Journal article
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.
- Abstract:
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 9.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-019-11576-0
Authors
- Publisher:
- Nature Research
- Journal:
- Nature Communications More from this journal
- Volume:
- 10
- Issue:
- 1
- Article number:
- 4130
- Publication date:
- 2019-09-11
- Acceptance date:
- 2019-07-23
- DOI:
- EISSN:
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2041-1723
- Pmid:
-
31511532
- Language:
-
English
- Keywords:
- Pubs id:
-
1053312
- Local pid:
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pubs:1053312
- Deposit date:
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2020-04-07
- ARK identifier:
Terms of use
- Copyright holder:
- Teumer et al.
- Copyright date:
- 2019
- Rights statement:
- Copyright © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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