Susceptibility Genes Distinct from Severity Genes in Crohn's Disease

The group of 170 gene variants that have been linked to the development of Crohn's disease has been found to operate independently from a second group of four variants, which determines how severe the disease will be.

Severity of an immune-mediated disease such as Crohn's may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to disease severity, but little evidence has been found for a proposed association between gene variants linked to severity and those linked to susceptibility.

To better characterize how genetic variation influences the severity of the disease, investigators at the University of Cambridge performed a within-cases genome-wide association study in two cohorts that comprised 2,700 individuals, who had been selected because they had experienced particularly mild or particularly aggressive forms of Crohn's disease.

The investigators identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease severity.

"This shows us that the genetic architecture of disease outcome is very different to that of disease risk," said senior author Dr. Kenneth G. C. Smith, professor of medicine at the University of Cambridge. "In other words, the biological pathways driving disease progression may be very different to those that initiate the disease itself. This was quite unexpected. Past work has focused on discovering genes underlying disease initiation, and our work suggests these may no longer be relevant by the time a patient sees the doctor. We may have to consider directing new therapies to quite different pathways in order to treat established disease"

The study was published in the January 9, 2017, online edition of the journal Nature Genetics.