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

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          Abstract

          Background: 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.

          Methods: 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 ( n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 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.

          Results: 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, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 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, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 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 P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).

          Conclusion: 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.

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          UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

          Cathie Sudlow, John Gallacher, Naomi Allen … (2017)
          Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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            Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

            Jack Bowden, George Davey Smith, Stephen Burgess (2016)
            Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.
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              Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

              Jack Bowden, George Davey Smith, Philip C. Haycock … (2017)
              ABSTRACT Developments in genome‐wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse‐variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite‐sample Type 1 error rates than the inverse‐variance weighted method, and is complementary to the recently proposed MR‐Egger (Mendelian randomization‐Egger) regression method. In analyses of the causal effects of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol on coronary artery disease risk, the inverse‐variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR‐Egger regression methods suggest a null effect of high‐density lipoprotein cholesterol that corresponds with the experimental evidence. Both median‐based and MR‐Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Cardiovasc Med
                Journal ID (iso-abbrev): Front Cardiovasc Med
                Journal ID (publisher-id): Front. Cardiovasc. Med.
                Title: Frontiers in Cardiovascular Medicine
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2297-055X
                Publication date (Electronic): 01 September 2021
                Publication date Collection: 2021
                Volume: 8
                Electronic Location Identifier: 736001
                Affiliations
                [1] 1Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College , Beijing, China
                [2] 2First Clinical Medical College of Norman Bethune Health Science Center, Jilin University , Changchun, China
                [3] 3Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, China
                [4] 4China-Japan Friendship Hospital, Jilin University , Changchun, China
                [5] 5Department of Nephrology, Affiliated Ningxia People's Hospital of Ningxia Medical University , Yinchuan, China
                Author notes

                Edited by: Modar Kassan, University of Tennessee Health Science Center (UTHSC), United States

                Reviewed by: Hui Lu, Capital Medical University, China; Lu Liu, Shandong University, China

                *Correspondence: Limeng Chen chenlimeng@ 123456pumch.cn

                This article was submitted to Hypertension, a section of the journal Frontiers in Cardiovascular Medicine

                Article
                DOI: 10.3389/fcvm.2021.736001
                PMC ID: 8440862
                SO-VID: 5b13bbd9-cf4a-4997-b018-87b467608ed5
                Copyright © Copyright © 2021 You, Chen, Xu, Zhang, Li, Shi, Zheng and Chen.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 04 July 2021
                Date accepted : 09 August 2021
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 45, Pages: 9, Words: 5687
                Categories
                Subject: Cardiovascular Medicine
                Subject: Original Research

                Keywords: uromodulin,hypertension,systolic blood pressure,diastolic blood pressure,mendelian randomization
                Data availability:
                Keywords: uromodulin, hypertension, systolic blood pressure, diastolic blood pressure, mendelian randomization

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