Dataset Information

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 ? 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.

SUBMITTER: Chuang LS

PROVIDER: S-EPMC5037012 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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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.

Chuang Ling-Shiang LS Villaverde Nicole N Hui Ken Y KY Mortha Arthur A Rahman Adeeb A Levine Adam P AP Haritunians Talin T Evelyn Ng Sok Meng SM Zhang Wei W Hsu Nai-Yun NY Facey Jody-Ann JA Luong Tramy T Fernandez-Hernandez Heriberto H Li Dalin D Rivas Manuel M Schiff Elena R ER Gusev Alexander A Schumm L Phillip LP Bowen Beatrice M BM Sharma Yashoda Y Ning Kaida K Remark Romain R Gnjatic Sacha S Legnani Peter P George James J Sands Bruce E BE Stempak Joanne M JM Datta Lisa W LW Lipka Seth S Katz Seymour S Cheifetz Adam S AS Barzilai Nir N Pontikos Nikolas N Abraham Clara C Dubinsky Marla J MJ Targan Stephan S Taylor Kent K Rotter Jerome I JI Scherl Ellen J EJ Desnick Robert J RJ Abreu Maria T MT Zhao Hongyu H Atzmon Gil G Pe'er Itsik I Kugathasan Subra S Hakonarson Hakon H McCauley Jacob L JL Lencz Todd T Darvasi Ariel A Plagnol Vincent V Silverberg Mark S MS Muise Aleixo M AM Brant Steven R SR Daly Mark J MJ Segal Anthony W AW Duerr Richard H RH Merad Miriam M McGovern Dermot P B DP Peter Inga I Cho Judy H JH

Gastroenterology 20160701 4

<h4>Background & aims</h4>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.<h4>Methods</h4>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 contr ...[more]

PMID: 27377463

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Project description:Macrophages are an important line of defence against invading pathogens. Human macrophages derived by different methods were tested for their suitability as models to investigate Listeria monocytogenes (Lm) infection and compared to macrophage-like THP-1 cells. Human primary monocytes were isolated by either positive or negative immunomagnetic selection and differentiated in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF) into pro- or anti-inflammatory macrophages, respectively. Regardless of the isolation method, GM-CSF-derived macrophages (GM-Mφ) stained positive for CD206 and M-CSF-derived macrophages (M-Mφ) for CD163. THP-1 cells did not express CD206 or CD163 following incubation with PMA, M- or GM-CSF alone or in combination. Upon infection with Lm, all primary macrophages showed good survival at high multiplicities of infection whereas viability of THP-1 was severely reduced even at lower bacterial numbers. M-Mφ generally showed high phagocytosis of Lm. Strikingly, phagocytosis of Lm by GM-Mφ was markedly influenced by the method used for isolation of monocytes. GM-Mφ derived from negatively isolated monocytes showed low phagocytosis of Lm whereas GM-Mφ generated from positively selected monocytes displayed high phagocytosis of Lm. Moreover, incubation with CD14 antibody was sufficient to enhance phagocytosis of Lm by GM-Mφ generated from negatively isolated monocytes. By contrast, non-specific phagocytosis of latex beads by GM-Mφ was not influenced by treatment with CD14 antibody. Furthermore, phagocytosis of Lactococcus lactis, Escherichia coli, human cytomegalovirus and the protozoan parasite Leishmania major by GM-Mφ was not enhanced upon treatment with CD14 antibody indicating that this effect is specific for Lm. Based on these observations, we propose macrophages derived by ex vivo differentiation of negatively selected human primary monocytes as the most suitable model to study Lm infection of macrophages.

Dataset Information

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

Publications

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

Similar Datasets

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