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 journalArticle

75 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)200-209
Number of pages10
JournalGastroenterology
Volume146
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

Fingerprint

Paneth Cells
Crohn Disease
Phenotype
Genetic Loci
Genetic Predisposition to Disease
Alleles
Secretory Vesicles
Muramidase
Granuloma
Paraffin
Formaldehyde
Cluster Analysis

Keywords

  • Diagnosis
  • Inflammatory Bowel Disease
  • Pathogenesis
  • Prognostic Factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease. / Vandussen, Kelli L.; Liu, Ta Chiang; Li, Dalin; Towfic, Fadi; Modiano, Nir; Winter, Rachel; Haritunians, Talin; Taylor, Kent D.; Dhall, Deepti; Targan, Stephan R.; Xavier, Ramnik J.; McGovern, Dermot P B; Stappenbeck, Thaddeus S.

In: Gastroenterology, Vol. 146, No. 1, 01.2014, p. 200-209.

Research output: Contribution to journalArticle

Vandussen, KL, Liu, TC, Li, D, Towfic, F, Modiano, N, Winter, R, Haritunians, T, Taylor, KD, Dhall, D, Targan, SR, Xavier, RJ, McGovern, DPB & Stappenbeck, TS 2014, 'Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease', Gastroenterology, vol. 146, no. 1, pp. 200-209. https://doi.org/10.1053/j.gastro.2013.09.048
Vandussen, Kelli L. ; Liu, Ta Chiang ; Li, Dalin ; Towfic, Fadi ; Modiano, Nir ; Winter, Rachel ; Haritunians, Talin ; Taylor, Kent D. ; Dhall, Deepti ; Targan, Stephan R. ; Xavier, Ramnik J. ; McGovern, Dermot P B ; Stappenbeck, Thaddeus S. / Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease. In: Gastroenterology. 2014 ; Vol. 146, No. 1. pp. 200-209.
@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.}",
year = "2014",
month = "1",
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 Ltd",
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.

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

UR - http://www.scopus.com/inward/record.url?scp=84890735514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890735514&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2013.09.048

DO - 10.1053/j.gastro.2013.09.048

M3 - Article

VL - 146

SP - 200

EP - 209

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 1

ER -