Genetics of inflammatory bowel disease - The candidate gene approach: Susceptibility versus disease heterogeneity

Ulcerative colitis and Crohn's disease are complex diseases of unknown etio logy. Several genes are involved in the susceptibility. These genes are nec essary to suffer from these diseases but not sufficient. Environmental fact ors trigger the inflammatory response. Evidence is accumulating that this r esponse is abnormal in these patients. Therefore, the study of genes that a re involved in the regulation of the inflammation may help to clarify the p athogenesis of the disease. The working hypothesis is that HLA and cytokine gene polymorphisms, of extreme importance in the regulation of inflammatio n, contribute to determining the heterogeneity of the disease and the progn osis. In this case, the candidate genes are those involved in the regulatio n of the immune response of the host. These studies may be of great importa nce in the tailoring of an appropriate treatment for particular subgroups o f patients. A premise for the success of these studies is to use a solid cl assification, which should take into account the dynamic process and the na tural evolution of the disease; to use a carefully selected and ethnically matched group of healthy controls, and to use the advanced molecular biolog ical typing techniques. In the present article, this concept is explored by taking into account some of the recent findings obtained with the HLA and cytokine gene polymorphisms in inflammatory bowel diseases. The results sup port the concept that these gene polymorphisms are of greater importance in determining the severity of the disease than in determining the susceptibi lity to suffer from the disease. From this point of view, these studies are complementary and a necessary addition to studies using the whole genome a pproach in the effort to understand the genetics of these chronic multifact orial diseases.