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.

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

BERTINETTO, FRANCESCA;AMOROSO, Antonio;Peruzzi L;
2014-01-01

Abstract

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.
2014
46
1187
1196
http://www.nature.com/ng/journal/v46/n11/full/ng.3118.html
Ig Nephropathy; GWAS; Genetics
Kiryluk K;Li Y;Scolari F;Sanna-Cherchi S;Choi M;Verbitsky M;Fasel D;Lata S;Prakash S;Shapiro S;Fischman C;Snyder HJ;Appel G;Izzi C;Viola BF;Dallera N;Del Vecchio L;Barlassina C;Salvi E;Bertinetto FE;Amoroso A;Savoldi S;Rocchietti M;Amore A;Peruzzi L;Coppo R;Salvadori M;Ravani P;Magistroni R;Ghiggeri GM;Caridi G;Bodria M;Lugani F;Allegri L;Delsante M;Maiorana M;Magnano A;Frasca G;Boer E;Boscutti G;Ponticelli C;Mignani R;Marcantoni C;Di Landro D;Santoro D;Pani A;Polci R;Feriozzi S;Chicca S;Galliani M;Gigante M;Gesualdo L;Zamboli P;Battaglia GG;Garozzo M;Maixnerová D;Tesar V;Eitner F;Rauen T;Floege J;Kovacs T;Nagy J;Mucha K;Pączek L;Zaniew M;Mizerska-Wasiak M;Roszkowska-Blaim M;Pawlaczyk K;Gale D;Barratt J;Thibaudin L;Berthoux F;Canaud G;Boland A;Metzger M;Panzer U;Suzuki H;Goto S;Narita I;Caliskan Y;Xie J;Hou P;Chen N;Zhang H;Wyatt RJ;Novak J;Julian BA;Feehally J;Stengel B;Cusi D;Lifton RP;Gharavi AG
File in questo prodotto:
File Dimensione Formato  
copertinaKiryluk2014nihms630801.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.28 MB
Formato Adobe PDF
1.28 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/149845
Citazioni
  • ???jsp.display-item.citation.pmc??? 259
  • Scopus 449
  • ???jsp.display-item.citation.isi??? 420
social impact