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

Ling-Shiang Chuang; Nicole Villaverde; Ken Y Hui; Arthur Mortha; Adeeb Rahman; Adam P Levine; Talin Haritunians; Sok Meng Evelyn Ng; Wei Zhang; Nai-Yun Hsu; Jody-Ann Facey; Tramy Luong; Heriberto Fernandez-Hernandez; Dalin Li; Manuel Rivas; Elena R Schiff; Alexander Gusev; L. Phillip Schumm; Beatrice M Bowen; Yashoda Sharma; Kaida Ning; Romain Remark; Sacha Gnjatic; Peter Legnani; James George; Bruce E Sands; Joanne M Stempak; Lisa W Datta; Seth Lipka; Seymour Katz; Adam S Cheifetz; Nir Barzilai; Nikolas Pontikos; Clara Abraham; Marla J Dubinsky; Stephan Targan; Kent Taylor; Jerome I Rotter; Ellen J Scherl; Robert J Desnick; Maria T Abreu; Hongyu Zhao; Gil Atzmon; Itsik Pe’er; Subra Kugathasan; Hakon Hakonarson; Jacob L McCauley; Todd Lencz; Ariel Darvasi; Vincent Plagnol; Mark S Silverberg; Aleixo M Muise; Steven R Brant; Mark J Daly; Anthony W Segal; Richard H Duerr; Miriam Merad; Dermot P.B McGovern; Inga Peter; Judy H Cho

doi:10.1053/j.gastro.2016.06.045

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

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

Ling-Shiang Chuang, Nicole Villaverde, Ken Y Hui, Arthur Mortha, Adeeb Rahman, Adam P Levine, Talin Haritunians, Sok Meng Evelyn Ng, Wei Zhang, Nai-Yun Hsu, …

Gastroenterology (New York, N.Y. 1943), Vol.151(4), pp.710-723.e2

10/2016

DOI: https://doi.org/10.1053/j.gastro.2016.06.045

PMID: 27377463

Abstract

Ethnic Variation

IBD

Inflammatory Bowel Disease

Risk Factor

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.

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Title: A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF
Creators: Ling-Shiang Chuang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Nicole Villaverde - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Ken Y Hui - Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut
Arthur Mortha - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Adeeb Rahman - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Adam P Levine - Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
Talin Haritunians - Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Sok Meng Evelyn Ng - Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Wei Zhang - Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Nai-Yun Hsu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Jody-Ann Facey - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Tramy Luong - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Heriberto Fernandez-Hernandez - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Dalin Li - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Manuel Rivas - Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
Elena R Schiff - Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
Alexander Gusev - Department of Epidemiology, Harvard University, Boston, Massachusetts
L. Phillip Schumm - Department of Health Studies, University of Chicago, Chicago, Illinois
Beatrice M Bowen - Department of Genetics, Yale University, New Haven, Connecticut
Yashoda Sharma - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Kaida Ning - Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Romain Remark - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Sacha Gnjatic - Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
Peter Legnani - Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
James George - Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
Bruce E Sands - Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
Joanne M Stempak - Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
Lisa W Datta - Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Seth Lipka - Department of Internal Medicine, University of South Florida, Tampa, Florida
Seymour Katz - Department of Medicine, New York University School of Medicine, New York, New York
Adam S Cheifetz - Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Nir Barzilai - Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
Nikolas Pontikos - Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
Clara Abraham - Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Marla J Dubinsky - Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
Stephan Targan - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Kent Taylor - Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California
Jerome I Rotter - Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California
Ellen J Scherl - The Division of Gastroenterology and Hepatology, Sanford I. Weill College of Cornell University—New York Presbyterian Hospital, New York, New York
Robert J Desnick - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Maria T Abreu - Division of Gastroenterology, University of Miami, Miller School of Medicine, Miami, Florida
Hongyu Zhao - Department of Biostatistics, Yale University, New Haven, Connecticut
Gil Atzmon - Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
Itsik Pe’er - Department of Computer Science, Columbia University, New York, New York
Subra Kugathasan - Department of Pediatrics, Emory University, Atlanta, Georgia
Hakon Hakonarson - Centre for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Jacob L McCauley - John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida
Todd Lencz - Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York
Ariel Darvasi - Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel
Vincent Plagnol - Genetics Institute, Division of Biosciences, University College, London, United Kingdom
Mark S Silverberg - Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
Aleixo M Muise - Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
Steven R Brant - Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Mark J Daly - Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
Anthony W Segal - Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
Richard H Duerr - Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Miriam Merad - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Dermot P.B McGovern - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Inga Peter - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Judy H Cho - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Publication Details: Gastroenterology (New York, N.Y. 1943), Vol.151(4), pp.710-723.e2
Date published: 10/2016
Publisher: Elsevier Inc
Grant note: DK092235 / National Institutes of Health RO1 (DK062420); RO1 (CA141743) / Inflammatory Bowel Disease Genetic Research Chair DK062422 / Genetic Research Center at the Icahn School of Medicine DK062429 / Inflammatory Bowel Disease Genetics Consortium RO1 (DK099097); U01 (DK062431) / New York Crohn’s Foundation, Consortium
Academic Unit: Medicine - Gastroenterology and Hepatology (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665257404646