Epidemiology, genes and inflammatory bowel diseases in childhood

Available online at www.sciencedirect.com

Digestive and Liver Disease 40 (2008) 3–11

Mini-Symposium

Epidemiology, genes and inflammatory bowel diseases in childhood M.B. de Mesquita a,1 , F. Civitelli a,1 , A. Levine b,∗,1 b

a Department of Pediatric Gastroenterology, University Hospital “La Sapienza”, Rome, Italy Pediatric Gastroenterology Unit and Molecular Biology Laboratory of the Wolfson Medical Center, Holon, Israel

Received 23 July 2007; accepted 26 July 2007 Available online 7 November 2007

Abstract There is evidence that inflammatory bowel disease is immunologically mediated and that genetic factors play an important aetiological role. The identification of disease susceptibility genes has led to significant progress in our understanding of the pathogenesis of Crohn’s disease. Genes linked to Crohn’s disease play critical roles in the normal function of the innate immune system, and genes linked to epithelial integrity may play a role in the pathogenesis of inflammatory bowel disease as well. However, the dynamic epidemiology of both Crohn’s disease and ulcerative colitis suggests that extrinsic environmental factors acting at the population level may be involved in their pathogenesis. These environmental factors may be responsible for the rising incidence of inflammatory bowel disease. © 2007 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Child; Crohn’s disease; Epidemiology; Ethnicity; Genes; IBD; Incidence; Ulcerative colitis

1. Introduction A sharp rise in the incidence of inflammatory bowel disease (IBD) has been observed in the western world since the early 1950s, making IBD the most common chronic inflammatory condition in this population after rheumatoid arthritis [1]. Epidemiological studies in IBD are important since various epidemiological data, (like differences in; occurrence between different age groups, geographic distribution and particularly changes in incidence over time within one area), can provide valuable insight into pathogenesis, associations, health burden and natural history of disease [2]. It is a general observation that the relative contribution of genetic (inherited) and environmental (acquired) factors is shifted more towards genes in younger patients and towards environment in the elderly patients. Therefore, the participation of young children in epidemiologic and genetic research is crucial to ∗ Corresponding author at: Sackler School of Medicine, Tel Aviv University, Paediatric Gastroenterology Unit, Wolfson Medical Center, POB 5, Holon 58100, Israel. Tel.: +972 3 5028808; fax: +972 3 5028807. E-mail address: [email protected] (A. Levine). 1 These authors contributed equally to this work.

understand the role of genetics and environmental factors in the development of IBD. The first and second parts of this review will focus on epidemiological aspects of childhood IBD and disease susceptibility genes, exploring their association with paediatric-onset IBD. Epidemiology of childhood IBD may provide badly needed information and is particularly important. Paediatric IBD patients in general have fewer co-morbid conditions and less surgical history and hence depict natural history of IBD much more accurately. Furthermore, parents are more readily accessible for genetic studies, which help to improve our understanding of IBD [3]. At present, IBD is fairly common in Western Europe, affecting 0.5–1.0% of the population during their lifetime. Childhood-onset IBD accounts for nearly 30% of total cases [2,4]. Although IBD is more common in the developed world than in the developing world, there are indications that in typically low-incidence areas southern Europe, the Middle East, eastern Asia, the Indian subcontinent, Latin America, and now Eastern Europe, more cases are being seen lately. These changes in incidence can only in part be explained by improvement in diagnosis or an increase in detection of sub-clinical disease, and suggest that environmental factors play a role in disease expression [5].

