Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension

Padmanabhan, S. et al. (2010) Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genetics, 6(10), e1001177. (doi:10.1371/journal.pgen.1001177)

Padmanabhan, S. et al. (2010) Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genetics, 6(10), e1001177. (doi:10.1371/journal.pgen.1001177)

[img]
Preview
Text
44027.pdf

1MB

Publisher's URL: http://dx.doi.org/10.1371/journal.pgen.1001177

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 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hastie, Dr Claire and Nicklin, Professor Stuart and Menni, Ms Cristina and Welsh, Dr Paul and Strachan, Mr David and Graham, Dr Delyth and Baker, Professor Andrew and Laing, Mr Stewart and McBride, Dr Martin and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Delles, Professor Christian and Connell, Professor John and Miller, Dr William and Pell, Professor Jill and McDonald, Dr Robert and Sattar, Professor Naveed and Lee, Dr Wai Kwong
Authors: Padmanabhan, S., Melander, O., Johnson, T., Di Blasio, A.M., Lee, W.K., Gentilini, D., 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., Connell, 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., McDonald, R.A., Pell, J.P., Sattar, N., Welsh, P., Munroe, P., Caulfield, M.J., Zanchetti, A., and Dominiczak, A.F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Centre for Population and Health Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7404
Published Online:01 January 2010
Copyright Holders:Copyright © 2010 The Authors
First Published:First published in PLoS Genetics 2010 6(10): e1001177
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences