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 59 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, 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.