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Autor: Ponticelli, Claudio

10 záznamů v Medvik Filtry

Článek

Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Kiryluk, Krzysztof
Autor Kiryluk, Krzysztof ORCID Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA. kk473@columbia.edu Institute for Genomic Medicine, Columbia University, New York City, NY, USA. kk473@columbia.edu
Sanchez-Rodriguez, Elena
Autor Sanchez-Rodriguez, Elena ORCID Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Zhou, Xu-Jie
Autor Zhou, Xu-Jie Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
Zanoni, Francesca
Autor Zanoni, Francesca Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Liu, Lili
Autor Liu, Lili ORCID Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Mladkova, Nikol
Autor Mladkova, Nikol Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Khan, Atlas
Autor Khan, Atlas ORCID Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Marasa, Maddalena
Autor Marasa, Maddalena Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Zhang, Jun Y
Autor Zhang, Jun Y ORCID Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA
Balderes, Olivia
Autor Balderes, Olivia Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA

Nature genetics. 2023 ; 55 (7) : 1091-1105. [pub] 20230619

Nat Genet
ISSN 1546-1718
Medvik
Zdroj

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

MeSH
celogenomová asociační studie MeSH
IgA nefropatie * farmakoterapie genetika diagnóza MeSH
imunoglobulin A genetika MeSH
myši MeSH
zvířata MeSH
Check Tag
myši MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH
Research Support, N.I.H., Extramural MeSH
Research Support, U.S. Gov't, Non-P.H.S. MeSH

Článek

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

Nature genetics. 2014 ; 46 (11) : 1187-96.

Nat Genet
ISSN 1546-1718
Medvik
Zdroj

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.