Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
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DOI：
10.1038/s41467-019-11576-0
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发表时间：
2019-09-11
影响因子：
16.6
通讯作者：
Koettgen, Anna
中科院分区：
文献类型：
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作者：
Teumer, Alexander;Li, Yong;Koettgen, Anna
尿白蛋白与肌酐比值（UACR）水平升高与肾脏疾病进展和心血管事件风险升高相关，但其潜在机制尚未完全了解。在这里，我们进行了跨种族（n = 564，257）和欧洲血统的UACR全基因组关联研究的荟萃分析，包括血统和糖尿病特异性分析，并确定了68个UACR相关基因座。在一个独立的电子病历数据库（n = 192，868）中进行的遗传相关性分析和风险评分关联揭示了与蛋白尿、高脂血症、痛风和高血压的联系。对47种组织中的基因表达和血浆蛋白水平进行的精细定位和trans-Omics分析表明，可能通过肾脏中的差异表达（包括TGFB 1、MUC 1、PRKCI和OAF）发挥作用的基因，并允许将UACR相关性与改变的血浆OAF浓度偶联。在果蝇肾细胞中敲低OAF和PRKCI直系同源物减少白蛋白内吞作用。使飞PRKCI沉默进一步损害狭缝隔膜形成。这些结果为减少白蛋白尿的转化研究产生了一个优先的基因和途径清单。
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.