The long and winding road: from genetic risk factors to the understanding of disease-pathogenesis in Crohn’s disease

Abstract

Crohn’s disease (CD) is a chronic, relapsing inflammatory disorder of the intestinal mucosa usually starting in young adults, causing a life-long burden for the patients. CD may occur anywhere in the gut from the mouth to the anus. Currently 80% of the patients must undergo at least one (often disabling) surgical removal of an intestinal segment [1]. Given the extent of morbidity and the unsatisfactory treatments available, research on pathogenesis as well as factors triggering disease flares is intense. In addition, CD has become a “prototype disease” for chronic autoinflammatory disorders with a polygenic background and multi-facetted, environmental trigger components. Environmental factors contribute to both pathogenesis and disease flares. Therefore, CD is a disease par excellence to study the interactions between host genetics, environmental factors, and “in-vironmental” factors—for example, our intestinal microbiome which is under control of our innate immune system. We have entered a period of ‘systems medicine’ where the power of highly parallel sequencing and other ‘omic technologies can be used to interrogate the mechanisms of human disease. CD led the field of polygenic disease genetic susceptibility discovery through the identification of mutations of Nucleotide-binding Oligomerisation Domain protein 2 (NOD2; CARD15) in 2001 that confer susceptibility to CD [2]. Judy Cho’s group that now presents another interesting manuscript in “Genes and Immunity” was the first (together with another group) to demonstrate the impact of NOD2 variants [3, 4]. Interestingly, NOD2 is an innate immune receptor, a receptor for muramyl dipeptide—which is a component of the bacterial cell wall. NOD2 mutants associated with susceptibility to CD are deficient in their recognition of bacterial wall products. Pattern recognition receptors are highly expressed in intestinal macrophages and epithelial cells—pointing to the importance of microbiota recognition by cells of the intestinal innate immune system [5]. During the last 15 years, tremendous advances have been made in determining further genetic risk factors for IBD. So far, more than 170 genetic risk factors have been identified [6]. Many IBD loci are shared with other inflammatory diseases, such as ankylosing spondylitis, psoriasis, diabetes, or lupus [7]. Whilst alterations in the human genome coding relevant variant protein products have most likely not emerged significantly over the last 50 years, the incidence of CD has dramatically increased in Western countries [8] and more recently in the Asian-Pacific area [9]. Unfortunately, the determination of the presence of risk genes does not allow predicting disease courses or clinical phenotypes in CD patients. Genotyping is not sufficient to understand the pathogenesis of CD. Functional impact for innate and adaptive immunity has been studied for a number of specific genetic variants; however, the selection usually was arbitrary. Gettler and co-workers in this issue of “Genes and Immunity” have used an “unbiased approach”. They used a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets (RNA-Seq data only from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls). Transcriptome-wide associations and co-expression network analyses were performed on those ileal RNA-Seq datasets. By this approach, Judy Cho’s group identified 40 genome-wide significant genes. Further co-expression network analysis identified “a single gene module” that was highly enriched for CD-locus genes. This “gene module” was most highly expressed in monocytes/macrophages. The authors find “the marked enrichment of genes ... within monocytes compared to dendritic cells ...unexpected”. In fact, we do not. Monocytes/macrophages have been shown to be of central importance in CD pathogenesis in the past. With respect to * Gerhard Rogler [email protected]