Genome Wide Association Study Of Blood Pressure Extremes Identifies Variant In Umod Associated With Hypertension

Background: Hypertension is a heritable and major contributor to the global burden of disease and the search for genetic determinants of hypertension has been difficult. Methods: 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. Results: We identified a locus on chromosome 16 in the 5' 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 and improved renal function. 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 = 0.0036; after eGFR adjustment: 0.89[0.85–0.95], p = 0.0001). In response to experimentally increased salt intake, the G allele is associated with a larger increase in measured GFR, extracellular fluid volume and a more effective reduction in plasma renin activity, in a sample of young healthy men. Urinary uromodulin is positively correlated with urinary sodium, cross-sectionally and after increased salt intake, and negatively with proximal tubular sodium reabsorption. Conclusions: Variation near the UMOD gene is involved in the causative mechanisms of hypertension, possibly by an effect on sodium homeostasis.