1590-8658/$30 © 2007 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi:10.1016/j.dld.2007.07.165

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In a recent very large prospective national study in the British Isles, the incidence of paediatric IBD per 100,000 per year was 3.1 (2.8–3.5) for Crohn’s disease (CD), 1.4 (1.2–1.7) for ulcerative colitis (UC) and 0.6 (0.5–0.8) for indeterminate colitis (where a clear distinction between CD and UC is not possible) [6]. Data from a U.S paediatric IBD consortium registry has shown a similar pattern [7]. Moreover up to 30% of all patients with IBD are diagnosed during childhood, they present closer to disease onset, thus identification of relevant environmental factors may be easier in a younger population in which duration of disease and exposure to risk factors can be more reliably determined. It is important but difficult to study the epidemiology of IBD in children, due to the variation of the upper age limit which varies between studies (14–17 years of age), the unusual higher prevalence of upper gastrointestinal involvement (as high as 55%) in some recent paediatric studies [8], because children frequently undergo routine gastroscopy even if upper GI symptoms are not present. In addition new diagnostic tools may lead to overinterpretation of IBD emergence (like small erosions during capsule endoscopy). To exclude this, new uniform criteria have been defined for the diagnosis of IBD in children by ESPGHAN, in its medical position paper [9].

2. Epidemiology and IBD 2.1. Changes in time Throughout the 1960s and onwards, an increasing number of incidence studies of both Crohn’s disease and ulcerative colitis have been published. As a whole most of these studies have been limited by the relatively small patient groups with data assembled retrospectively with incomplete case ascertainment and short time periods of follow up. However, some conclusions can be drawn, especially since in some parts of the world IBD incidence has been monitored prospectively by regularly repeated studies [1]. On balance these studies show a noticeable rise in the incidence of ulcerative colitis and Crohn’s disease after World War II, especially in the United States, Great Britain and Scandinavia. The increase in the incidence of ulcerative colitis precedes the increase in the incidence of Crohn’s disease with a time lag of approximately 15–20 years [10]. Assessing time trends in the incidence of both diseases, in most areas of the western world, the incidence of CD may now have reached a plateau, while the picture of UC which is less clear, mainly because of differences in case ascertainment, has shown little variation in the incidence during the past decades. Recent retrospective European studies and a single prospective population based survey from Great Britain have suggested that the incidence of IBD in children and adolescents has significantly increased over the last 35 years, as seen in adults. These paediatric studies also suggest that there has been a change in the patterns of disease, because the incidence of

CD has risen above that of UC [11,12]. The reason for the increase in incidence of CD is not clear. Though it could partly be due to the general greater awareness of Crohn’s disease with the advent of diagnostic accuracy, thus resulting in earlier diagnosis, it is indisputable that the increase is real. This notion is also supported by the increase in more severe cases. A report from Scotland described three-fold increase in childhood CD between 1968 and 1983, the incidence of UC remained unchanged during this period, which would seem to parallel the increase seen in adults. A similar increase in incidence was also reported from various other European countries such as Wales [13], North France [14], Brittany [15], Great Britain [12], Norway [16], Sweden [17] and the USA [18]. However, very recent data suggests that the incidence of CD may now have reached a plateau and the incidence of UC may be rising. 2.2. Incidence The geographical incidence of IBD in adults varies considerably. Most of the published data come from the United States and Western Europe. It is more common in developed more industrialized countries, the highest rates being reported in the Scandinavian countries and Scotland followed by England and Southern Europe [19]. The first and largest prospective study of childhood IBD to be reported so far was from the British Isles [12]. In this survey, 739 cases of paediatric IBD were identified prospectively for a period of 13 months, documenting an incidence of 5.2/100,000 children aged less than 16 years per year. Another study found that the incidence of paediatriconset Crohn’s disease in Scotland increased by 30% between 1983 and 1995, and although less markedly, the reported incidence of paediatric-onset ulcerative colitis also increased [20]. Several other recent studies have reported incidences of childhood IBD from various other parts of Europe and USA including Sweden [17], Netherlands [21], Iceland [22], France [14], Copenhagen and Wisconsin, USA [18]. Direct comparison of results of these studies is difficult due to difference in study design, population size, age groups and time periods [23]. And many of these studies simply compare crude incidence rates over time or place. Longitudinal series of patients with IBD outside the western world are rare. Available data usually come from case reports and small, hospital-based series and are biased by methodological shortcomings. The general impression one gets from these publications is that IBD is not frequently observed in most of these areas [2]. Adult studies show that rates from Eastern Europe are very similar to those found in Western Europe during the 1940s and 1950s, with the increase of UC incidence preceding that of CD. Following the temporal trends in these areas during the coming years should prove to be of great interest, as this may shed some light on the role of environmental factors – particularly in this part of the world, which lifestyle, including the diet is becoming

