Genetics of Inflammatory Bowel Disease

Jean-Paul Achkar, MD, Bret A. Lashner, MD, Cleveland Clinic Foundation, Cleveland, Ohio


April 19, 2002

In This Article

Genotypic and Phenotypic Heterogeneity: CD as an Example

It is likely that IBD is not a single disease entity, but rather comprises several disorders that share clinical features. Evidence for genetic heterogeneity in IBD comes in part from the varying results of genetic linkage mapping studies.[13,14,15,16,17,18,19,20,21,22,23] The detection of linkage to established IBD susceptibility loci in some but not all study populations is likely due at least to genetic heterogeneity. Furthermore, genetic heterogeneity within CD clearly exists at the NOD2 and the chromosome 5q loci, because only a minority of patients with CD have the identified CD-associated mutations.[23,36,38] Data from 3 published studies demonstrate that NOD2 variants are found in only 20% to 30% of CD patients.[36,37,38] Similarly, Rioux and colleagues[23] found that 5q locus mutations contributed to CD susceptibility principally in families with young age of CD onset. What is the implication of these findings? The implication is that there are likely other, as yet unidentified CD susceptibility genes that will account for the remaining cases of CD.

Since the original description in 1932 by Crohn and colleagues[40] of a disease characterized by subacute or chronic inflammation of the terminal ileum affecting primarily young adults, it has been shown that Crohn's disease is a heterogeneous disorder with varied clinical symptoms, intestinal sites of involvement, and complications.[41,42] One of the first attempts to classify subgroups of patients with CD dates back to 1975, when Farmer and coworkers[43] stratified 651 CD patients on initial disease location and found that this phenotype was a major determinant of symptoms, clinical course, and prognosis. For patients with involvement of both ileum and colon, there were frequent perianal fistulas (38%), internal fistulas (34%), intestinal obstruction (44%), and need for surgery (73%). For patients with isolated colonic disease, megacolon and arthritis were more frequent, and patients with small bowel disease were more likely to develop intestinal obstruction. In a follow-up evaluation of this cohort for a mean of more than 13 years, patients with ileocolonic disease were much more likely to have required surgical resection (92%) than those with either isolated small intestinal disease (66%) or colonic disease (58%); P < .001.[44]

Another example of phenotypic heterogeneity in CD relates to disease behavior. CD "disease behavior" generally can be classified as follows: (1) fistulizing/perforating; (2) stricturing; or (3) inflammatory.[45] Such classifications may define different disease courses in patients with CD. For example, Greenstein and colleagues[46] proposed that perforating (acute perforation, abscess, fistula) and nonperforating (obstruction, medical intractability, hemorrhage) indications for surgery define 2 distinct clinical forms of CD. Patients with perforating indications for surgical intervention tend to manifest the same disease pattern when they require further surgery, whereas those with nonperforating disease retain a nonperforating clinical pattern at diagnosis of postoperative recurrence.[46,47,48,49] Patients with a perforating indication for surgery also are more likely to develop an early postoperative recurrence.[46] Such differences in disease behavior among CD patients may be related to differences in the host immune response.[50]

Finally, age at diagnosis may also define different subgroups within CD. A study of 552 patients with CD examined the association between age at diagnosis and disease location and behavior.[51] Patients of younger age at diagnosis (less than 20 years old), when compared with those of older age at diagnosis (40 years or older), were more likely to have small bowel involvement (89% vs 58%; P < .0005), stricturing disease (46% vs 29%; P < .005), surgery frequency (71% vs 55%; P < .001), and a family history of IBD (30% vs 14%; P < .005). Conversely, colonic disease and inflammatory behavior were significantly more common in patients diagnosed with CD at the age of 40 years or older. The study authors concluded that younger age at diagnosis represents a separate and more severe phenotype of CD, with a different genetic component.

Based on the above discussion, defining more homogeneous groups of CD patients is clearly important in examining genetic determinants of the disease. Genetic studies are more likely to be productive if they are conducted on a phenotypically homogenous population. To help standardize such phenotyping studies, there was an initial working party classification of patient subgroups in CD known as the "Rome classification"[45] and a subsequent simplified classification, the "Vienna criteria."[52] The Rome classification defined disease location, disease behavior, extent of disease, and operative history as important phenotypic endpoints.[45] This system, however, could theoretically lead to as many as 756 subgroups of CD.[52] In the subsequent Vienna classification system, 3 variables were chosen as primary phenotypic endpoints: (1) age at diagnosis (< 40 years or > 40 years); (2) disease location (terminal ileum, colon, ileocolon, or upper gastrointestinal tract); and (3) disease behavior (nonstricturing, nonpenetrating, stricturing, or penetrating).[52] Other phenotypic markers were considered as "further data to be collected," and included sex, race, Jewish ethnicity, family history of IBD, and extraintestinal manifestations.


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