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 & 40 others Kaida Ning, Romain Remark, Sacha Gnjatic, Peter Legnani, James George, Bruce E. Sands, Joanne M. Stempak, Lisa 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 journalArticle

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 (US)
Pages (from-to)710-723.e2
JournalGastroenterology
Volume151
Issue number4
DOIs
StatePublished - Oct 1 2016

Fingerprint

Jews
Granulocyte-Macrophage Colony-Stimulating Factor
Crohn Disease
Monocytes
Frameshift Mutation
Granulocytes
Macrophages
Mucous Membrane
Leukocytes
Genotype
Phosphorylation
Exome
Colony-Stimulating Factors
Immune Tolerance
Aldehyde Dehydrogenase
Adenomatous Polyposis Coli
HEK293 Cells
Rare Diseases
Transducers
Innate Immunity

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Chuang, L. S., Villaverde, N., Hui, K. Y., Mortha, A., Rahman, A., Levine, A. P., ... Cho, J. H. (2016). A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology, 151(4), 710-723.e2. https://doi.org/10.1053/j.gastro.2016.06.045

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. / Chuang, Ling Shiang; Villaverde, Nicole; Hui, Ken Y.; Mortha, Arthur; Rahman, Adeeb; Levine, Adam P.; Haritunians, Talin; Evelyn Ng, Sok Meng; Zhang, Wei; Hsu, Nai Yun; Facey, Jody Ann; Luong, Tramy; Fernandez-Hernandez, Heriberto; Li, Dalin; Rivas, Manuel; Schiff, Elena R.; Gusev, Alexander; Schumm, L. Phillip; Bowen, Beatrice M.; Sharma, Yashoda; Ning, Kaida; Remark, Romain; Gnjatic, Sacha; Legnani, Peter; George, James; Sands, Bruce E.; Stempak, Joanne M.; Datta, Lisa; Lipka, Seth; Katz, Seymour; Cheifetz, Adam S.; Barzilai, Nir; Pontikos, Nikolas; Abraham, Clara; Dubinsky, Marla J.; Targan, Stephan; Taylor, Kent; Rotter, Jerome I.; Scherl, Ellen J.; Desnick, Robert J.; Abreu, Maria T.; Zhao, Hongyu; Atzmon, Gil; Pe'er, Itsik; Kugathasan, Subra; Hakonarson, Hakon; McCauley, Jacob L.; Lencz, Todd; Darvasi, Ariel; Plagnol, Vincent; Silverberg, Mark S.; Muise, Aleixo M.; Brant, Steven R.; Daly, Mark J.; Segal, Anthony W.; Duerr, Richard H.; Merad, Miriam; McGovern, Dermot P B; Peter, Inga; Cho, Judy H.

In: Gastroenterology, Vol. 151, No. 4, 01.10.2016, p. 710-723.e2.