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“westernized” quite rapidly – in the aetiology of IBD [2]. In Eastern Europe, a recent study reported a marked increase in the incidence of paediatric CD in the Czech Republic [24]. The same trend has been reported from Melbourne Australia [25]. Rates for Japan suggest that this Asian population is now affected with approximately equal frequency as western populations with regard to ulcerative colitis; Crohn’s disease, in contrast, is still less common [26]. Although IBD is uncommon in Asian children, a recent study from Taiwan reported 17 children diagnosed with IBD [27]. The prevalence of Crohn’s disease in the Chinese populations in Hong Kong and Singapore appears to be increasing, and more cases have also been observed lately in central China [28–30]. A recent very large, well-conducted prospective, adult study from Punjab by Sood et al. found that the incidence of UC among this population might be similar to that in the UK [31]. In 1999, Mehta et al. from India reported that in their experience, 5% of children admitted for colonic disorders were diagnosed as UC. A half century later, history appears to be repeating itself across the globe, the Asian Pacific region showing a rise in the rate of IBD, with a predominance of UC cases early and a rise in CD approximately 1 decade later, mimicking the mid1990s explosion of IBD in European countries [32]. This could be due to a greater awareness, and better availability of health care and/or improved study methods. However, it may also be a real increase, reflecting changing environmental factors [2]. The incidence of IBD in developing countries has been postulated as being low but data is limited. There are few cases from other parts of Asia and Africa, with the exception of South Africa [33,34]. IBD also seems to be uncommon in Central and South America and Cuba [35]. Prospective studies in children from the developing countries are very much needed. 2.3. Ethnicity The distribution of IBD among ethnic and racial groups remains dynamic. It is known that the incidence differs among different ethnic groups living in the same geographic region. This fact is mostly observed in Asian countries [32,36]. Epidemiological studies have reported highest prevalence rates of IBD in people of Caucasian and Ashkenazi Jewish origin [37,38], lower rates in Black Americans and Hispanics, with the lowest rates in Asians. These data should be interpreted with caution: the incidence of UC in Asian populations residing in western countries appears to be higher than that in native population both in children and adults [39]. In paediatric IBD, the recent data from British Isles have shown that significantly greater proportion of children of Asian origin feature among the under 5s with UC (25% vs. 6%) with a relative risk of 3.9. This may reflect a greater genetic predisposition to IBD in Asians that is uncovered by exposure to environmental factors. Racial gaps are closing with an increasing true incidence of both UC and CD in diverse

