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

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.Author Summary: Hypertension is the leading contributor to global mortality with a global prevalence of 26.4% in 2000, projected to increase to 29.2% by 2025. While 50%–60% of population variation in blood pressure can be attributable to additive genetic factors, all the genetic variants robustly identified so far explain only 1%–2% of the population variance indicating the presence of additional undiscovered risk variants. Using an extreme case-control strategy, we have discovered a SNP in the promoter region of the uromodulin gene (UMOD) to be associated with hypertension (minor allele protective against hypertension). We then validated this association using large-scale population and case-control studies, where similar extreme criteria for selection of cases and controls have been used (21,466 cases and 18,240 controls). As the locus was related to uromodulin, a protein exclusively expressed in the kidneys, we show that the association is independent of renal dysfunction. We also show preliminary evidence that the SNP allele which is protective against hypertension is also protective against cardiovascular events in 26,654 Swedish subjects followed-up for 12 years. The newly discovered UMOD locus for hypertension has the potential to give unique insights into the role of uromodulin in BP regulation and to identify novel drugable targets.