Scientific Abstract

The prevalence of inflammatory bowel disease (IBD) is high in North America, Northern Europe, and the United Kingdom, while both Crohn's disease and ulcerative colitis remain relatively rare in South America, Africa, and Asia. In analogy to other autoimmune diseases, IBD incidence has been steadily increasing in the developed world since 1950. The so called “hygiene hypothesis” rests on the idea that humans have evolved in a pathogen-replete environment that exerted a strong selective pressure on immune system genes; in industrialized societies, low exposure to environmental pathogens may result in unbalanced immune responses and eventually predispose to IBD and other autoimmune conditions. Several studies, mainly based on retrospective epidemiological surveys, have addressed the relevance of the hygiene hypothesis for IBD with contrasting results.

 

Our previous studies have indicated that a portion of IBD susceptibility alleles have been subjected to the selective pressure imposed by pathogens. In this project, we aim at addressing the relevance of pathogen-driven selective pressure on genes with a role in IBD and evaluate whether these analyses support the hygiene hypothesis or provide clues as to whether this same hypothesis should be modified to account for complex interactions among immune response genes and the different infectious agents humans have been long exposed to. Also, we aim at exploiting the selection signatures left on human genes by infectious agents in order to identify novel IBD susceptibility variants among genes that code for interactors of known loci involved in bowel inflammation.

 

As a further step in our project, genes and gene regions carrying variants subjected to pathogen-driven selection will be resequenced in three human populations with different ancestry. This procedure, in addition to allowing a comprehensive description of nucleotide variability at these loci, is expected to provide relevant information concerning the underlying selective regime and the location of the functional allele(s). We will then integrate these data with haplotype analysis and in vitro assays to prioritize variants/haplotypes that will be genotyped in a case/control association study.

 

The steps above are expected to result in the identification of novel IBD susceptibility loci and to provide information about causal variants within previously described IBD genes; also, the distribution of IBD risk alleles in populations with European, African, and Asian descent will be analyzed so as to gain better understanding of the relative contribution of genetic vs. environmental risk factors in IBD.

 

As a final step, the functional relationships among genes carrying variants significantly associated with IBD will be analyzed so as to define protein interaction networks. This represents the final goal of our projects as the identification of molecular networks can provide mechanistic hypotheses about the causes of the disease and relevant information on the potential points for therapeutic intervention (i.e., drug targets).