Multiple Causes

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Science  16 Jul 2010:
Vol. 329, Issue 5989, pp. 259
DOI: 10.1126/science.329.5989.259-a
CREDIT: CADWELL ET AL., CELL 141, 1135 (2010)

Complex diseases, like the inflammatory bowel condition Crohn's disease, are thought to arise from a combination of genetic and environmental factors. This two-hit pathway to disease development would explain why a genetic susceptibility allele for Crohn's disease, the autophagy gene ATG16L1, is present at approximately 50% frequency in populations of European descent, yet the incidence of Crohn's disease in these populations is quite rare. Cadwell et al. provide evidence that in mice, virus infection can interact with susceptibility genes to promote a Crohn's disease-like pathology. Mice hypomorphic for Atg16L1 and housed in an enhanced-barrier facility exhibited intestinal pathology only when infected with a persistent strain of mouse norovirus, an RNA virus that causes gastroenteritis. When mice were treated with a compound that induces intestinal injury, Atg16L1-hypomorphic virus-infected mice developed pathology (thickening of the muscularis propria and submucosal fibrosis) that resembled what is seen in Crohn's disease patients, whereas uninfected mice that expressed the hypomorphic allele did not develop Crohn's disease-like pathology, nor did virus-infected wild-type mice. Thus, an interaction between a virus and a susceptibility gene, in the presence of additional environmental factors, can determine host response phenotypes in inflammatory disease.

Cell 141, 1135 (2010).

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