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minority populations [40]. Overall evidence from literature indicates that environmental factors, not genetics with ethnicity as a proxy, are the major driving factor for the increase in incidence over time [10]. 2.4. Geographic differences A north–south gradient was recently reported for the incidence of juvenile-onset Crohn’s disease in Scotland [41]. Several well-designed epidemiologic studies have supported the presence of a north–south gradient in the incidence of IBD within North America and Europe [42], although a larger study carried out by the European Collaborative Study Group on IBD (EC-IBD), including 20 different European centres indicated however that the observed excess in northern centres was less than previously suggested. This might reflect recent increases in the incidence of IBD in southern Europe, whereas those in the north may have stabilized. However, the uniform study design may also be partly responsible for narrowing the gap. Contrasting data exist regarding an association between differences in socio-economic status or education and incidence rates of IBD [10,42–44]. Interestingly, there was a strong positive relation between incidence of disease, gross national product (GNP) and northern latitude [2]. However no data exist regarding the more relevant factor; the economic status of the patient’s family during childhood [40]. Furthermore, it is worth pointing out that socio-economic status is not a biologic relevant exposure as such. It stands for differences in diet, crowding and hygiene, exposures that change over time in a society [10]. There may be geographic variations in the subtype of IBD. In the UK and USA, the incidence of childhood CD exceeds that of UC, similar to overall population data. However, in Sweden and Netherlands, paediatric UC may be more common than CD although in the case of Sweden, the pattern may be changing with CD now becoming more common [17,21,45,46]. 2.5. Demographic influence Not only is the number of paediatric IBD patients steadily increasing but also affected children are increasingly younger. Although both UC and CD are rare below the age of 11 years, it is well established that both CD and UC can occur in children younger than 10 years [7,14,47–50]. The incidence of these diseases increase rapidly after puberty, peaking at about 14 years of age, and further increase in adolescence and young adulthood [23]. The finding of a higher percentage of boys compared with girls diagnosed with CD in the paediatric setting, contrasts with the slight female preponderance of CD seen in the adult populations [14,51]. The inversion of the sex ratio for CD among children compared with adults could indicate that intrinsic age-related factors (like hormonal changes related to age) could play a role in the cause of CD [14]. In contrast to CD, paediatric-onset UC has equal sex ratio.

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A lower incidence of UC compared with CD was observed in most paediatric studies [14]. But within the group of paediatric IBD, a study from the British Isles and of IBD in American children, confirmed recently by a study of Heyman et al., showing that early-onset disease (under 5 years of age) appears to have different characteristics with UC predominating over CD. Furthermore, early-onset IBD seems to be characterised by predominance of colonic disease (UC, IC or Crohn’s colitis) [7,52]. Polito et al. reported the proportion of patients with relatives affected with IBD according to the age at diagnosis in the proband, showing that the younger the age of onset, the higher the rate of family history of IBD. Thirty percent of patients diagnosed under age 20 years had a positive family history, decreasing to 18% for those diagnosed between 20 and 39 years of age, and to 13% among those diagnosed after 40 years [53]. A positive family history of IBD in siblings or parents was associated with a 75% increase in the risk of early-onset IBD [7], suggesting that genetic susceptibility is playing a greater role in the development of the disease in early-onset IBD [23]. An explanation that has been suggested for the increasing incidence of IBD over the longer term is genetic anticipation. It is argued that these genomic changes result in more severe disease manifestation and an earlier age of onset through mechanisms such as expansion of unstable genomic triple repeats between successive generations [54]. 2.6. Environmental factors in paediatric-onset IBD The hypothesis that exposure to a specific infectious agent could predispose to IBD was put forward as early as 1913, when Dalziel proposed Mycobacterium paratuberculosis as the agent for Crohn’s disease [55]. Since then, smoking, appendicitis, gastrointestinal infections, bottle feeding, and better hygiene during childhood have been implicated as risk factors or protective factors for UC and CD [56–58]. Improved hygiene accompanied by a decrease in chronic infestations and reduced morbidity during childhood has been implicated as a possible cause of many autoimmune diseases. This is often referred to as the hygiene hypothesis. The hygiene hypothesis suggests that persons with higher living standards may be protected from childhood infections because of cleaner environments and smaller households, resulting in altered immune response in genetically susceptible hosts. Furthermore infections acquired during the immediate perinatal period or early infancy may establish aberrant immune responses to microbes encountered at a later time, while early-to-mid-childhood infections may promote tolerance to like organisms. Evidence for this hypothesis is conflicting at present [59–61]. Recent large epidemiologic studies have documented in increase in IBD after documented gastrointestinal infections [62]. A paper by Sorenen et al., found seasonal variation by birth month for risk of paediatric-onset Crohn’s disease in Denmark, with a peak occurring in late sum-

mer/autumn births, in contradiction with an earlier British study [46,63]. The importance of environmental factors is reinforced by the shift in incidence from high socio-economic strata in the population to the absence of such an association, and the disappearance of the previously noted north–south gradient. An obvious line of investigation for future research is therefore to follow what happens in low incidence areas such as Asia or Eastern Europe as they become increasingly exposed to western life styles [10].

