AUTHOR=You Ruilian , Chen Lanlan , Xu Lubin , Zhang Dingding , Li Haitao , Shi Xiaoxiao , Zheng Yali , Chen Limeng 

TITLE=High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.736001

DOI=10.3389/fcvm.2021.736001

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.</p><p><bold>Methods:</bold> We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (<italic>n</italic> = 46,188), systolic blood pressure (SBP, <italic>n</italic> = 1,194,020), and diastolic blood pressure (DBP, <italic>n</italic> = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.</p><p><bold>Results:</bold> MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, <italic>P</italic> &lt; 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, <italic>P</italic> = 8.92E-06) and 0.03 (SE = 0.01, <italic>P</italic> = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, <italic>P</italic> = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, <italic>P</italic> = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all <italic>P</italic> &lt; 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, <italic>P</italic> = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, <italic>P</italic> = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, <italic>P</italic> = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, <italic>P</italic> = 8.41E-09).</p><p><bold>Conclusion:</bold> Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.</p>