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Current Status of Genetics Research in Inflammatory Bowel Disease Genes and Immunity (2005) 6, 637–645 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene REVIEW Current status of genetics research in inflammatory bowel disease S Vermeire1 and P Rutgeerts1 1University Hospital Gasthuisberg Leuven, Division of Gastroenterology - Herestraat, Leuven, Belgium The research on genetic susceptibility of inflammatory bowel diseases (IBD) has been tremendous and over 10 chromosomal regions have been identified by genome-wide scanning. Further fine mapping as well as candidate gene studies have already led to the identification of a number of susceptibility genes including CARD15, DLG5, OCTN1 and 2, NOD1, HLA, and TLR4. The CARD15 gene is undoubtedly replicated most widely and most understood at present. CARD15 is involved in the recognition of bacterial peptidoglycan-derived muramyl dipeptide (MDP) and will stimulate secretion of antimicrobial peptides including alpha-defensins (also called cryptdins) to protect the host from invasion. Genetic research in IBD has advanced our understanding of the clinical heterogeneity of the disease and has started to tackle the complex interactions between genetic risk factors and environmental risk factors in IBD. Genes also interfere with the metabolization of drugs and may influence the clinical response and the drug-related toxicity. Interesting pharmacogenetic data with respect to steroids, azathioprine, and infliximab have been generated in IBD. Overall, it is anticipated that genetic markers in the future will be implemented in an integrated molecular diagnostic and prognostic approach of our patients. Genes and Immunity (2005) 6, 637–645. doi:10.1038/sj.gene.6364257; published online 18 August 2005 Keywords: inflammatory bowel disease; Crohn’s disease; ulcerative colitis; genetics Introduction Genetic epidemiology The inflammatory bowel diseases (IBD), Crohn’s disease Several lines of evidence suggest a genetic contribution (CD) and ulcerative colitis (UC) are chronic relapsing to the pathogenesis of IBD. First, there are considerable inflammatory diseases of the gastrointestinal tract. The differences in the prevalence of IBD among ethnic precise aetiology of the disease is unknown, but an groups.1,2 The highest prevalence is seen among Cauca- interplay of environmental risk factors and immunologic sians. Afro-American and Asian individuals carry a changes will trigger the onset of the disease in a much lower risk, although the incidence of IBD is rising genetically susceptible host. Epidemiological studies in even in these ethnic groups. The prevalence in the Jewish the past suggested a genetic susceptibility that has been population is two to four times higher than any other confirmed by molecular data from total genome scans and ethnic group and is independent from geographic from candidate gene studies. Since the start of genetics location and the period of analysis. The highest risk research in IBD 10 years ago, important progress has been is seen among Ashkenazi Jews, in comparison with made and a number of susceptibility genes have been Sephardic Oriental Jews. identified. These have further advanced researchers in Family studies have reported an important familial unravelling the pathophysiology of IBD. In this respect, association of the disease.3–5 Around 5.5–22.5% of the identification of the caspase-recruitment domain patients with IBD report having another family member (CARD)15 gene has underscored the importance of the also affected with IBD. In fact, the most important risk bacterial flora and has focused attention on the role of factor for IBD is having a family member with the pattern recognition receptors (PRRs) and other pathways disease. The relative risk for a sibling of a CD patient to of the innate immune system. The clinical impact of the also become affected is 13–36, and for a sibling of a UC genetic findings so far is situated in understanding the patient this risk is 7–17. The greatest risk appears for heterogeneity of IBD in terms of location, age at onset and children of whom both parents have IBD (430% at the behaviour, and also in predicting answer to and side age of 28 years).6 effects of particular treatments. Patients with IBD and a familial history tend to get their disease at an earlier age than patients without a familial history and show an increased Correspondence: Dr S Vermeire, University Hospital Gasthuisberg concordance in disease type (CD or UC) and probably Leuven, Division of Gastroenterology – Herestraat, Leuven 49 - 3000, Belgium. E-mail: [email protected] also disease location. The severity of the disease, in Received 11 July 2005; accepted 11 July 2005; published online 18 contrast, does not differ between familial or sporadic