Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

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dc.contributor.authorPadmanabhan, Sandosh
dc.contributor.authorMelander, Olle
dc.contributor.authorJohnson, Toby
dc.contributor.authorDi Blasio, Anna Maria
dc.contributor.authorLee, Wai K.
dc.contributor.authorGentilini, Davide
dc.contributor.authorHastie, Claire E.
dc.contributor.authorMenni, Cristina
dc.contributor.authorMonti, Maria Cristina
dc.contributor.authorDelles, Christian
dc.contributor.authorLaing, Stewart
dc.contributor.authorCorso, Barbara
dc.contributor.authorNavis, Gerjan
dc.contributor.authorKwakernaak, Arjan J.
dc.contributor.authorvan der Harst, Pim
dc.contributor.authorBochud, Murielle
dc.contributor.authorMaillard, Marc
dc.contributor.authorBurnier, Michel
dc.contributor.authorHedner, Thomas
dc.contributor.authorKjeldsen, Sverre
dc.contributor.authorWahlstrand, Bjorn
dc.contributor.authorSjogren, Marketa
dc.contributor.authorFava, Cristiano
dc.contributor.authorMontagnana, Martina
dc.contributor.authorDanese, Elisa
dc.contributor.authorTorffvit, Ole
dc.contributor.authorHedblad, Bo
dc.contributor.authorSnieder, Harold
dc.contributor.authorConnell, John M. C.
dc.contributor.authorBrown, Morris
dc.contributor.authorSamani, Nilesh J.
dc.contributor.authorFarrall, Martin
dc.contributor.authorCesana, Giancarlo
dc.contributor.authorMancia, Giuseppe
dc.contributor.authorSignorini, Stefano
dc.contributor.authorGrassi, Guido
dc.contributor.authorEyheramendy, Susana
dc.contributor.authorWichmann, H. Erich
dc.contributor.authorLaan, Maris
dc.contributor.authorStrachan, David P.
dc.contributor.authorSever, Peter
dc.contributor.authorShields, Denis Colm
dc.contributor.authorStanton, Alice
dc.contributor.authorVollenweider, Peter
dc.contributor.authorTeumer, Alexander
dc.contributor.authorVoelzke, Henry
dc.contributor.authorRettig, Rainer
dc.contributor.authorNewton Cheh, Christopher
dc.contributor.authorArora, Pankaj
dc.contributor.authorZhang, Feng
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorSpector, Timothy D.
dc.contributor.authorLucas, Gavin
dc.contributor.authorKathiresan, Sekar
dc.contributor.authorSiscovick, David S.
dc.contributor.authorLuan, Jian'an
dc.contributor.authorLoos, Ruth J. F.
dc.contributor.authorWareham, Nicholas J.
dc.contributor.authorPenninx, Brenda W.
dc.contributor.authorNolte, Ilja M.
dc.contributor.authorMcBride, Martin
dc.contributor.authorMiller, William H.
dc.contributor.authorNicklin, Stuart A.
dc.contributor.authorBaker, Andrew H.
dc.contributor.authorGraham, Delyth
dc.contributor.authorMcDonald, Robert A.
dc.contributor.authorPell, Jill P.
dc.contributor.authorSattar, Naveed
dc.contributor.authorWelsh, Paul
dc.contributor.authorMunroe, Patricia
dc.contributor.authorCaulfield, Mark J.
dc.contributor.authorZanchetti, Alberto
dc.contributor.authorDominiczak, Anna F.
dc.contributor.authorGlobal BPgen Consortium
dc.date.accessioned2024-01-10T13:48:48Z
dc.date.available2024-01-10T13:48:48Z
dc.date.issued2010
dc.description.abstractHypertension 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 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-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.
dc.description.funderBritish Heart Foundation (BHF) Chair
dc.description.funderBHF
dc.description.funderEuropean Community
dc.description.funderFondazione Istituto Auxologico Italiano
dc.description.funderRegione Lombardia
dc.description.funderMedical Research Council
dc.description.funderNational Institute for Health Research
dc.fechaingreso.objetodigital2024-05-07
dc.format.extent11 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1371/journal.pgen.1001177
dc.identifier.issn1553-7390
dc.identifier.pubmedidMEDLINE:21082022
dc.identifier.urihttps://doi.org/10.1371/journal.pgen.1001177
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/79398
dc.identifier.wosidWOS:000283647800009
dc.information.autorucMatemática; Eyheramendy S;S/I;82611
dc.issue.numero10
dc.language.isoen
dc.nota.accesoSin adjunto
dc.publisherPUBLIC LIBRARY SCIENCE
dc.revistaPLOS GENETICS
dc.rightsregistro bibliográfico
dc.subjectTAMM-HORSFALL PROTEIN
dc.subjectCHRONIC KIDNEY-DISEASE
dc.subjectURINARY-EXCRETION
dc.subjectRISK-FACTORS
dc.subjectLOCI
dc.subjectNEPHROPATHY
dc.subjectFEASIBILITY
dc.subjectMUTATIONS
dc.subjectMORTALITY
dc.subjectBURDEN
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleGenome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension
dc.typeartículo
dc.volumen6
sipa.codpersvinculados82611
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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