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Gastroenterology. 2016 Oct;151(4):710-723.e2. doi: 10.1053/j.gastro.2016.06.045. Epub 2016 Jul 1.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

Author information

1
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
2
Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut; Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
4
Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom.
5
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
6
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
7
Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics Research, University of Oxford, Oxford, United Kingdom.
8
Department of Epidemiology, Harvard University, Boston, Massachusetts.
9
Department of Health Studies, University of Chicago, Chicago, Illinois.
10
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut.
11
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
12
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California.
13
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
14
Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
15
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
16
Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
17
Department of Internal Medicine, University of South Florida, Tampa, Florida.
18
Department of Medicine, New York University School of Medicine, New York, New York.
19
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
20
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
21
Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
22
Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California.
23
The Division of Gastroenterology and Hepatology, Sanford I. Weill College of Cornell University-New York Presbyterian Hospital, New York, New York.
24
Division of Gastroenterology, University of Miami, Miller School of Medicine, Miami, Florida.
25
Department of Biostatistics, Yale University, New Haven, Connecticut.
26
Department of Computer Science, Columbia University, New York, New York.
27
Department of Pediatrics, Emory University, Atlanta, Georgia.
28
Centre for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
29
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida; Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida.
30
Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York.
31
Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
32
Genetics Institute, Division of Biosciences, University College, London, United Kingdom.
33
Inflammatory Bowel Disease Centre and Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
34
Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts.
35
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
36
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: Judy.cho@mssm.edu.

Abstract

BACKGROUND & AIMS:

Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. 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 Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes 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 mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted 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 factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance.

CONCLUSIONS:

In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in 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.

KEYWORDS:

Ethnic Variation; IBD; Inflammatory Bowel Disease; Risk Factor

PMID:
27377463
PMCID:
PMC5037012
DOI:
10.1053/j.gastro.2016.06.045
[Indexed for MEDLINE]
Free PMC Article

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