Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion

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dc.contributor.authorNewhouse, Stephen
dc.contributor.authorFarrall, Martin
dc.contributor.authorWallace, Chris
dc.contributor.authorHoti, Mimoza
dc.contributor.authorBurke, Beverley
dc.contributor.authorHoward, Philip
dc.contributor.authorOnipinla, Abiodun
dc.contributor.authorLee, Kate
dc.contributor.authorShaw Hawkins, Sue
dc.contributor.authorDobson, Richard
dc.contributor.authorBrown, Morris
dc.contributor.authorSamani, Nilesh J.
dc.contributor.authorDominiczak, Anna F.
dc.contributor.authorConnell, John M.
dc.contributor.authorLathrop, G. Mark
dc.contributor.authorKooner, Jaspal
dc.contributor.authorChambers, John
dc.contributor.authorElliott, Paul
dc.contributor.authorClarke, Robert
dc.contributor.authorCollins, Rory
dc.contributor.authorLaan, Maris
dc.contributor.authorOrg, Elin
dc.contributor.authorJuhanson, Peeter
dc.contributor.authorVeldre, Gudrun
dc.contributor.authorViigimaa, Margus
dc.contributor.authorEyheramendy, Susana
dc.contributor.authorCappuccio, Francesco P.
dc.contributor.authorJi, Chen
dc.contributor.authorIacone, Roberto
dc.contributor.authorStrazzullo, Pasquale
dc.contributor.authorKumari, Meena
dc.contributor.authorMarmot, Michael
dc.contributor.authorBrunner, Eric
dc.contributor.authorCaulfield, Mark
dc.contributor.authorMunroe, Patricia B.
dc.date.accessioned2024-01-10T13:16:20Z
dc.date.available2024-01-10T13:16:20Z
dc.date.issued2009
dc.description.abstractWNK1-a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control-is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95% CI: 1.23-4.9), DBP 1.9 mmHg (95% CI: 0.7-3.2) and hypertension, odds ratio (OR: 1.3 [95% CI: 1.0-1.7]). We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10(-7)). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.
dc.description.funderWellcome Trust International Senior Research Fellowship
dc.description.funderEstonian Ministry of Education and Science
dc.description.funderMedical Research Council of Great Britain
dc.description.funderBritish Heart Foundation
dc.description.funderThe William Harvey Research Foundation
dc.description.funderEconomic and Social Research Council
dc.description.funderHealth and Safety Executive
dc.description.funderNational Heart Lung and Blood Institute, US, NIH
dc.description.funderNational Institute on Aging, US, NIH
dc.description.funderAgency for Health Care Policy Research
dc.description.funderJohn D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health
dc.description.funderDepartment of Health
dc.description.funderBritish Heart Foundation
dc.description.funderMedical Research Council
dc.description.funderAGENCY FOR HEALTHCARE RESEARCH AND QUALITY
dc.description.funderNATIONAL HEART, LUNG, AND BLOOD INSTITUTE
dc.description.funderNATIONAL INSTITUTE ON AGING
dc.format.extent14 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1371/journal.pone.0005003
dc.identifier.issn1932-6203
dc.identifier.pubmedidMEDLINE:19347040
dc.identifier.urihttps://doi.org/10.1371/journal.pone.0005003
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/78577
dc.identifier.wosidWOS:000265500900001
dc.information.autorucMatemática;Eyheramendy S;S/I;82611
dc.issue.numero4
dc.language.isoen
dc.nota.accesoSin adjunto
dc.publisherPUBLIC LIBRARY SCIENCE
dc.revistaPLOS ONE
dc.rightsregistro bibliográfico
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePolymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion
dc.typeartículo
dc.volumen4
sipa.codpersvinculados82611
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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