Bioinformatics Laboratory, Scientific Institute IRCCS E Medea, Bosisio Parini, LC, Italy.
Mol Biol Evol. 2013 May;30(5):1077-87. doi: 10.1093/molbev/mst020. Epub 2013 Feb 6.
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.
先前的研究表明，一些自身免疫性疾病的风险变异体受到病原体驱动的选择。然而，仍有待评估病原体靶向的风险基因座的比例以及施加最强压力的传染病原的类型。我们评估了不同病原体是否对已知的克罗恩病（CD）风险变异体施加了压力，并证明这些单核苷酸多态性（SNP）是原生动物驱动选择的优先靶标（P = 0.008）。特别是，与 CD 相关的 19%的 SNP 受到原生动物驱动的选择压力。全基因组关联研究（GWAS）和荟萃分析的 P 值分析表明，与非选择变异体相比，原生动物选择的 SNP 与 CD 具有更强的相关性。其他自身免疫性疾病的 GWAS 未观察到相同的行为。因此，我们整合了选择特征和荟萃分析结果，以优先在意大利队列中对五个基因 SNP 进行复制。三个 SNP 与 CD 风险显著相关，并且与荟萃分析结果相结合，产生了 P 值<4×10(-6)。真正的风险等位基因位于 ARHGEF2 中，它是 NOD2 的相互作用物，NSF 是参与自噬的基因，HEBP1 编码炎症的可能介质。通路分析表明，ARHGEF2 和 NSF 参与了一个分子网络，该网络还包含 VAMP3（先前与 CD 相关），并以 miR-31 为中心（已知在 CD 中失调）。因此，我们表明，原生动物驱动的选择压力在塑造 CD 易感性方面发挥了重要作用。我们接下来利用这些信息确定了三个真正的新易感基因座。
