Genotypes and phenotypes in Crohn's disease: do they help in clinical management?
Authors: C Gasche, P Grundtner
Journal: Gut (2004)

ather than a unique disorder, Crohn's disease is regarded as a common denominator for various immune mediated inflammatory diseases of the gastrointestinal tract.These various subforms of Crohn's disease are characterised by T cell mediated tissue destruction in the gut.In contrast with autoimmune diseases where autoantibodies react with self antigens, inflammation in Crohn's disease is directed against antigens that are mainly derived from the environment. 1Although it may sound trivial, this adjustment in the understanding of the pathogenetic mechanisms has a vast number of consequences for the search of the disease causing factors and identification of therapeutic targets. CROHN'S PHENOTYPES cThe various subforms of Crohn's disease have not been recognised until recently.Historically, colonic Crohn's disease was not distinguished from ulcerative colitis.Approximately 30 years ago, the first studies highlighted the diverse natural history of colonic and ileal Crohn's disease. 2 Inherent differences in disease behaviour (obstructing versus perforating) were later recognised by a group of physicians at Mount Sinai Hospital in New York. 3 Biological discrimination between various subgroups of Crohn's patients led to a proposal for a phenotypic classification, 4 which was taken up and further developed and evaluated by an international working group, leading to the Vienna classification. 5Accordingly, Crohn's disease is separated into three categories: age at diagnosis, location, and behaviour (table 1).Several teams have now tested the Vienna classification in their databases 6-8 and found that it is feasible and reproducible.The behaviour and age categories earned some criticism which will be discussed later.The location category was found to be very useful and was also stable over time, with only one of seven patients having changes over a 10 year observation period. 7 CLASSIFICATION BY AETIOLOGYThe best classification would be by cause of disease, but unfortunately this is not known.However, there is overwhelming indirect evidence for the presence of environmental triggers, although the specific antigen(s) that drives the immune reaction in Crohn's disease is still obscure.Cigarette smoking is the only confirmed external factor involved in the pathogenesis of Crohn's disease.It has been linked to disease progression and unfavourable disease outcome across the world.The underlying mechanism is incompletely understood. 9Smoking seems to be a disease aggravating rather than a disease causing factor.In fact, smokers are more likely to develop strictures or fistulae. 10No other external trigger has been generally recognised. CROHN'S GENOTYPESApart from the disease causing environment, variations in the human genome contribute to disease susceptibility and shape the clinical phenotype.The higher frequency of Crohn's disease in certain ethnic groups (particularly in Caucasians), familial aggregation, and a greater disease concordance in monozygotic twins are strong indicators of the impact of genetic factors in disease pathogenesis.However, the genetic trait of Crohn's disease is complex, with genetic heterogeneity and incomplete phenotype penetrance.To date, seven susceptibility loci have been identified cosegregating preferentially with disease phenotype 11 but no dominant inflammatory bowel disease gene has been detected.Genetic variations are loading the gun but the environmental factor still pulls the trigger.This paradigm was further supported by identification of caspase activation and recruitment domain 15 (CARD15) variants that confer susceptibility to Crohn's disease. 12What have we learned about the function of CARD15?CARD15/NOD2