Genetic Mutations Associated with Crohn's Disease May Need a Helping Hand

Not long after the full sequence of the human genome was elucidated, numerous studies sought to link the mutation of specific genes with certain diseases. A common trend in these studies is low penetrance. That is, discovered risk alleles cause disease in a small number of individuals and the presence of the characterized mutation does not guarantee the development of a corresponding disease. Crohn's disease is an example of such a disease described above.

Crohn's is a chronic recurrent inflammatory disorder of the gastrointestinal tract that produces frequent diarrhea, abdominal pain, and weight loss due to malabsorption of nutrients in more severe cases. With a Crohn's mouse model, a novel study published in the journal Cell described the interplay between a risk allele found in humans and a pathogen derived from the environment. The study offers general insight into why certain risk alleles may have low penetrance in human disease.

The authors studied the Crohn's susceptibility allele Atg16L1 in mice, which the investigators point out, is present in nearly 50% of Europeans and confers less than a 2 fold increase in Crohn's risk . Interestingly, the authors observed that when mice were isolated from their littermates, the mutation of Atg16L1 confers a phenotype very similar to wild type mice. However, when raised with other mice, Atg16L1 mutation mimics a phenotype observed in the gastrointestinal tract similar to Crohn's disease. Specifically an abnormality in paneth cells, a cell type that releases enzymes involved in host defense in the intestines.

The investigators found that taking isolated mice with the mutation, which have paneth cells similar to wild type, and infecting them with a gastrointestinal specific virus was sufficient to trigger the Crohn's like paneth cell phenotype. Suggesting, that the environment and inflammation may play an significant role in the penetrance of Crohn's risk alleles. The authors observed that inoculating mutant mice with virus followed by treatment with dextran sodium sulfate (DSS), a gastrointestinal irritating agent, led to inflammation very similar to what is present in Crohn's disease. Like Crohn's disease, this inflammation and damage could be ameliorated with anti-TNF and antibiotics in the mice.

This study suggests that although disease risk alleles may have low penetrance within a population, their ability to induce disease may be regulated by outside factors. The example described in this study was a viral infection interacting with a gene that regulates host defense. Without the virus, the mutation did not confer a Crohn's phenotype. The observations made by the investigators of this study further underscores the importance of the interplay between environment and genetics in understanding disease.

References:

Cadwell, K. et, al. Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine. Cell 141, 1135-1145, June 25, 2010