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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Univ Med Greifswald, Inst Community Med, Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
Univ Freiburg, Fac Med & Med Ctr, Dept Biometry Epidemiol & Med Bioinformat, Inst Genet Epidemiol, Freiburg, Germany.
Univ Med Greifswald, Inst Community Med, Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
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2019 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 4130Article in journal (Refereed) Published
Abstract [en]

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.
Place, publisher, year, edition, pages
2019. Vol. 10, article id 4130
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Medical Genetics and Genomics
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URN: urn:nbn:se:uu:diva-394955DOI: 10.1038/s41467-019-11576-0ISI: 000485216900016PubMedID: 31511532OAI: oai:DiVA.org:uu-394955DiVA, id: diva2:1362678
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2025-02-10Bibliographically approved

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