Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.
Nat Commun
; 10(1): 4130, 2019 09 11.
Article
in En
| MEDLINE
| ID: mdl-31511532
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Meta-Analysis as Topic
/
Chromosome Mapping
/
Albuminuria
/
Genome-Wide Association Study
Type of study:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2019
Document type:
Article
Affiliation country:
Germany