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.

Cagliani, R., Pozzoli, U., Forni, D., Cassinotti, A., Fumagalli, M., Giani, M., et al. (2013). Crohn's Disease Loci Are Common Targets of Protozoa-Driven Selection. MOLECULAR BIOLOGY AND EVOLUTION, 30(5), 1077-1087 [10.1093/molbev/mst020].

Crohn's Disease Loci Are Common Targets of Protozoa-Driven Selection

Sironi M
2013

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.
Articolo in rivista - Articolo scientifico
Crohn's disease; GWAS; pathogen-driven selection; protozoa;
English
2013
30
5
1077
1087
reserved
Cagliani, R., Pozzoli, U., Forni, D., Cassinotti, A., Fumagalli, M., Giani, M., et al. (2013). Crohn's Disease Loci Are Common Targets of Protozoa-Driven Selection. MOLECULAR BIOLOGY AND EVOLUTION, 30(5), 1077-1087 [10.1093/molbev/mst020].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/513382
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