Molecular genetics of Crohn’s disease

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Abstract

Progress in the genetics of complex diseases has been slow over the past two decades compared to many simple Mendelian traits. However, rapid advances are now being made in inflammatory bowel disease genetics, leading already to identification of the first gene linked to Crohn’s disease susceptibility: NOD2/CARD15. Since its discovery three years ago, there has been replication of the association of NOD2/CARD15 mutations with Crohn’s disease in many populations, together with identification of phenotypic correlations. Functional studies promise to increase understanding of the primary pathophysiology involved in Crohn’s disease and these discoveries may yet change clinical practice.

Introduction

The inflammatory bowel diseases (IBDs) Crohn’s disease (CD; OMIM 266600) and ulcerative colitis (UC; OMIM 191390) are common causes of chronic gastrointestinal disease in the developed world, with reported prevalence rates of 1 in 250 in Northern European populations [1]. The diseases are particularly common in young people and have a major effect on quality of life. Whereas UC is characterised by a continuous distribution of mucosal/submucosal inflammation within the colon, CD may result in focal areas of disease in any part of the gastrointestinal tract from the mouth to the anus. The inflammation is transmural and almost inevitably progresses over time, often leading to stricturing or fistulising complications [2]. Extra-intestinal complications affecting eyes, skin and joints occur in both illnesses.

The pathogenesis of CD is complex and both environmental and genetic factors contribute to its aetiology. Familial clustering of disease, ethnic variability and twin studies provide conclusive evidence for the presence of genetic determinants of susceptibility and progression [3]. There is widespread disease heterogeneity in disease phenotype — disease location, age of onset, need for surgery, behaviour, extraintestinal manifestations — and the subclassification of the disease by phenotypic characteristics has remained controversial [4]. Nonetheless it seems likely that the phenotypic heterogeneity reflects extensive genetic heterogeneity, and that the term ‘Crohn’s disease’ may represent a number of closely related multifactorial diseases [5].

The complementary techniques of candidate gene analysis and genome-wide scanning (GWS) have been used to identify genes that influence disease susceptibility and progression in CD. The candidate genes studied to date have been prioritised on the basis of functional and pathobiological relevance and the results of the linkage studies. Candidate gene studies have involved linkage analysis, case control studies and family-based transmission disequilibrium testing [3].

Section snippets

Genome wide scans in Crohn’s disease

The success of GWS in replicating regions of linkage in relative pairs with CD has at least matched the progress in many other common complex diseases. There have been eleven scans for CD since 1996 and a much larger number of replication studies. A summary of the GWS appears in Table 1 and Figure 1. Using the criteria set out by Lander and Kruglyak [6] (Table 2) four chromosomal regions show confirmed linkage to CD.

IBD1: from linkage region to gene identification

In the first study reported, Hugot et al. used a two-stage approach to demonstrate the first CD susceptibility locus on chromosome 16q12: IBD1 (OMIM 605956) [7]. The first stage identified linkage in three areas on chromosome 16 and in the second stage in a separate patient group, two of the markers demonstrated linkage with a p value of <0.01. Despite the relatively low lod score in the initial study, this locus was successfully replicated in different populations throughout the world. The

Population genetics

Many studies have addressed the allele frequencies of the NOD2/CARD15 mutations in selected CD populations throughout the world (Table 3). The NOD2/CARD15 mutations are absent in Asian CD populations and controls [13], whilst the highest recorded frequencies are reported in a small study of 55 paediatric patients in Europe with two thirds of the patients having at least one NOD2/CARD15 mutation [14]. Within Europe, there is evidence of a north–south gradient with lower allele frequencies in the

NOD2/CARD15 expression

The expression of NOD2/CARD15 was originally thought to be confined to cells of the monocyte lineage but it is now clear that expression is also found in primary epithelial cells in culture and intestinal epithelial cells in the small and large intestine 22., 23.. Within the intestinal epithelium, NOD2/CARD15 expression appears to be highest in the specialised epithelial Paneth cells [24], which are located in the crypts of the small intestine and secrete a number of anti-bacterial substances

NOD2/CARD15 structure

The NOD2/CARD15 protein (Figure 2) contains two N-terminal CARDs that are involved in protein–protein interactions, a centrally located nucleotide-binding domain that mediates self oligomerisation; at the C terminus are the LRR domains that are important for bacterial binding. NOD2/CARD15 shares sequence homology in the nucleotide-binding and LRR domains with a wider family of ∼20 proteins that are involved in apoptosis and inflammation collectively known as the CATERPILLER (‘CARD transcription

Animal models

A murine NOD2/CARD15 clone has been developed and shares common features with human NOD2/CARD15 [32]. The structure of the murine gene is similar to human, it stimulates NF-κB within the cell, it is expressed in most mouse cell lines and NOD2/CARD15 mRNA levels increase in response to LPS and TNF-α/IFN-γ. A NOD2/CARD15 knockout mouse model has also been developed [33]. These NOD2−/− mice do not develop intestinal pathology, and in fact are more likely to survive endotoxin challenge at high

Other replicated regions: IBD2–6

In the only GWS of IBD susceptibility performed to date in the UK, Satsangi et al. [34] demonstrated a susceptibility locus for both CD and UC on chromosome 12p13: IBD2 (OMIM 601458). A lod score of 5.47 was achieved. In the IBD consortium study that presented convincing evidence for IBD1, the IBD2 locus achieved a lod score of only 1.2 in CD [8], it is now generally accepted that IBD2 may be more strongly involved in UC than CD [35].

The chromosome 6p21 locus that involves the major

Conclusions

The discovery of a susceptibility gene for CD heralds a new era in understanding the pathophysiology of this disease and, moreover, has provided valued proof of principle for positional cloning strategies in complex diseases. Many key research areas still need to be addressed (Box 1): these include identification of novel CD susceptibility genes, NOD2/CARD15 stratified GWS, studies of NOD2/CARD in childhood populations, examination of the role of homologous NOD2/CARD15 family members as well as

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

RK Russell is supported by the University of Edinburgh Medical Faculty Fellowship. ER Nimmo is supported by the Wellcome trust.

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