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 SharmaKaida 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)710-723.e2
JournalGastroenterology
Volume151
Issue number4
DOIs
StatePublished - 1 Oct 2016
Externally publishedYes

Bibliographical note

Funding Information:
Funding Supported by the National Institutes of Health ( DK092235 ), Inflammatory Bowel Disease Genetics Consortium ( DK062429 ), Genetic Research Center at the Icahn School of Medicine ( DK062422 ), New York Crohn’s Foundation, Consortium ancillary RO1 (DK099097) and U01 (DK062431) , Inflammatory Bowel Disease Genetic Research Chair , RO1 (DK062420) and RO1 (CA141743) , the Atran Foundation, and the Sanford J. Grossman Charitable Trust. Researchers at University College of London were funded by the Wellcome Trust, Charles Wolfson Charitable Trust, and the Irwin Joffe Memorial Fellowship. Inflammatory bowel disease Research at Cedars-Sinai is supported by U.S. Public Health Service grant PO1 (DK046763) and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. Project investigators are supported by The Helmsley Charitable Trust (D.P.B.M.), The European Union (D.P.B.M.), The Crohn's and Colitis Foundation of America (D.P.B.M.), The Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics (D.P.B.M.), and grants DK062413, DK046763-19, AI067068, and HS021747 (D.P.B.M.).

Publisher Copyright:
© 2016 AGA Institute

Keywords

  • Ethnic Variation
  • IBD
  • Inflammatory Bowel Disease
  • Risk Factor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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