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

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Padmanabhan, Sandosh (author)

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

Article/chapterEnglish2010

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2010-10-28
Public Library of Science (PLoS),2010
electronicrdacarrier

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LIBRIS-ID:oai:lup.lub.lu.se:25b3d4ea-e329-4e1c-9b8a-0f88f5cddb45
https://lup.lub.lu.se/record/1752786URI
https://doi.org/10.1371/journal.pgen.1001177DOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype

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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 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.

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Melander, OlleLund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-ome (author)
Johnson, Toby (author)
Di Blasio, Anna Maria (author)
Lee, Wai K. (author)
Gentilini, Davide (author)
Hastie, Claire E. (author)
Menni, Cristina (author)
Monti, Maria Cristina (author)
Delles, Christian (author)
Laing, Stewart (author)
Corso, Barbara (author)
Navis, Gerjan (author)
Kwakernaak, Arjan J. (author)
van der Harst, Pim (author)
Bochud, Murielle (author)
Maillard, Marc (author)
Burnier, Michel (author)
Hedner, Thomas (author)
Kjeldsen, Sverre (author)
Wahlstrand, Bjorn (author)
Sjögren, MarketaLund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-msj (author)
Fava, CristianoLund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-cfa (author)
Montagnana, MartinaLund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine(Swepub:lu)med-mmn (author)
Danese, Elisa (author)
Torffvit, OleLund University,Lunds universitet,Njurmedicin,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Nephrology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-oto (author)
Hedblad, BoLund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine(Swepub:lu)medf-bhe (author)
Snieder, Harold (author)
Connell, John M. C. (author)
Brown, Morris (author)
Samani, Nilesh J. (author)
Farrall, Martin (author)
Cesana, Giancarlo (author)
Mancia, Giuseppe (author)
Signorini, Stefano (author)
Grassi, Guido (author)
Eyheramendy, Susana (author)
Wichmann, H. Erich (author)
Laan, Maris (author)
Strachan, David P. (author)
Sever, Peter (author)
Shields, Denis Colm (author)
Stanton, Alice (author)
Vollenweider, Peter (author)
Teumer, Alexander (author)
Voelzke, Henry (author)
Rettig, Rainer (author)
Newton-Cheh, Christopher (author)
Arora, Pankaj (author)
Zhang, Feng (author)
Soranzo, Nicole (author)
Spector, Timothy D. (author)
Lucas, Gavin (author)
Kathiresan, Sekar (author)
Siscovick, David S. (author)
Luan, Jian'an (author)
Loos, Ruth J. F. (author)
Wareham, Nicholas J. (author)
Penninx, Brenda W. (author)
Nolte, Ilja M. (author)
McBride, Martin (author)
Miller, William H. (author)
Nicklin, Stuart A. (author)
Baker, Andrew H. (author)
Graham, Delyth (author)
McDonald, Robert A. (author)
Pell, Jill P. (author)
Sattar, Naveed (author)
Welsh, Paul (author)
Munroe, Patricia (author)
Caulfield, Mark J. (author)
Zanchetti, Alberto (author)
Dominiczak, Anna F. (author)
Kardiovaskulär forskning - hypertoniForskargrupper vid Lunds universitet (creator_code:org_t)

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By the author/editor: Padmanabhan, San ...; Melander, Olle; Johnson, Toby; Di Blasio, Anna ...; Lee, Wai K.; Gentilini, David ...; show more...; Hastie, Claire E ...; Menni, Cristina; Monti, Maria Cri ...; Delles, Christia ...; Laing, Stewart; Corso, Barbara; Navis, Gerjan; Kwakernaak, Arja ...; van der Harst, P ...; Bochud, Murielle; Maillard, Marc; Burnier, Michel; Hedner, Thomas; Kjeldsen, Sverre; Wahlstrand, Bjor ...; Sjögren, Marketa; Fava, Cristiano; Montagnana, Mart ...; Danese, Elisa; Torffvit, Ole; Hedblad, Bo; Snieder, Harold; Connell, John M. ...; Brown, Morris; Samani, Nilesh J ...; Farrall, Martin; Cesana, Giancarl ...; Mancia, Giuseppe; Signorini, Stefa ...; Grassi, Guido; Eyheramendy, Sus ...; Wichmann, H. Eri ...; Laan, Maris; Strachan, David ...; Sever, Peter; Shields, Denis C ...; Stanton, Alice; Vollenweider, Pe ...; Teumer, Alexande ...; Voelzke, Henry; Rettig, Rainer; Newton-Cheh, Chr ...; Arora, Pankaj; Zhang, Feng; Soranzo, Nicole; Spector, Timothy ...; Lucas, Gavin; Kathiresan, Seka ...; Siscovick, David ...; Luan, Jian'an; Loos, Ruth J. F.; Wareham, Nichola ...; Penninx, Brenda ...; Nolte, Ilja M.; McBride, Martin; Miller, William ...; Nicklin, Stuart ...; Baker, Andrew H.; Graham, Delyth; McDonald, Robert ...; Pell, Jill P.; Sattar, Naveed; Welsh, Paul; Munroe, Patricia; Caulfield, Mark ...; Zanchetti, Alber ...; Dominiczak, Anna ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Urology and Neph ...

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