尿调蛋白在降低肾尿酸排泄与蛋白尿之间的通路中的作用。

Center for Cardiovascular Prevention, First Faculty of Medicine and Thomayer Hospital, Charles University in Prague, Prague, Czech Republic.

Centre de recherche du CHUM, Montréal, Quebec, Canada.

Am J Hypertens. 2019 Mar 16;32(4):384-392. doi: 10.1093/ajh/hpy190.

BACKGROUND

The mechanism explaining the inverse association between renal urate and albumin excretion remains unclear. First, we evaluated the impact of candidate variants in the main urate transporter genes (i.e., SLC2A9, SLC22A12, ABCG2) on the association between fractional excretion of uric acid (FEUA) and urinary albumin/creatinine ratio (uACR). Second, we examined uromodulin and sodium excretion as mediators of the association between FEUA and uACR.

METHODS

We performed cross-sectional analysis of 737 French Canadians from the CARTaGENE cohort, a random sample of the Quebec population aged 40-69 years (a total of 20,004 individuals). Individuals with available genotyping and urinary data were obtained from a sub-study including gender-matched pairs with high and low Framingham Risk Score and vascular rigidity index. We further excluded individuals with an estimated glomerular filtration rate <60 ml/min/1.73 m2, glycosuria, and use of confounding medication. A spot urine sample was analyzed. Genotyping was performed using the Illumina Omni2.5-8 BeadChips. Genetic variants were analyzed using an additive model.

RESULTS

Final analyses included 593 individuals (45.5% of men; mean age 54.3 ± 8.6). We observed an antagonistic interaction between rs13129697 variant of the SLC2A9 gene and FEUA tertiles on uACR (P = 0.002). Using the mediation analysis, uromodulin explained 32%, fractional excretion of sodium (FENa) 44%, and uromodulin together with FENa explained 70% of the inverse relationship between FEUA and uACR. Bootstrapping process confirmed the role of both mediators.

CONCLUSIONS

Our data suggest that the association of albuminuria with decreased renal urate excretion may be modified by the transporter SLC2A9, and mediated by uromodulin and sodium handling.

背景

解释尿酸盐与白蛋白排泄之间负相关关系的机制尚不清楚。首先，我们评估了主要尿酸转运体基因（即 SLC2A9、SLC22A12、ABCG2）中的候选变异对尿酸排泄分数（FEUA）与尿白蛋白/肌酐比（uACR）之间关联的影响。其次，我们研究了尿调蛋白和钠排泄作为 FEUA 与 uACR 之间关联的中介。

方法

我们对来自 CARTaGENE 队列的 737 名法裔加拿大人进行了横断面分析，CARTaGENE 队列是魁北克 40-69 岁人群的随机样本（共有 20004 人）。从包括按性别匹配的高和低弗雷明汉风险评分和血管僵硬指数的对子的子研究中获得了具有可用基因分型和尿液数据的个体。我们进一步排除了肾小球滤过率估计值<60 ml/min/1.73 m2、糖尿和使用混杂药物的个体。分析了一份随机尿液样本。使用 Illumina Omni2.5-8 BeadChips 进行基因分型。使用加性模型分析遗传变异。

结果

最终分析包括 593 名个体（45.5%为男性；平均年龄 54.3 ± 8.6）。我们观察到 SLC2A9 基因的 rs13129697 变体与 FEUA 三分位与 uACR 之间存在拮抗相互作用（P=0.002）。使用中介分析，尿调蛋白解释了 32%，钠排泄分数（FENa）解释了 44%，尿调蛋白和 FENa 共同解释了 FEUA 与 uACR 之间的负相关关系的 70%。自举过程证实了两种介质的作用。