Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension

Abstract

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.

Figure 1. Manhattan plot of genomewide –log₁₀(p-value) from association analysis of BP extremes in the discovery sample.

Figure 2. Quantile-Quantile plot of observed versus expected p-value distributions in the discovery sample.

Figure 3. Association plot of the genomic region around rs13333226 showing both typed and imputed SNPs with location of genes and recombination rate.

Figure 4. Forest Plots of association with rs13333226 and hypertension (adjustment for population stratification was applied using principal components as appropriate for each cohort).

A: Forest plot of association analysis unadjusted for any covariates −21,466 cases and 18,240 controls. B: Forest plot of association analysis adjusted age, age², sex and BMI −21,466 cases and 18,240 controls. C: Forest plot of association analysis in the cohorts where eGFR was available and adjusted for age, age², sex, BMI −7427 controls and 5739 cases. D: Forest plot of association analysis in the cohorts where eGFR was available and adjusted for age, age², sex, BMI and eGFR −7427 controls and 5739 cases.