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

• DOI: 10.1371/journal.pgen.1001177
• Publication Date: 2010-10-28T20:55:10Z
• Authors: Sandosh Padmanabhan; Olle Melander; Toby Johnson; Anna Maria Di Blasio; Wai K. Lee; Davide Gentilini; Claire E. Hastie; Cristina Menni; Maria Cristina Monti; Christian Delles; Stewart Laing; Barbara Corso; Gerjan Navis; Arjan J. Kwakernaak; Pim van der Harst; Murielle Bochud; Marc Maillard; Michel Burnier; Thomas Hedner; Sverre Kjeldsen; Björn Wahlstrand; Marketa Sjögren; Cristiano Fava; Martina Montagnana; Elisa Danese; Ole Torffvit; Bo Hedblad; Harold Snieder; John M. C. Connell; Morris Brown; Nilesh J. Samani; Martin Farrall; Giancarlo Cesana; Giuseppe Mancia; Stefano Signorini; Guido Grassi; Susana Eyheramendy; H. Erich Wichmann; Maris Laan; David P. Strachan; Peter Sever; Denis Colm Shields; Alice Stanton; Peter Vollenweider; Alexander Teumer; Henry Völzke; Rainer Rettig; Christopher Newto...; Pankaj Arora; Feng Zhang; Nicole Soranzo; Timothy D. Spector; Gavin Lucas; Sekar Kathiresan; David S. Siscovick; Jian'an Luan; Ruth J. F. Loos; Nicholas J. Wareham; Brenda W. Penninx; Ilja M. Nolte; Martin McBride; William H. Miller; Stuart A. Nicklin; Andrew H. Baker; Delyth Graham; Robert A. McDonald; Jill P. Pell; Naveed Sattar; Paul Welsh; ; Patricia Munroe; Mark J. Caulfield; Alberto Zanchetti; Anna F. Dominiczak
• Keywords: CHRONIC KIDNEY-DISEASE; Male; 0301 basic medicine; URINARY-EXCRETION; cardiovascular disorders; tamm-horsfall protein chronic kidney-disease urinary-excretion risk-factors loci nephropathy feasibility mutations mortality burden; LOCI; Blood Pressure; Genomewide Association Study; Blood Pressure; UMOD; Hypertension; QH426-470; Gene Frequency; Risk Factors; Cardiac and Cardiovascular Systems; TAMM-HORSFALL PROTEIN; genetics of disease; Single Nucleotide; Middle Aged; Colaus Study; genetics and genomics; 3. Good health; Hypertension; Female; BURDEN; Male; Chromosomes, Human, Pair 16; Linear Models; Glomerular Filtration Rate; Multivariate Analysis; Alleles; Middle Aged; Survival Analysis; Female; Polymorphism, Single Nucleotide; Uromodulin; Risk Factors; Genotype; Humans; Meta-Analysis as Topic; Gene Frequency; Blood Pressure; Genome-Wide Association Study; Aged; Proportional Hazards Models; Hypertension; Genetic Predisposition to Disease; Human; Research Article; Glomerular Filtration Rate; hypertension; FEASIBILITY; Genotype; NEPHROPATHY; 610; Polymorphism, Single Nucleotide; Chromosomes; complex traits; 03 medical and health sciences; Meta-Analysis as Topic; 616; Uromodulin; Genetics; Urology and Nephrology; Humans; Genetic Predisposition to Disease; Polymorphism; Alleles; Aged; Proportional Hazards Models; genome-wide association study; Pair 16; MUTATIONS; MORTALITY; Survival Analysis; Multivariate Analysis; RISK-FACTORS; Linear Models; Chromosomes, Human, Pair 16; Genome-Wide Association Study

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.