Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
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BiBTeXIncreased 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.
DOI: 10.1038/s41467-019-11576-0
Projects: Genetical Statistics and Systems Biology
Publication type: Journal article
Journal: Nature communications
Human Diseases: No Human Disease specified
Citation: Nat Commun 10(1),4130
Date Published: 1st Dec 2019
Registered Mode: imported from a bibtex file
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Created: 15th Sep 2020 at 08:43
Last updated: 7th Dec 2021 at 17:58
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The group is interested in omic-level studies including the genome, methylome, transcriptome, and metabolome of the general population as well as of various diseases including cardiovascular diseases, pneumonia, sepsis, obesity, and brain cancers. Additionally, we aim at transfering results of biomathematical model simulations into clinical practice e.g. by haematopoietic growth-factor opimization during cytotoxic chemotherapy and optimization of EPO applications in chronic kidney disease.
The ...
Programme: This Project is not associated with a Programme
Public web page: http://www.imise.uni-leipzig.de/en/Groups/GenStat/
Start date: 1st Jan 2013
https://orcid.org/0000-0002-5307-6936
Projects: LHA - Leipzig Health Atlas, LIFE Adult, LIFE - Leipzig Research Center for Civilization Diseases, LIFE HNC - Head and Neck Cancer Group, MMML - Molecular mechanisms in malignant lymphoma, GLA - German Lymphoma Alliance, MMML Demonstrators - Molecular Mechanisms in Malignant Lymphomas - Demonstrators of Personalized Medicine, MMML-MYC-SYS, Genetical Statistics and Systems Biology, SepNet - German Competence Network Sepsis, HaematoSys - Systems biology of haematopoiesis and haematopoietic neoplasia, e:Med, SMITH - Smart Medical Information Technology for Healthcare, Task Force COVID-19 Leipzig, NFDI4Health, POLAR - Polypharmacy, Drug Interactions, Risks
Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig
Prof. Dr. Markus Löffler Universität Leipzig Institut für Medizinische Informatik, Statistik und Epidemiologie Härtelstraße 16-18 04107 Leipzig
Projects: LIFE Heart, LIFE - Leipzig Research Center for Civilization Diseases, HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles, e:Med, Genetical Statistics and Systems Biology, Task Force COVID-19 Leipzig, NFDI4Health
Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE)
Markus Scholz Scientific Speaker Institution Institut für Medizinische Informatik, Statistik und Epidemiologie Universität Leipzig Härtelstraße 16-18 04107 Leipzig
