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; Ng, Sok Meng Evelyn; Zhang, Wei; Hsu, Nai Yun; Facey, Jody-Ann; Luong, Tramy; Fernandez-Hernandez, Heriberto; Li, Dalin; Rivas, Manuel A.; Schiff, Elena R.; Gusev, Alexander; Schumm, L. Philip; Bowen, Beatrice M.; Sharma, Yashoda; Ning, Kaida; Remark, Romain; Gnjatic, Sacha; Legnani, Peter; George, James; Sands, Bruce E.; Stempak, Joanne M.; Datta, Lisa W.; Lipka, Seth; Katz, Seymour; Cheifetz, Adam S.; Barzilai, Nir; Pontikos, Nikolas; Abraham, Clara; Dubinsky, Marla; Targan, Stephan R.; Taylor, Kent D.; Rotter, Jerome I.; Scherl, Ellen; Desnick, Robert J.; Abreu, María T.; Zhao, Hongyu; Atzmon, Gil; Pe’er, Itsik; Kugathasan, Subramaniam; Hákonarson, Hákon; McCauley, Jacob L.; Lencz, Todd; Darvasi, Ariel; Plagnol, Vincent; Silverberg, Mark S.; Muise, A; Brant, Steven R.; Daly, Mark J.; Segal, Anthony W.; Duerr, Richard H.; Mérad, Miriam; McGovern, Dermot P.; Peter, Inga; Cho, Judy H.

doi:10.1053/j.gastro.2016.06.045

Cited by 56 publications

(56 citation statements)

References 37 publications

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“…1 A rare dominant negative frameshift mutation in the GM-CSF receptor beta chain gene CSF2RB reduces GM-CSF activation of STAT5 in monocytes and increases risk for adult-onset CD. 9,10 We discovered that common neutralizing GMAb, which inhibit GM-CSF signaling in a cell-extrinsic manner, are associated with reduced neutrophil bacterial killing and higher rates of stricturing complications in pediatric and adult-onset CD. 4,5 In the current study, we have identified a subset of pediatric CD patients characterized by low/normal neutrophil-intrinsic GMSI, which was in turn associated with a CSF2RA A17G missense mutation, alterations in wound healing and cell survival gene programs, and high rates of disease complications.…”

Section: Discussionmentioning

confidence: 99%

“…1 We therefore asked whether differences in neutrophil bacterial killing with GMSI would be specific to the GM-CSF:STAT5 pathway or if they reflect a broader dysregulation of cell signaling networks. 9 We conducted an unbiased survey of 10 key cell signaling phospho-protein targets under steady-state conditions. Although we did not observe significant differences in phospho-protein abundance that survived corrections for multiple comparisons, we did observe nominal increases in STAT1 and NFkB activation in the GMSI-Hi neutrophils, which were supported by the gene expression data.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 The authors identified increased carriage of the same heterozygous frameshift mutation in the GM-CSF receptor beta common subunit gene, CSF2RB, in 2 independent cohorts of Ashkenazi Jewish (AJ) CD patients. Studies using primary monocytes from CD patients with and without heterozygous risk variant carriage confirmed that the CSF2RB frameshift mutation resulted in reduced GM-CSF-induced tyrosine phosphorylation of the STAT5 transcription factor in a dominant-negative manner.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

Denson

Jurickova

Karns

et al. 2018

Inflammatory Bowel Diseases

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Background: Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. Methods:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. Results:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). Conflicts of interest:The authors have no financial arrangements with any company whose product figures prominently in the submitted manuscript or with a company making a competing product. Dr. Denson has received grant support from Janssen and holds a patent for the use of GM-CSF auto-antibodies as a diagnostic doi: 10.1093/ibd/izy265 Published online 13 August 2018 test in inflammatory bowel disease. Dr. Dubinsky has served as a consultant for Abbvie, Takeda, Janssen, and Pfizer and has received research support from Abbvie, Janssen, and Prometheus. Dr. Guthery has received research support in the last year from Regeneron Pharmaceuticals. Dr. Leleiko or his immediate family have equity interests in Celgene, Vericel, Ionis, Vertex, and Alnylam, and he has served as a consultant for CRICO. The remaining authors have nothing to declare. 2Denson et al from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001).Conclusions: Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

Denson

Jurickova

Karns

et al. 2018

Inflammatory Bowel Diseases

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“…Based on our finding, we predict that while the genetic landscape of the second-generation immigrants will be similar to their parents, the genetic correlation to Paneth cell defects will trend more toward European ancestry North American CD. In addition, conducting genetic-Paneth cell defect analysis with focused ethnic groups (e.g., Ashkenazi Jewish) (61,62) and with cross-ethnic groups (5) may provide additional insight into potential gene-gene interactions in triggering Paneth cell defect.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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IntroductionCrohn's disease (CD) and ulcerative colitis are 2 main classical types of inflammatory bowel disease (IBD) (1, 2). The etiology of IBD involves genetic susceptibility and environmental triggers. Over 200 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to IBD (3-7). This complex genetic network indicates that IBD likely encompasses more than the 2 classical subtypes. Therefore, novel, rationally designed biomarkers that can lead to disease stratification and personalized treatments are needed (8). One candidate method to subtype CD is to define the morphological patterns of small intestinal Paneth cells based on the intracellular distribution of granules containing antimicrobial proteins (Paneth cell phenotypes) (7). Paneth cells are specialized secretory cells located at the bases of the crypts of Lieberkühn in the small intestine (9-11). These cells produce a wide repertoire of antimicrobial BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy.

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“…They identified a frameshift mutation in CSF2RB as a strong causal candidate which was associated with CD at p<3.5×10 -6 and an OR of 1.5 369 . This variant is rare in the non-AJ population.…”

Section: Other Investigations To Identify Causal Moleculesmentioning

confidence: 99%

Making sense of the cause of Crohn’s – a new look at an old disease

Segal

2016

F1000Res

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The cause of Crohn’s disease (CD) has posed a conundrum for at least a century. A large body of work coupled with recent technological advances in genome research have at last started to provide some of the answers. Initially this review seeks to explain and to differentiate between bowel inflammation in the primary immunodeficiencies that generally lead to very early onset diffuse bowel inflammation in humans and in animal models, and the real syndrome of CD. In the latter, a trigger, almost certainly enteric infection by one of a multitude of organisms, allows the faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. Direct investigation of patients’ inflammatory response together with genome-wide association studies (GWAS) and DNA sequencing indicate that in CD the failure of acute inflammation and the clearance of bacteria from the tissues, and from within cells, is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. In this review I will examine the contemporary evidence that has led to this understanding, and look for explanations for the recent dramatic increase in the incidence of this disease.

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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

Cited by 56 publications

References 37 publications

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Making sense of the cause of Crohn’s – a new look at an old disease

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