From the AGA Journals

CSF2RB mutation, common in Ashkenazim, linked to Crohn’s

View on the News

Discovery could pave way to studies on Crohn’s disease development

Genome-wide association studies (GWASs) have identified over 200 DNA mutations (mainly single nucleotide polymorphisms, SNPs) contributing to inflammatory bowel disease. However, their causality in IBD remains unknown. In the post-GWAS era, functional characterization and mechanistic elucidation of these SNPs is a major challenge. SNPs impacting the protein-coding genes can drastically alter protein function and play an important role in molecular pathogenesis. However, most SNPs are in noncoding genes and their impact on gene regulation and disease outcome remains largely unknown. This study reveals a frameshift mutation in the CSF2RB gene associated with Crohn’s disease in an Ashkenazi Jewish population. A frameshift mutation results in the deletion or insertion in a DNA sequence that shifts the way the sequence is transcribed into RNA. The most well described frameshift mutation in Crohn’s disease with clinical relevance is in the NOD2 gene, which results in impaired immune response to microbial stimuli. Because GWASs show association not causality, the biological consequence of the CSF2RB frameshift mutation in intestinal macrophages leads to a decrease in its response to granulocyte-monocyte stimulating factor (GM-CSF) providing a potential mechanistic role for the mutation in Crohn’s disease pathogenesis in a disease-relevant cell and site. This study will pave the way for future important studies that reveal the impact of SNPs on Crohn’s disease development, prognosis, and eventually response to therapy.

Shehzad Z. Sheikh MD, PhD, assistant professor of medicine, department of medicine, division of gastroenterology and hepatology, University of North Carolina, Chapel Hill.



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.

Next Article: