Journal Article

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

Choi, Murim, Tesar, Vladimir, Cusi, Daniele, Appel, Gerald, Viola, Battista Fabio, Pani, Antonello, Panzer, Ulf, Feehally, John, Prakash, Sindhuri, Izzi, Claudia, Floege, Jürgen, Wyatt, Robert J, Boland, Anne, Li, Yifu, Di Landro, Domenico, Kovacs, Tibor, Del Vecchio, Lucia, Caridi, Gianluca, Metzger, Marie, Amoroso, Antonio, Allegri, Landino, Chicca, Silvana, Lugani, Francesca, Battaglia, Giovanni Giorgio, Rauen, Thomas, Salvadori, Maurizio, Mignani, Renzo, Roszkowska-Blaim, Maria, Suzuki, Hitoshi, Hou, Ping, Pawlaczyk, Krzysztof, Caliskan, Yasar, Chen, Nan, Fasel, David, Delsante, Marco, Feriozzi, Sandro, Maixnerová, Dita, Garozzo, Maurizio, Ghiggeri, Gian Marco, Canaud, Guillaume, Maiorana, Mariarosa, Narita, Ichiei, Nagy, Judit, Zaniew, Marcin, Magistroni, Riccardo, Amore, Alessandro, Magnano, Andrea, Shapiro, Samantha, Sanna-Cherchi, Simone, Julian, Bruce A, Coppo, Rosanna, Galliani, Marco, Gale, Daniel, Marcantoni, Carmelita, Boer, Emanuela, Bodria, Monica, Stengel, Benedicte, Rocchietti, Marcella, Kiryluk, Krzysztof, Scolari, Francesco, Fischman, Clara, Salvi, Erika, Gharavi, Ali G, Barlassina, Cristin

2014

Overview

Ali Gharavi and colleagues report a genome-wide association analysis of IgA nephropathy in over 20,000 individuals of European and East Asian ancestry. They identify genome-wide significant signals at three new loci near VAV3 , CARD9 and ITGAM - ITGAX and correlations between genetic risk and pathogen diversity. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 49/22 / 631/208/205/2138 / 631/208/457 / 692/699/1585/2759/1522 / Age of Onset / Agriculture / Animal Genetics and Genomics / Asian Americans / Biomedicine / Biopsy / Cancer Research / CARD Signaling Adaptor Proteins - genetics / CD11b Antigen - genetics / Chromosomes / Gene Function / Genealogy / Genes / Genetic aspects / Genetic Loci - genetics / Genetic Pleiotropy - genetics / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Glomerulonephritis, IGA - genetics / Health aspects / HLA-D Antigens - genetics / Host-Pathogen Interactions - genetics / Human Genetics / Humans / Identification and classification / Immunity / Immunity - genetics / Intestines / Intestines - immunology / Intestines - parasitology / Kidney diseases / Life Sciences / Pathogenic microorganisms / Pathogens / Physiological aspects / Polymorphism, Single Nucleotide - genetics / Proto-Oncogene Proteins c-vav - genetics / Quantitative trait loci / Studies