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

孟德尔随机化 肾脏疾病 塔姆-霍斯法尔蛋白 血压 医学 肾功能 内科学 优势比 人口 置信区间 内分泌学 心脏病学 生物 遗传学 基因型 基因 环境卫生 遗传变异
作者
Belén Ponte,Marie C. Sadler,Eric Olinger,Péter Vollenweider,Murielle Bochud,Sandosh Padmanabhan,Caroline Hayward,Zoltán Kutalik,Olivier Devuyst
出处
期刊:Kidney International [Elsevier BV]
卷期号:100 (6): 1282-1291 被引量:32
标识
DOI:10.1016/j.kint.2021.08.032
摘要

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.
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