title: A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ling-Shiang
authors.initials: LS
authors.lastname: Chuang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nicole
authors.initials: N
authors.lastname: Villaverde
authors.affiliation: 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.
authors.forename: Ken Y
authors.initials: KY
authors.lastname: Hui
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Arthur
authors.initials: A
authors.lastname: Mortha
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Adeeb
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Levine
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Sok Meng
authors.initials: SM
authors.lastname: Evelyn Ng
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nai-Yun
authors.initials: NY
authors.lastname: Hsu
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jody-Ann
authors.initials: JA
authors.lastname: Facey
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Tramy
authors.initials: T
authors.lastname: Luong
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Heriberto
authors.initials: H
authors.lastname: Fernandez-Hernandez
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Dalin
authors.initials: D
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rivas
authors.affiliation: Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Schiff
authors.affiliation: Department of Epidemiology, Harvard University, Boston, Massachusetts.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: Department of Health Studies, University of Chicago, Chicago, Illinois.
authors.forename: L Phillip
authors.initials: LP
authors.lastname: Schumm
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Bowen
authors.affiliation: 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.
authors.forename: Yashoda
authors.initials: Y
authors.lastname: Sharma
authors.affiliation: 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.
authors.forename: Kaida
authors.initials: K
authors.lastname: Ning
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Romain
authors.initials: R
authors.lastname: Remark
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.affiliation: Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Legnani
authors.affiliation: Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: James
authors.initials: J
authors.lastname: George
authors.affiliation: Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Sands
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Stempak
authors.affiliation: 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.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Datta
authors.affiliation: Department of Internal Medicine, University of South Florida, Tampa, Florida.
authors.forename: Seth
authors.initials: S
authors.lastname: Lipka
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York.
authors.forename: Seymour
authors.initials: S
authors.lastname: Katz
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Cheifetz
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.affiliation: Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
authors.affiliation: 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.
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Dubinsky
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Stephan
authors.initials: S
authors.lastname: Targan
authors.affiliation: Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California.
authors.forename: Kent
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: The Division of Gastroenterology and Hepatology, Sanford I. Weill College of Cornell University-New York Presbyterian Hospital, New York, New York.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Scherl
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Division of Gastroenterology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
authors.affiliation: Department of Biostatistics, Yale University, New Haven, Connecticut.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.affiliation: Department of Computer Science, Columbia University, New York, New York.
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.affiliation: Centre for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: 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.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.affiliation: Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York.
authors.forename: Todd
authors.initials: T
authors.lastname: Lencz
authors.affiliation: Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
authors.affiliation: Genetics Institute, Division of Biosciences, University College, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.affiliation: 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.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: 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.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Brant
authors.affiliation: 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.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.affiliation: 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.
authors.forename: Judy H
authors.initials: JH
authors.lastname: Cho
mesh_terms: D016022:Case-Control Studies; D003424:Crohn Disease / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000473:pathology; D007585:Jews / Q000235:genetics*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Ethnic Variation; IBD; Inflammatory Bowel Disease; Risk Factor