Crohn's disease loci are common targets of protozoa-driven selection

Rachele Cagliani, Uberto Pozzoli, Diego Forni, Andrea Cassinotti, Matteo Fumagalli, Matteo Giani, Maria Fichera, Marta Lombardini, Sandro Ardizzone, Rosanna Asselta, Roberto De Franchis, Stefania Riva, Mara Biasin, Giacomo P. Comi, Nereo Bresolin, Mario Clerici, Manuela Sironi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1077-1087
Number of pages11
JournalMolecular Biology and Evolution
Volume30
Issue number5
DOIs
Publication statusPublished - May 2013

Keywords

  • Crohn's disease
  • GWAS
  • pathogen-driven selection
  • protozoa

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics

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