3. Genes and IBD Genetic susceptibility plays an important role in the pathogenesis of both Crohn’s disease and ulcerative colitis. These diseases have long been recognized to occur more often in families and in certain ethnic groups such as Jews of Eastern European ancestry (Ashkenazi Jews). Up to 22% of patients with CD may have a family member with CD [64]. The strongest evidence for a genetic basis for familial disease came from twin studies. Concordance for CD ranges from 36 to 48% in monozygotic twins, but only in 4% of dizygotic twins [65–67]. In UC, concordance rates for monozygotic twins are low, ranging around 16% in these studies. The prevalent hypothesis for IBD pathogenesis is CD and UC are related polygenic diseases that may share some but not all susceptibility genes. Furthermore, differences in disease phenotype and behaviour may be due to differences in susceptibility genes, or in disease modifying genes. Identification of susceptibility genes has become a major goal for IBD research. Identifying these genes may enable us to understand the pathogenesis of the disease, to identify genotype–phenotype associations, to find surrogate markers that help identify subtypes of the disease that may have a different disease behaviour and thus require different management strategies, and to develop new treatment modalities. Advances in our understanding of susceptibility genes have been derived from two major sources, genome wide screening and case control studies using candidate genes. In both methods, the frequency of a mutation or haplotype are compared between a control population and patients with IBD, CD or UC. A second methodology for confirming disease susceptibility of a gene with one of theses diseases is by testing for transmission disequilibrium in familial disease (showing that the suspected allele is transferred to family members with the disease). In the following sections of this review we will explore our present knowledge of disease susceptibility genes, and the association between these genes and paediatric-onset IBD. Since paediatric data regarding genetic associations with UC are lacking, the focus will be on genetic aspects of CD or IBD in general. At present, validated susceptibility genes or loci fall into several categories of genes. The first category includes defects in genes associated with the innate immune system.

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The genes identified so far play critical roles in identifying bacterial invasion of the epithelium, regulating the response to bacteria, or management of intracellular bacteria. The second category includes genes which may be associated with epithelial integrity or protection against xenobiotics. 3.1. NOD2/CARD15 The first breakthrough in our understanding of the genetic basis for CD occurred in 2001, with identification of the NOD2/CARD15 gene in the pericentromeric region of chromosome 16 [68–70]. The gene encodes for a cytosolic pattern recognition receptor which under normal circumstances becomes activated by a bacterial peptidoglycan product, muramyl dipeptide, leading to activation of NFkappaB [71]. One of three mutations (R702W, G908R, L1007fsinsC) in the leucine rich repeat binding region, leading to loss of function, may be associated with CD. NOD2/CARD15 mutations may be found in 30–43% of European, Jewish or Caucasian North American CD patients [68–72]. These mutations are less common in patients with CD from Scotland, Ireland and Scandinavia [73,74]. The odds ratio for developing the disease is 2–4 for a single mutation, and between 17 and 44 for carriage of two mutations, with the highest risk being found with the L1007fsinsC variant [75]. The risk for developing the disease in a healthy individual with homozygous mutations has been estimated to be 1/25, and exceedingly uncommon for individuals with a single mutation. Mutations in NOD2/CARD15 have been clearly associated with ileal disease and inversely associated with colitis. They are also associated with the anti-sacchromyces cervisae antibody (ASCA) positivity. Though several studies have found an association with stricturing disease, recent data question this association [76–80]. These mutations cause loss of function. The mechanism by which loss of function in a pathway that triggers NFkappaB leads to a disease characterized by excessive activation of NFkappaB and a subsequent TH1/TH17 response remains enigmatic. Proposed theories with contradictory studies have included excessive activation of NFkappa B via the Toll like receptor 2 pathway [81–85], and decreased apoptosis of dendritic cells leading to ongoing stimulation of the adaptive immune response [86]. Studies in paediatric cohorts have replicated the importance of the NOD2/CARD15 gene as a susceptibility gene in paediatric-onset CD as well [87–91]. Earlier studies indicating that mutations in the NOD2/CARD15 gene may be linked to an earlier age of onset [92] were not reproduced in a subsequent study in the same population [93]. A recent multinational cohort involving over 700 patients from three countries with CD, and a high allele frequency for NOD2/CARD15 mutations did not find a role for NOD2/CARD15 on age of onset [52].

