Advanced

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

Padmanabhan, Sandosh; Melander, Olle LU ; Johnson, Toby; Di Blasio, Anna Maria; Lee, Wai K.; Gentilini, Davide; Hastie, Claire E.; Menni, Cristina; Monti, Maria Cristina and Delles, Christian, et al. (2010) In PLoS Genetics 6(10).
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
6
issue
10
publisher
Public Library of Science
external identifiers
  • wos:000283647800009
  • scopus:78449233580
ISSN
1553-7404
DOI
10.1371/journal.pgen.1001177
language
English
LU publication?
yes
id
25b3d4ea-e329-4e1c-9b8a-0f88f5cddb45 (old id 1752786)
date added to LUP
2011-01-04 07:40:09
date last changed
2018-07-01 03:20:27
@article{25b3d4ea-e329-4e1c-9b8a-0f88f5cddb45,
  abstract     = {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.},
  author       = {Padmanabhan, Sandosh and Melander, Olle and Johnson, Toby and Di Blasio, Anna Maria and Lee, Wai K. and Gentilini, Davide and Hastie, Claire E. and Menni, Cristina and Monti, Maria Cristina and Delles, Christian and Laing, Stewart and Corso, Barbara and Navis, Gerjan and Kwakernaak, Arjan J. and van der Harst, Pim and Bochud, Murielle and Maillard, Marc and Burnier, Michel and Hedner, Thomas and Kjeldsen, Sverre and Wahlstrand, Bjorn and Sjögren, Marketa and Fava, Cristiano and Montagnana, Martina and Danese, Elisa and Torffvit, Ole and Hedblad, Bo and Snieder, Harold and Connell, John M. C. and Brown, Morris and Samani, Nilesh J. and Farrall, Martin and Cesana, Giancarlo and Mancia, Giuseppe and Signorini, Stefano and Grassi, Guido and Eyheramendy, Susana and Wichmann, H. Erich and Laan, Maris and Strachan, David P. and Sever, Peter and Shields, Denis Colm and Stanton, Alice and Vollenweider, Peter and Teumer, Alexander and Voelzke, Henry and Rettig, Rainer and Newton-Cheh, Christopher and Arora, Pankaj and Zhang, Feng and Soranzo, Nicole and Spector, Timothy D. and Lucas, Gavin and Kathiresan, Sekar and Siscovick, David S. and Luan, Jian'an and Loos, Ruth J. F. and Wareham, Nicholas J. and Penninx, Brenda W. and Nolte, Ilja M. and McBride, Martin and Miller, William H. and Nicklin, Stuart A. and Baker, Andrew H. and Graham, Delyth and McDonald, Robert A. and Pell, Jill P. and Sattar, Naveed and Welsh, Paul and Munroe, Patricia and Caulfield, Mark J. and Zanchetti, Alberto and Dominiczak, Anna F.},
  issn         = {1553-7404},
  language     = {eng},
  number       = {10},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1001177},
  volume       = {6},
  year         = {2010},
}