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Teumer, Alexander; Li, Yong; Ghasemi, Sahar; Prins, Bram P.; Wuttke, Matthias; Hermle, Tobias; Giri, Ayush; Sieber, Karsten B.; Qiu, Chengxiang; Kirsten, Holger; Tin, Adrienne; Chu, Audrey Y.; Bansal, Nisha; Feitosa, Mary F.; Wang, Lihua; Chai, Jin-Fang; Cocca, Massimiliano; Fuchsberger, Christian; Gorski, Mathias; Hoppmann, Anselm; Horn, Katrin; Li, Man; Marten, Jonathan; Noce, Damia; [...]

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

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  • Medientyp: E-Artikel
  • Titel: Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
  • Beteiligte: Teumer, Alexander; Li, Yong; Ghasemi, Sahar; Prins, Bram P.; Wuttke, Matthias; Hermle, Tobias; Giri, Ayush; Sieber, Karsten B.; Qiu, Chengxiang; Kirsten, Holger; Tin, Adrienne; Chu, Audrey Y.; Bansal, Nisha; Feitosa, Mary F.; Wang, Lihua; Chai, Jin-Fang; Cocca, Massimiliano; Fuchsberger, Christian; Gorski, Mathias; Hoppmann, Anselm; Horn, Katrin; Li, Man; Marten, Jonathan; Noce, Damia; [...]
  • Erschienen: Springer Science and Business Media LLC, 2019
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-019-11576-0
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 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 (<jats:italic>n</jats:italic> = 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 <jats:italic>TGFB1</jats:italic>, <jats:italic>MUC1</jats:italic>, <jats:italic>PRKCI</jats:italic>, and <jats:italic>OAF</jats:italic>), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of <jats:italic>OAF</jats:italic> and <jats:italic>PRKCI</jats:italic> orthologs in <jats:italic>Drosophila</jats:italic> 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.</jats:p>
  • Zugangsstatus: Freier Zugang