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3.2. IBD5 locus The second important disease susceptibility loci, termed the IBD5 locus, was found on Chromosome 5. This locus has been linked to susceptibility in Caucasian populations but not in Jewish cohorts [94–99]. Identification of the causal gene has been hampered by the large number of genes in the region coupled with tight linkage disequilibrium. Peltekova et al. identified a haplotype involving two genes within the IBD5 locus. The genes initially thought to be involved were the organic cationic transporter genes OCTN1 (SLC22A41672C/T) and OCTN2 (SLC22A5-207G/C) [90], and the TC haplotype has been associated with CD [97]. However subsequent studies have cast doubt whether this association is due to these SNP’s or haplotype, or due to linkage to alternative genes in the loci. Thus, the actual genes involved in susceptibility remain to be determined. Various phenotypic characteristics have been reported but not validated in other cohorts, most notably the association with perianal disease [99]. A recent study focused on identifying factors associated with perianal disease [38] in a Jewish cohort did not find any association between the TC haplotype and perianal disease. Paediatric data have confirmed susceptibility in paediatric cohorts from the U.S., Scotland and Canada, but not in Italian and Israeli cohorts, emphasizing that the effect of the IBD5 locus appears to be different in various ethnic groups [8,88,100]. To date, there does not appear to be any effect of this gene on age of onset or site of disease in paediatric cohorts. 3.3. Toll-like receptor 4 (TLR4) Intestinal epithelial cells express toll like receptors which are an integral part of the innate immune system. After the discovery of the NOD2/CARD15 gene as a susceptibility gene, other candidate genes in the innate immune system were evaluated for an association with IBD primarily by case control studies. A key player in the innate immune response to bacteria is TLR4, which binds lipopolysaccharide, and activates NFkappaB. The Asp299Gly mutation is a loss of function mutation in the leucine rich repeat area of the TLR4 gene, and is in linkage disequilibrium with the Thr399ile polymorphism. Several studies have found an association between the Asp299Gly mutation and CD [101,102]. The association has been found in populations from Belgium, Holland, Canada, Italy and Israel, but not in the Scottish or Hungarian population [89,101,102]. This association has also been found in paediatric CD cohorts from Belgium, Italy, Canada and Israel. It does not appear to affect age of onset, but may be associated with colonic disease in the paediatric population. The odds ratio for developing CD with the Asp299Gly mutation in the Belgian cohort was identical to the risk for NOD2/CARD15. Since the TLR4 mutation did not show up in several large genome wide screened cohorts, it may be a susceptibility gene

