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

• Published in: PLoS genetics Vol. 6; no. 10; p. e1001177
• Main Authors: Padmanabhan, Sandosh, Melander, Olle, Johnson, Toby, Di Blasio, Anna Maria, Lee, Wai K., Gentilini, Davide, Hastie, Claire E., Menni, Cristina, Monti, Maria Cristina, Delles, Christian, Laing, Stewart, Corso, Barbara, Navis, Gerjan, Kwakernaak, Arjan J., van der Harst, Pim, Bochud, Murielle, Maillard, Marc, Burnier, Michel, Hedner, Thomas, Kjeldsen, Sverre, Wahlstrand, Björn, Sjögren, Marketa, Fava, Cristiano, Montagnana, Martina, Danese, Elisa, Torffvit, Ole, Hedblad, Bo, Snieder, Harold, Connell, John M. C., Brown, Morris, Samani, Nilesh J., Farrall, Martin, Cesana, Giancarlo, Mancia, Giuseppe, Signorini, Stefano, Grassi, Guido, Eyheramendy, Susana, Wichmann, H. Erich, Laan, Maris, Strachan, David P., Sever, Peter, Shields, Denis Colm, Stanton, Alice, Vollenweider, Peter, Teumer, Alexander, Völzke, Henry, Rettig, Rainer, Newton-Cheh, Christopher, Arora, Pankaj, Zhang, Feng, Soranzo, Nicole, Spector, Timothy D., Lucas, Gavin, Kathiresan, Sekar, Siscovick, David S., Luan, Jian'an, Loos, Ruth J. F., Wareham, Nicholas J., Penninx, Brenda W., Nolte, Ilja M., McBride, Martin, Miller, William H., Nicklin, Stuart A., Baker, Andrew H., Graham, Delyth, McDonald, Robert A., Pell, Jill P., Sattar, Naveed, Welsh, Paul, Munroe, Patricia, Caulfield, Mark J., Zanchetti, Alberto, Dominiczak, Anna F.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.10.2010; Public Library of Science (PLoS)
• Subjects: Age; Aged; Alleles; Blood Pressure; Body mass index; burden; Cardiac and Cardiovascular Systems; Cardiology and Cardiovascular Disease; Cardiovascular Disorders/Hypertension; Chromosomes, Human, Pair 16 - genetics; chronic kidney-disease; Clinical Medicine; Confidence intervals; feasibility; Female; Gene Frequency; Genetic Predisposition to Disease; Genetics and Genomics/Complex Traits; Genetics and Genomics/Genetics of Disease; Genome-Wide Association Study - methods; Genome-Wide Association Study - statistics & numerical data; Genomes; Genotype; Glomerular Filtration Rate; Health risk assessment; Heart attacks; Humans; Hypertension - genetics; Hypertension - physiopathology; Kardiologi; Kardiologi och kardiovaskulära sjukdomar; Klinisk medicin; Linear Models; loci; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Meta-Analysis as Topic; Middle Aged; Mortality; Multivariate Analysis; mutations; nephropathy; Polymorphism, Single Nucleotide; Population; Proportional Hazards Models; Risk assessment; Risk Factors; Studies; Survival Analysis; tamm-horsfall protein; urinary-excretion; Uromodulin - blood; Uromodulin - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1001177

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.