Mendelian randomization to assess causality between uromodulin, blood pressure and chronic kidney disease.

Details

Serval ID
serval:BIB_98D5CE7FC2F2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mendelian randomization to assess causality between uromodulin, blood pressure and chronic kidney disease.
Journal
Kidney international
Author(s)
Ponte B., Sadler M.C., Olinger E., Vollenweider P., Bochud M., Padmanabhan S., Hayward C., Kutalik Z., Devuyst O.
ISSN
1523-1755 (Electronic)
ISSN-L
0085-2538
Publication state
Published
Issued date
12/2021
Peer-reviewed
Oui
Volume
100
Number
6
Pages
1282-1291
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
UMOD variants associated with higher levels of urinary uromodulin (uUMOD) increase the risk of chronic kidney disease (CKD) and hypertension. However, uUMOD levels also reflect functional kidney tubular mass in observational studies, questioning the causal link between uromodulin production and kidney damage. We used Mendelian randomization to clarify causality between uUMOD levels, kidney function and blood pressure in individuals of European descent. The link between uUMOD and estimated glomerular filtration rate (eGFR) was first investigated in a population-based cohort of 3851 individuals. In observational data, higher uUMOD associated with higher eGFR. Conversely, when using rs12917707 (an UMOD polymorphism) as an instrumental variable in one-sample Mendelian randomization, higher uUMOD strongly associated with eGFR decline. We next applied two-sample Mendelian randomization on four genome wide association study consortia to explore causal links between uUMOD and eGFR, CKD risk (567,460 individuals) and blood pressure (757,461 individuals). Higher uUMOD levels significantly associated with lower eGFR, higher odds for eGFR decline or CKD, and higher systolic or diastolic blood pressure. Each one standard deviation (SD) increase of uUMOD decreased log-transformed eGFR by -0.15 SD (95% confidence interval -0.17 to -0.13) and increased log-odds CKD by 0.13 SD (0.12 to 0.15). One SD increase of uUMOD increased systolic blood pressure by 0.06 SD (0.03 to 0.09) and diastolic blood pressure by 0.08 SD (0.05 to 0.12). The effect of uUMOD on blood pressure was mediated by eGFR, whereas the effect on eGFR was not mediated by blood pressure. Thus, our data support that genetically driven levels of uromodulin have a direct, causal and adverse effect on kidney function outcome in the general population, not mediated by blood pressure.
Keywords
CKD, GWAS, Mendelian randomization, blood pressure, eGFR, uromodulin, Genome-Wide Association Study, chronic kidney disease, estimated glomerular filtration rate
Pubmed
Web of science
Create date
19/10/2021 12:30
Last modification date
11/12/2021 7:36
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