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only in certain ethnic groups, or a source of spontaneous as opposed to familial CD. 3.4. Disc large homolog 5 gene (DLG5) A genome-wide scan in European patients with inflammatory bowel disease identified a disease locus on chromosome 10. The Drosophilia discs large homologe gene (DLG5) is postulated to have a role in maintenance of epithelial cells, and mutations within the gene have been linked to increased gut permeability. Conflicting results from different cohorts may indicate that if DLG5 is a susceptibility gene, considerable ethnic variability may be present. Subsequently, Friedrichs et al. described gender distortion in the transmission of the variant allele in CD [103]. This group found that the R30Q variant is a susceptibility factor for Crohn’s disease in men but not in women, indicating that gender may serve as a confounding factor, DLG5 is a susceptibility gene, it confers only a very modest risk for CD [103,104]. Recent paediatric data have added to the confusion. While case control studies in the Scottish and Italian cohorts did not find an association with CD, a recent study in a paediatric population confirmed the association between DLG5 and CD in males [104]. Interestingly, this was shown in a case control group but not by transmission dysequilibrium test (TDT). This data was subsequently replicated in a Scottish paediatric cohort. This data may suggest that DLG5 is a minor susceptibility gene, or that it may act primarily as a disease-modifying gene. 3.5. IBD3 locus-TNFalpha promoter and HLA genes One of the first sites identified on genome wide scans was the IBD3 locus on chromosome 6 p. This locus unfortunately is one of the most gene-dense regions, characterized by strong linkage disequilibrium. The strongest candidates in this region are the HLA genes and TNF alpha promoter gene. Preliminary evidence has suggested a role for this locus with site of disease. A phenotype characterized by Crohn’s colitis has been attributed to both variants in the HLADRB1*0103 allele and TNF alpha promoter [64,76,93,105,106]. Paediatric data from Israel have suggested that TNF alpha promoter variants may be associated with paediatric- (as opposed to adult) onset, but substantiation of these findings awaits confirmation in other cohorts [93]. 3.6. New candidate susceptibilty genes Two recently published studies have cast light on the effect of additional genes on disease susceptibility. A mutation in the IL23 receptor was recently identified by genome wide screening to have a protective effect. This mutation was less frequent in patients with CD than in a control population. The second gene identified in 2006–2007 to be associated with CD, in this case in a cohort from Germany and the UK, using genome wide screening, was the autophagyrelated 16 like 1 (ATG16L1) gene. Hampe and colleagues

evaluated 735 cases, and replicated their findings in 380 independent trios. The gene product appears to play a role in autophagy of intracellular bacteria, thus having biological plausibility as a susceptibility gene. Paediatric data have confirmed the protective effect of the IL23 receptor variant in North American and Israeli children, but paediatric data for the ATG16 variant have not been published as yet [107].

4. Conclusion There is evidence that IBD is immunologically mediated and that genetic factors play an important aetiological role. However, the dynamic epidemiology of both conditions suggests that extrinsic environmental factors acting at the population level may be involved in its pathogenesis. Furthermore, the remarkable increase in the incidence of IBD, and CD in particular, during the last half century points to changes in the environment, since genetic variations are negligible in such a short period of time, and the “hygiene hypothesis” of allergic and autoimmune diseases has been invoked to explain the world-wide spreading of IBD, also in non-western parts of the world as Asia and South-America. Identification of susceptibility genes has highlighted the importance of the innate immune system, and specifically, abnormal detection or handling of gut bacteria as a cause for Crohn’s disease. If we are to prevent IBD, we clearly need to be able to identify the enigmatic environmental factors that cause the disease. Soundly designed and carefully conducted epidemiological studies will be necessary to help confirm or refute these environmental factors, and to allow us to fully comprehend the complex interplay between environmental and genetic risk factors that underlie the pathogenesis of the disease.

Practice points • The increasing incidence and prevalence of paediatric IBD appear to be rising, This is being driven by as yet unidentified environmental factors. • Factors associated with paediatric-onset and especially early-onset Crohn’s disease, include a positive family history, male gender and presentation with colonic involvement. • Genes linked to Crohn’s disease are play critical roles in identifying bacterial invasion of the epithelium, regulating the response to bacteria, or management of intracellular bacteria. These include NOD2/CARD15, Toll like receptor 4, the IL23 receptor, TNF alpha promoter and the ATG16L1 autophagy gene.

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Research agenda • Soundly designed prospective epidemiological studies are urgently required in order to identify the responsible environmental factors. • Genome wide screening should be targeted to identify genes that may be associated with early-onset paediatric disease.

Conflicts of interest statement None declared.

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