journal.pgen.1001177
WOS ID 000283647800009
Scopus ID 78449233580
Erfassungsdatum 2010-11-11
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