title: Crohn's disease loci are common targets of protozoa-driven selection.
abstract: Previous studies indicated that a few risk variants for autoimmune diseases are subject to pathogen-driven selection. Nonetheless, the proportion of risk loci that has been targeted by pathogens and the type of infectious agent(s) that exerted the strongest pressure remain to be evaluated. We assessed whether different pathogens exerted a pressure on known Crohn's disease (CD) risk variants and demonstrate that these single-nucleotide polymorphisms (SNPs) are preferential targets of protozoa-driven selection (P = 0.008). In particular, 19% of SNPs associated with CD have been subject to protozoa-driven selective pressure. Analysis of P values from genome-wide association studies (GWASs) and meta-analyses indicated that protozoan-selected SNPs display significantly stronger association with CD compared with nonselected variants. This same behavior was not observed for GWASs of other autoimmune diseases. Thus, we integrated selection signatures and meta-analysis results to prioritize five genic SNPs for replication in an Italian cohort. Three SNPs were significantly associated with CD risk, and combination with meta-analysis results yielded P values < 4 × 10(-6). The bona fide risk alleles are located in ARHGEF2, an interactor of NOD2, NSF, a gene involved in autophagy, and HEBP1, encoding a possible mediator of inflammation. Pathway analysis indicated that ARHGEF2 and NSF participate in a molecular network, which also contains VAMP3 (previously associated to CD) and is centered around miR-31 (known to be disregulated in CD). Thus, we show that protozoa-driven selective pressure had a major role in shaping predisposition to CD. We next used this information for the identification of three bona fide novel susceptibility loci.
authors: Bioinformatics Laboratory, Scientific Institute IRCCS E Medea, Bosisio Parini, LC, Italy.
authors: Rachele
authors: R
authors: Cagliani
authors: Uberto
authors: U
authors: Pozzoli
authors: Diego
authors: D
authors: Forni
authors: Andrea
authors: A
authors: Cassinotti
authors: Matteo
authors: M
authors: Fumagalli
authors: Matteo
authors: M
authors: Giani
authors: Maria
authors: M
authors: Fichera
authors: Marta
authors: M
authors: Lombardini
authors: Sandro
authors: S
authors: Ardizzone
authors: Rosanna
authors: R
authors: Asselta
authors: Roberto
authors: R
authors: de Franchis
authors: Stefania
authors: S
authors: Riva
authors: Mara
authors: M
authors: Biasin
authors: Giacomo P
authors: GP
authors: Comi
authors: Nereo
authors: N
authors: Bresolin
authors: Mario
authors: M
authors: Clerici
authors: Manuela
authors: M
authors: Sironi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D003424:Crohn Disease / Q000235:genetics*; D017125:Genes, Protozoan / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors; D012641:Selection, Genetic / Q000235:genetics; D051040:Vesicle-Associated Membrane Protein 3 / Q000235:genetics
chemical_list: C577356:ARHGEF2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D020662:Guanine Nucleotide Exchange Factors; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C101633:PA2G4 protein, human; D016601:RNA-Binding Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C494946:VAMP3 protein, human; D051040:Vesicle-Associated Membrane Protein 3