Genome-wide association studies have identified significant association of 5’ Uromodulin gene (UMOD) SNPs with hypertension, eGFR and urinary uromodulin excretion. UMOD is exclusively expressed in the thick ascending limb of the loop of Henle, implicating sodium balance as a putative underpinning mechanism. However, given the association of UMOD SNPs with renal function, their association with blood pressure may be confounded. Genetic variants are unlikely to be affected by confounders and cannot be influenced by reverse causation. We investigated the causal effect of uromodulin on blood pressure using instrumental variable (IV) Mendelian randomization (MR) analysis.Methods:
We performed two-sample and multivariable MR analysis using previously published summary statistics of GWAS meta-analysis. The most significant SNP (rs12917707) associated with urinary uromodulin (primary exposure) was selected. The outcomes were SBP, DBP (N = 317754), Arterial Stiffness Index (ASI) (N = 109813), urine Na+ and K+ from UK-Biobank genome wide analysis. We conducted two-sample MR and multivariable MR using two SNPs associated with both uromodulin excretion and eGFR (rs12917707, rs4494548). The analyses were performed on the MR-Base platform.Results:
Two sample MR (Figure) showed a causal relationship between genetically determined urinary uromodulin and DBP (causal estimate 0.05 mmHg per unit change in urinary uromodulin, p = 4.3E-09) and SBP (causal estimate 0.04 mmHg per unit change in urinary uromodulin, p = 0.0003). Multivariable MR including eGFR as exposures confirmed the causal effect of uromodulin on SBP (p = 0.004) and DBP (p = 0.01) but not for ASI, urine Na+ and K+.Conclusion:
Genetically determined urinary uromodulin is causally associated with SBP and DBP but not arterial stiffness or urinary Na+ or K+ excretion.