A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF
2016
Background & Aims Crohn's disease (CD) has the highest prevalence in
Ashkenazi Jewishpopulations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. Methods We performed exome sequencing and array-based genotype analyses of 1477
Ashkenazi Jewishindividuals with CD and 2614
Ashkenazi Jewishindividuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for
frameshift mutationsin the
colony-stimulating factor2–receptor β common subunit gene ( CSF2RB ). Intestinal tissues and blood samples were collected from patients with CD;
lamina proprialeukocytes were isolated and expression of CSF2RB and
granulocyte-macrophage colony–stimulating factor–responsive cells were defined by
adenomatous polyposis coli(APC) time-of-flight
mass cytometry(CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. Results In the discovery cohort, we associated CD with a
frameshift mutationin CSF2RB ( P = 8.52 × 10 -4 ); the finding was validated in the replication cohort (combined P = 3.42 × 10 -6 ). Incubation of intestinal
lamina proprialeukocytes with
granulocyte-macrophage colony–stimulating factorresulted in high levels of phosphorylation of signal transducer and activator of transcription (
STAT5) and lesser increases in phosphorylation of extracellular signal–regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with
granulocyte-macrophage colony–stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the
frameshift mutation(6% of CD cases analyzed) had reduced responses to
granulocyte-macrophage colony–stimulating factorand markedly decreased activity of
aldehyde dehydrogenase; activity of this enzyme has been associated with
immune tolerance. Conclusions In a genetic analysis of
Ashkenazi Jewishindividuals, we associated CD with a
frameshift mutationin CSF2RB . Intestinal monocytes from carriers of this mutation had reduced responses to
granulocyte-macrophage colony–stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.
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