Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease

Kelli L. Vandussen; Ta Chiang Liu; Dalin Li; Fadi Towfic; Nir Modiano; Rachel Winter; Talin Haritunians; Kent D. Taylor; Deepti Dhall; Stephan R. Targan; Ramnik J. Xavier; Dermot P.B. McGovern; Thaddeus S. Stappenbeck

doi:10.1053/j.gastro.2013.09.048

Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease

Kelli L. Vandussen
, Ta Chiang Liu
, Dalin Li
, Fadi Towfic
, Nir Modiano
, Rachel Winter
, Talin Haritunians
, Kent D. Taylor
, Deepti Dhall
, Stephan R. Targan
, Ramnik J. Xavier
, Dermot P.B. McGovern
, Thaddeus S. Stappenbeck

Research output: Contribution to journal › Article › peer-review

172 Scopus citations

Abstract

Background & Aims Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. Methods We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. Results The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Conclusions Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.

Original language	English (US)
Pages (from-to)	200-209
Number of pages	10
Journal	Gastroenterology
Volume	146
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2013.09.048
State	Published - Jan 2014
Externally published	Yes

Funding

Funding K.L.V. was supported by a National Institutes of Health training grant ( T32 AI007163 ). The research was funded by a Washington University Institute of Clinical and Translational Sciences Pilot Award ( CTSA308 ). The Washington University Digestive Disease Research Core Center is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Disease ( P30DK052574 ). IBD Research at Cedars-Sinai is supported by US Public Health Service grant PO1DK046763 and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. Genotyping at Cedars-Sinai Medical Center is supported in part by the National Center for Research Resources grant M01-RR00425 , UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute grant ( UL1 TR000124-01 ), the Southern California Diabetes and Endocrinology Research grant ( DK063491 ). 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 (CCFA) (D.P.B.M.), The Feintech Family Chair in IBD (S.R.T.), The Joshua L. and Lisa Z. Greer Chair in IBD Genetics (D.P.B.M.), and grants DK043351 , DK097485 , DK092405 (R.J.X.), DK062413 , DK046763-19 , AI067068 , HS021747 (D.P.B.M.), and AI084887 (T.S.S.). T.S.S. and R.J.X. are supported by the CCFA Genetics initiative .

Funders	Funder number
Crohn's and Colitis Foundation of America	DK092405, DK097485, AI067068, DK043351, AI084887, HS021747, DK062413, DK046763-19
Clinical and Translational Sciences Institute	CTSA308
Southern California Diabetes and Endocrinology Research	DK063491
Leona M. and Harry B. Helmsley Charitable Trust
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	T32 AI007163
European Commission
National Center for Research Resources	M01-RR00425
Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK052574
Penn State Clinical and Translational Science Institute	UL1 TR000124-01
U.S. Public Health Service	PO1DK046763

Keywords

Diagnosis
Inflammatory Bowel Disease
Pathogenesis
Prognostic Factor

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2013.09.048

Cite this

Vandussen, K. L., Liu, T. C., Li, D., Towfic, F., Modiano, N., Winter, R., Haritunians, T., Taylor, K. D., Dhall, D., Targan, S. R., Xavier, R. J., McGovern, D. P. B., & Stappenbeck, T. S. (2014). Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease. Gastroenterology, 146(1), 200-209. https://doi.org/10.1053/j.gastro.2013.09.048

@article{0982ce9f235b4710bebc68163b9925dd,

title = "Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease",

abstract = "Background \& Aims Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. Methods We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. Results The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Conclusions Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.",

keywords = "Diagnosis, Inflammatory Bowel Disease, Pathogenesis, Prognostic Factor",

author = "Vandussen, \{Kelli L.\} and Liu, \{Ta Chiang\} and Dalin Li and Fadi Towfic and Nir Modiano and Rachel Winter and Talin Haritunians and Taylor, \{Kent D.\} and Deepti Dhall and Targan, \{Stephan R.\} and Xavier, \{Ramnik J.\} and McGovern, \{Dermot P.B.\} and Stappenbeck, \{Thaddeus S.\}",

note = "Funding Information: Funding K.L.V. was supported by a National Institutes of Health training grant ( T32 AI007163 ). The research was funded by a Washington University Institute of Clinical and Translational Sciences Pilot Award ( CTSA308 ). The Washington University Digestive Disease Research Core Center is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Disease ( P30DK052574 ). IBD Research at Cedars-Sinai is supported by US Public Health Service grant PO1DK046763 and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. Genotyping at Cedars-Sinai Medical Center is supported in part by the National Center for Research Resources grant M01-RR00425 , UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute grant ( UL1 TR000124-01 ), the Southern California Diabetes and Endocrinology Research grant ( DK063491 ). 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 (CCFA) (D.P.B.M.), The Feintech Family Chair in IBD (S.R.T.), The Joshua L. and Lisa Z. Greer Chair in IBD Genetics (D.P.B.M.), and grants DK043351 , DK097485 , DK092405 (R.J.X.), DK062413 , DK046763-19 , AI067068 , HS021747 (D.P.B.M.), and AI084887 (T.S.S.). T.S.S. and R.J.X. are supported by the CCFA Genetics initiative . ",

year = "2014",

month = jan,

doi = "10.1053/j.gastro.2013.09.048",

language = "English (US)",

volume = "146",

pages = "200--209",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "1",

}

TY - JOUR

T1 - Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease

AU - Vandussen, Kelli L.

AU - Liu, Ta Chiang

AU - Li, Dalin

AU - Towfic, Fadi

AU - Modiano, Nir

AU - Winter, Rachel

AU - Haritunians, Talin

AU - Taylor, Kent D.

AU - Dhall, Deepti

AU - Targan, Stephan R.

AU - Xavier, Ramnik J.

AU - McGovern, Dermot P.B.

AU - Stappenbeck, Thaddeus S.

N1 - Funding Information: Funding K.L.V. was supported by a National Institutes of Health training grant ( T32 AI007163 ). The research was funded by a Washington University Institute of Clinical and Translational Sciences Pilot Award ( CTSA308 ). The Washington University Digestive Disease Research Core Center is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Disease ( P30DK052574 ). IBD Research at Cedars-Sinai is supported by US Public Health Service grant PO1DK046763 and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. Genotyping at Cedars-Sinai Medical Center is supported in part by the National Center for Research Resources grant M01-RR00425 , UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute grant ( UL1 TR000124-01 ), the Southern California Diabetes and Endocrinology Research grant ( DK063491 ). 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 (CCFA) (D.P.B.M.), The Feintech Family Chair in IBD (S.R.T.), The Joshua L. and Lisa Z. Greer Chair in IBD Genetics (D.P.B.M.), and grants DK043351 , DK097485 , DK092405 (R.J.X.), DK062413 , DK046763-19 , AI067068 , HS021747 (D.P.B.M.), and AI084887 (T.S.S.). T.S.S. and R.J.X. are supported by the CCFA Genetics initiative .

PY - 2014/1

Y1 - 2014/1

N2 - Background & Aims Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. Methods We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. Results The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Conclusions Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.

AB - Background & Aims Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. Methods We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. Results The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Conclusions Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.

KW - Diagnosis

KW - Inflammatory Bowel Disease

KW - Pathogenesis

KW - Prognostic Factor

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DO - 10.1053/j.gastro.2013.09.048

M3 - Article

AN - SCOPUS:84890735514

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VL - 146

SP - 200

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JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -

Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease

Abstract

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Keywords

ASJC Scopus subject areas

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