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)

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 Graham, Dr Delyth and Baker, Professor Andrew and Laing, Mr Stewart and McBride, Dr Martin and Connell, Professor John and McDonald, Dr Robert and Lee, Dr Wai Kwong and Nicklin, Professor Stuart and Menni, Ms Cristina and Welsh, Professor Paul and Strachan, Mr David and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Delles, Professor Christian and Miller, Dr William and Pell, Professor Jill and Sattar, Professor Naveed
• 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 > School of Health & Wellbeing > Public Health; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
39252	1	Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease	Eleanor Davies	Medical Research Council (MRC)	G0400874	Institute of Cardiovascular and Medical Sciences
39252	2	Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease	Eleanor Davies	Medical Research Council (MRC)	G0400874	Institute of Cardiovascular and Medical Sciences