A frameshift mutation in the CSF2RB gene that is common in Ashkenazi Jews has been linked to Crohn’s disease, according to a report in Gastroenterology.

The Ashkenazi Jewish population has a four- to sevenfold higher prevalence of Crohn’s disease than does the general population. To identify possible genetic mutations associated with the disease, researchers performed exome sequencing of samples from 1,477 Ashkenazi Jewish patients with Crohn’s disease and 2,614 Ashkenazi Jewish control subjects who didn’t have the disorder. All the study participants were enrolled at medical centers throughout North America, Europe, and Israel, noted Ling-Shiang Chuang, PhD, a postdoctoral fellow in genetics and genomic sciences, Mount Sinai Medical Center, New York, and his associates.

They genotyped 224 frameshift mutations and identified one in the colony-stimulating factor 2–receptor beta common subunit (CSF2RB) gene that was significantly associated with Crohn’s disease. They validated this association in a replication cohort of 1,515 Ashkenazi Jewish patients with Crohn’s disease and 7,052 health Ashkenazi control subjects, observing nearly identical allele frequencies and odds ratios as in the discovery cohort.

Since the CSF2RB gene encodes for the receptor for GM-CSF (granulocyte-macrophage colony-stimulating factor) cytokines, the mutation would be expected to reduce GM-CSF signaling in monocytes obtained from carriers. The investigators found this was true when they examined monocytes taken from intestinal-tissue samples and peripheral-blood samples from affected patients.

“The present findings of a loss-of-function frameshift variant in the CSF2RB gene argue for a primary pathogenic role of decreased GM-CSF signaling in driving a subset of Crohn’s disease cases. As many as 30% of cases have increased levels of anti-GM-CSF antibodies, which can neutralize GM-CSF activity, indicating that impaired GM-CSF signaling plays a major role in Crohn’s disease,” Dr. Chuang and his associates wrote (Gastroenterol. 2016;151:710-23.e2. doi: 10.1053/j.gastro.2016.06.045 ).

Future research may identify subgroups of Crohn’s patients in which treatments that target GM-CSF signaling may be effective, and it may also point the way to novel therapies for the broader population of patients with Crohn’s disease, they added.

This study was supported by the National Institutes of Health, the Inflammatory Bowel Disease Genetics Consortium, the Genetic Research Center at Mount Sinai Medical Center, New York’s Crohn’s Foundation, and several others. Dr. Chuang and his associates reported having no relevant financial disclosures.


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