Research output: Contribution to journalArticle

Chuang, LS, Villaverde, N, Hui, KY, Mortha, A, Rahman, A, Levine, AP, Haritunians, T, Evelyn Ng, SM, Zhang, W, Hsu, NY, Facey, JA, Luong, T, Fernandez-Hernandez, H, Li, D, Rivas, M, Schiff, ER, Gusev, A, Schumm, LP, Bowen, BM, Sharma, Y, Ning, K, Remark, R, Gnjatic, S, Legnani, P, George, J, Sands, BE, Stempak, JM, Datta, L, Lipka, S, Katz, S, Cheifetz, AS, Barzilai, N, Pontikos, N, Abraham, C, Dubinsky, MJ, Targan, S, Taylor, K, Rotter, JI, Scherl, EJ, Desnick, RJ, Abreu, MT, Zhao, H, Atzmon, G, Pe'er, I, Kugathasan, S, Hakonarson, H, McCauley, JL, Lencz, T, Darvasi, A, Plagnol, V, Silverberg, MS, Muise, AM, Brant, SR, Daly, MJ, Segal, AW, Duerr, RH, Merad, M, McGovern, DPB, Peter, I & Cho, JH 2016, 'A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF', Gastroenterology, vol. 151, no. 4, pp. 710-723.e2. https://doi.org/10.1053/j.gastro.2016.06.045
Chuang, Ling Shiang ; Villaverde, Nicole ; Hui, Ken Y. ; Mortha, Arthur ; Rahman, Adeeb ; Levine, Adam P. ; Haritunians, Talin ; Evelyn Ng, Sok Meng ; Zhang, Wei ; Hsu, Nai Yun ; Facey, Jody Ann ; Luong, Tramy ; Fernandez-Hernandez, Heriberto ; Li, Dalin ; Rivas, Manuel ; Schiff, Elena R. ; Gusev, Alexander ; Schumm, L. Phillip ; Bowen, Beatrice M. ; Sharma, Yashoda ; Ning, Kaida ; Remark, Romain ; Gnjatic, Sacha ; Legnani, Peter ; George, James ; Sands, Bruce E. ; Stempak, Joanne M. ; Datta, Lisa ; Lipka, Seth ; Katz, Seymour ; Cheifetz, Adam S. ; Barzilai, Nir ; Pontikos, Nikolas ; Abraham, Clara ; Dubinsky, Marla J. ; Targan, Stephan ; Taylor, Kent ; Rotter, Jerome I. ; Scherl, Ellen J. ; Desnick, Robert J. ; Abreu, Maria T. ; Zhao, Hongyu ; Atzmon, Gil ; Pe'er, Itsik ; Kugathasan, Subra ; Hakonarson, Hakon ; McCauley, Jacob L. ; Lencz, Todd ; Darvasi, Ariel ; Plagnol, Vincent ; Silverberg, Mark S. ; Muise, Aleixo M. ; Brant, Steven R. ; Daly, Mark J. ; Segal, Anthony W. ; Duerr, Richard H. ; Merad, Miriam ; McGovern, Dermot P B ; Peter, Inga ; Cho, Judy H. / A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. In: Gastroenterology. 2016 ; Vol. 151, No. 4. pp. 710-723.e2.
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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",
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",
author = "Chuang, {Ling Shiang} and Nicole Villaverde and Hui, {Ken Y.} and Arthur Mortha and Adeeb Rahman and Levine, {Adam P.} and Talin Haritunians and {Evelyn Ng}, {Sok Meng} and Wei Zhang and Hsu, {Nai Yun} and Facey, {Jody Ann} and Tramy Luong and Heriberto Fernandez-Hernandez and Dalin Li and Manuel Rivas and Schiff, {Elena R.} and Alexander Gusev and Schumm, {L. Phillip} and Bowen, {Beatrice M.} and Yashoda Sharma and Kaida Ning and Romain Remark and Sacha Gnjatic and Peter Legnani and James George and Sands, {Bruce E.} and Stempak, {Joanne M.} and Lisa Datta and Seth Lipka and Seymour Katz and Cheifetz, {Adam S.} and Nir Barzilai and Nikolas Pontikos and Clara Abraham and Dubinsky, {Marla J.} and Stephan Targan and Kent Taylor and Rotter, {Jerome I.} and Scherl, {Ellen J.} and Desnick, {Robert J.} and Abreu, {Maria T.} and Hongyu Zhao and Gil Atzmon and Itsik Pe'er and Subra Kugathasan and Hakon Hakonarson and McCauley, {Jacob L.} and Todd Lencz and Ariel Darvasi and Vincent Plagnol and Silverberg, {Mark S.} and Muise, {Aleixo M.} and Brant, {Steven R.} and Daly, {Mark J.} and Segal, {Anthony W.} and Duerr, {Richard H.} and Miriam Merad and McGovern, {Dermot P B} and Inga Peter and Cho, {Judy H.}",
year = "2016",
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journal = "Gastroenterology",
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TY - JOUR

T1 - A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF

AU - Chuang, Ling Shiang

AU - Villaverde, Nicole

AU - Hui, Ken Y.

AU - Mortha, Arthur

AU - Rahman, Adeeb

AU - Levine, Adam P.

AU - Haritunians, Talin

AU - Evelyn Ng, Sok Meng

AU - Zhang, Wei

AU - Hsu, Nai Yun

AU - Facey, Jody Ann

AU - Luong, Tramy

AU - Fernandez-Hernandez, Heriberto

AU - Li, Dalin

AU - Rivas, Manuel

AU - Schiff, Elena R.

AU - Gusev, Alexander

AU - Schumm, L. Phillip

AU - Bowen, Beatrice M.

AU - Sharma, Yashoda

AU - Ning, Kaida

AU - Remark, Romain

AU - Gnjatic, Sacha

AU - Legnani, Peter

AU - George, James

AU - Sands, Bruce E.

AU - Stempak, Joanne M.

AU - Datta, Lisa

AU - Lipka, Seth

AU - Katz, Seymour

AU - Cheifetz, Adam S.

AU - Barzilai, Nir

AU - Pontikos, Nikolas

AU - Abraham, Clara

AU - Dubinsky, Marla J.

AU - Targan, Stephan

AU - Taylor, Kent

AU - Rotter, Jerome I.

AU - Scherl, Ellen J.

AU - Desnick, Robert J.

AU - Abreu, Maria T.

AU - Zhao, Hongyu

AU - Atzmon, Gil

AU - Pe'er, Itsik

AU - Kugathasan, Subra

AU - Hakonarson, Hakon

AU - McCauley, Jacob L.

AU - Lencz, Todd

AU - Darvasi, Ariel

AU - Plagnol, Vincent

AU - Silverberg, Mark S.

AU - Muise, Aleixo M.

AU - Brant, Steven R.

AU - Daly, Mark J.

AU - Segal, Anthony W.

AU - Duerr, Richard H.

AU - Merad, Miriam

AU - McGovern, Dermot P B

AU - Peter, Inga

AU - Cho, Judy H.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - Ethnic Variation

KW - IBD

KW - Inflammatory Bowel Disease

KW - Risk Factor

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DO - 10.1053/j.gastro.2016.06.045

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JF - Gastroenterology

SN - 0016-5085

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