August 2005 disease. Current status of genetics research in IBD S Vermeire and P Rutgeerts 638 Twin studies provide solid evidence for the contribu- Candidate gene analysis uses case–control cohorts or tion of genetic and/or environmental factors.7–10 The fact trios of affected offspring with both parents. Here, that monozygotic twins with CD have a much higher authors will investigate a specific gene, which has a disease concordance (37%) than dizygotic twins (7%) known or potential interest for the disease under study. indicates that genetic factors play an important role. For The allelic frequencies (in the case of case–control study) UC, the concordance rates are less (10 vs 3% for or the transmission of a single-nucleotide polymorphism monozygotic and dizygotic twins, respectively), suggest- (SNP) towards affected offspring (in the case of trios) will ing a less important genetic impact, in comparison with be studied and differences between patients and controls CD. or an overtransmission towards affected children might A number of subclinical markers have been identified point towards implication of this particular gene in the in unaffected family members of IBD patients. These pathogenesis of the disease under investigation. markers might indicate who is at risk of developing The human genome contains approximately 10 million the disease or in whom early disease is already present. SNPs and its genetic sequence is organized in haplotypes The markers studied most are intestinal permeability, or stretches of DNA. SNPs that lie closely together ( ¼ on and a number of anti-microbial antibodies: anti-Sacchar- the same haplotype block) tend to be inherited together, omyces cerevisiae antibodies (ASCA) and atypical pANCA whereas SNPs in different haplotype blocks are less (perinuclear antineutrophil cytoplasmic antibodies).11–15 likely to be inherited together. Recently, an International Other microbial antibodies found in IBD patients as anti- Haplotype Mapping (HapMap) Consortium was estab- OmpC (directed against the outermembrane porin C of lished to develop a HapMap of the genome, with the Escherichia coli), I2 (antibodies directed against Pseudo- frequencies of common polymorphisms in the human monas fluorescens) and Cbir 1 (anti-flagellin antibodies) genome in various populations in the world and with the have not been studied in asymptomatic family mem- extent of linkage disequilibrium (LD) between these bers.16–18 However, the presence of these subclinical polymorphisms and the haplotype blocks in which they markers has no clinical implications yet and longitudinal fall.19 This information is freely available on the internet studies are needed first to evaluate their exact meaning. (http://www.hapmap.org/). Therefore, instead of geno- typing all SNPs in the genome, genotyping haplotype- tagging SNPs (which are representative of a unique Identification of susceptibility genes haplotype) will undoubtedly facilitate the identification of causal variants in complex diseases. for IBD Also, technology has advanced greatly and the Segregation studies have not supported a simple introduction of the so-called chip-arrays, containing up Mendelian model of inheritance for IBD. Instead, CD to 100 000 SNPs (with even larger chips being developed and UC are considered to be complex polygenic as we speak), has allowed high-throughput and high- disorders. This means that several genes, together with resolution genotyping of the whole genome. However, environmental factors, contribute to the final clinical the high costs and also the informatics to analyse these phenotype, which inevitably will be heterogeneous. How huge amount of data are at this moment the bottle neck many susceptibility genes underlie IBD and how they for wide-spread use of these techniques. interact with each other and with environmental factors is not precisely known, but the list of genes and environmental factors is growing each month. Since both Results from linkage and candidate gene forms of IBD can coexist in single families (and maybe analyses in IBD also in the same individual?) with a frequency greater than expected by chance alone, CD and UC are likely to A total of 11 total genome-wide scans have been share some susceptibility genes. Orholm et al3 showed performed in IBD (Table 1), resulting in a number of that the crossdisease relative risks are 3.85 for UC, given susceptibility regions on chromosomes 1, 3, 4, 5, 6, 7, 10, a CD proband and 1.72 conversely, further suggesting 12, 14, 16, 19 and X. 20–30 the presence of shared genes among CD and UC. According to their initial date of reporting, and However, also disease-specific genes will exist since CD independent confirmations, the regions on chromosomes and UC are also very distinct in clinical
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