Genetic factors

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The genetic component of IBD was initially suggested by early reports of familial aggregation of these diseases. In 1934, Crohn and colleagues reported the first familial aggregation of CD. In the 1950s and 1960s many other groups confirmed that IBD are more familial than expected by chance. On average, 6-8% of UC patients and 8-10% of CD patients have at least one affected relative (for review see Russell and Satsangi, 2004). Interestingly, values as high as 20% or more have been reported in children, suggesting that either pediatric CD is more genetic or that familial environmental risk factors are important. The non-random distribution of the affected siblings within sibships with multiple cases strongly argues for the second hypothesis of an environmental factor shared by nuclear family members (Hugot et al., 2003b).

Pedigrees of IBD patients do not exhibit a Mendelian model of inheritance. The lifetime risk of developing IBD for first-degree relatives has been estimated from 1% to 10% with a lower risk for UC relatives (Russell and Satsangi, 2004). This large range of values is mainly explained by methodological differences between studies. Siblings of CD patients have the highest risk with an estimated sib risk ratio (Is) value from 25 to 42 (Bayless et al., 1996; Monsen et al., 1987; Peeters et al., 1996; Roth et al., 1989). The risk seems to decrease rapidly for more distant relatives with a risk tenfold lower in second-degree relatives and a risk comparable to the general population in third-degree relatives. On the basis of the pedigrees of IBD patients, segregation analyses were performed in the 1990s and proposed a major gene with dominant or recessive modes of inheritance in UC and CD respectively (Kuster et al., 1989; Monsen, 1990; Orholm et al., 1993).

The entire spectrum of IBD phenotypes may be encountered in familial cases. The phenotypic resemblance between affected relatives has been studied by many groups and most of them (but not all) retained a good concordance rate for age at onset and location of the disease between CD family members (Bayless et al., 1996; Colombel et al., 1996; Lee and Lennard-Jones, 1996; Satsangi et al., 1996a). This result may suggest that IBD consists of a group of several similar phenotypes under the control of several Mendelian genes. In fact, such an interpretation has to be modified by the fact that extreme phenotypes such as CD and UC are often encountered in the same families. In addition, limited reports on the offspring of couples with two IBD parents suggest a genetic link between UC and CD (Bennett et al., 1991; Laharie et al., 2001). Indeed, more than 50% of the offspring of these couples develop an IBD before their twentieth birthday (Bennett et al., 1991). Among them, the majority have a CD phenotype, even in the offspring of (CD/UC) and (UC/UC) couples. As a result, the rough concordance between affected relatives suggests some degree of genetic heterogeneity, which can also be seen at the phenotype level, but it does not allow a conclusion in favor of a patchwork of separate Mendelian disorders.

Genetic anticipation, the tendency for earlier presentation in successive generations, has been discussed in IBD following the initial report by Polito etal. (1996) that the age at onset (but not the severity) of the disease decreases by an average of 15 years with successive generations (Polito et al., 1996). This difference has been widely confirmed but the explanation underlying the observation is the subject of debate. In fact, follow-up time biases and/or secular trends in disease presentation have been put forward as explanations rather than genetic anticipation.

Many individual cases of concordant twins and even concordant monozygotic triplets have been reported (Purrmann et al., 1986). Twin studies performed on the basis of national registers are available from Sweden and Denmark ((Halfvarson et al., 2003; Orholm et al., 2000; Tysk et al., 1988) and Table 20.2). The concordance rate between monozygotic twins was estimated to be 50% in CD and 16% in UC arguing for an environmental

Table 20.2. Summary of the twin studies from Sweden and Denmark

Crohn's disease Ulcerative colitis Total cases

Monozygotes Dizygotes Monozygotes Dizygotes

Denmark 5/10 0/27 3/21 3/45 103

(Tysk et al., 1988; Halfvarson et al., 2003; Orholm et al., 2000).

component for both diseases with a stronger effect in UC than in CD. In contrast, the concordance rate between dizygotic twins was estimated to be 2% in CD and 5% in UC. As a result, by comparing the two categories of twins, a strong genetic component for CD and a weaker one for UC can be proposed. Such a conclusion is in accordance with the lower percentage of familial aggregation seen in UC (see above).

Numerous genetically engineered mice have been proposed as human IBD models (for review see Bouma and Strober, 2003 and Table 20.3). In fact, mouse knockouts for genes as varied as IL10, Gai2, NF-kB or N-cadherin lead to colitis. However, all of these models are not expected to be relevant to IBD and it appears more likely that colitis is a common phenotype in numerous disorders of the immune system or intestinal barrier. The mouse models most similar to CD are probably the SAMP1/Yit model and the mouse deleted for the Alu sequences of the TNFa promoter (TNFAARE) which both develop a spontaneous ileitis with granuloma formation (Matsumoto et al., 1998; Pizarro et al., 2003). Interestingly, numerous animal models have some common features with IBD, including modulation of the phenotype by the intestinal flora and the occurrence of adenomas in the inflammatory lesions. Unfortunately, it was not possible until recently to apply the findings provided by these animal models to the human disease.

On the bases of evidence from twin and familial studies, geneticists have tried to identify IBD susceptibility genes. Many studies focused on candidate genes, most of them being immune regulatory genes (see Hugot et al., 1999 and

Table 20.3. Genetically defined animal models developing a colitis

Knock-out mice

Transgenic animals

Spontaneous colitis









Trefoil peptide









MHC Class II


Table 20.4). Several associations have been found, most often in case-control studies. Unfortunately the majority of these associations were not confirmed in subsequent studies, making it difficult to understand if the first reports were false positive statistical results or genetic heterogeneity. Finally, many of the proposed associations were found with anonymous polymorphisms with no established functional effect. As a result, the literature on the candidate genes in IBD appears sometimes confusing and difficult to summarise. To date, the most convincing associations were reported for polymorphisms located in the major histocompatibility complex (where a linkage peak has also been demonstrated) and the Multidrug Resistance 1 gene (Brant et al., 2003; Yap et al., 2004).

Table 20.4. Functional candidate genes investigated in IBD

Candidate genes with

Investigated genes

an association reported

with no reported

at least once


HLA Class II








Vitamin D receptor









Interferon g



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