Comment

A “working model” of the pathophysiology of Crohn's disease (CD) is of an abnormal immune response to enteric bacteria in genetically susceptible individuals. There is a greater concordance for CD in monozygotic than dizygotic twins (concordance for CD in monozygotic twins 37% compared with 7% for dizygotic twins), suggesting a major genetic contribution to the pathogenesis of CD. The risk to siblings of affected individuals relative to the general population (λs) is 15–40 for CD and the calculated heritability for CD is greater than that for schizophrenia or asthma and at least equal to that of type 1 diabetes.1 ,2

Evidence for the role of enteric bacteria in the pathogenesis of CD comes from data demonstrating that genetically modified mice utilised as models for inflammatory bowel disease/CD fail to manifest the disease in germ free environments and only develop disease when exposed to normal enteric commensal organisms. In addition, Crohn's colitis frequently improves when the faecal stream is diverted following formation of a loop ileostomy and symptoms from CD are transiently improved following administration of antibiotics.

Geneticists have proposed that the genes for complex genetic diseases will be discovered by one or more of the following three methods:

• Positional cloning using microsatellite markers and single nucleotide polymorphisms (SNPs) in multiply affected families.

• Identification of candidate genes through an understanding of the pathophysiology of the underlying defects leading to disease.

• Gene expression studies (for example, microarrays) comparing differential gene expression in tissue from affected and unaffected individuals.

In 1996, Jean-Pierre Hugot et al published the first genome wide scan identifying a susceptibility locus for CD adjacent to the centromere on …