The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis

Andrea D. Tyler, Raquel Milgrom, Joanne M. Stempak, Wei Xu, John Hunter Brumell, Aleixo M. Muise, Rishabh Sehgal, Zane Cohen, Walter Koltun, Bo Shen, Mark S. Silverberg

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Abstract

Background: Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common. Objective: To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn's disease-like (CDL) phenotype. Design: 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype. Results: Clinical and genetic data were available on 714 individuals. 487 (68.2%) were classified as NCP, 118 (16.5%) CP and 109 (15.3%) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The NOD2insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10-5). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in NOX3 (rs6557421, rs12661812), DAGLB (rs836518) and NCF4 (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-Saccharomyces cerevisiae antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10-7) for NCP versus CP/CDL and 3.22 (p=4.11×10-8) for NCP versus CDL, respectively. Conclusion: Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.

Original languageEnglish (US)
Pages (from-to)1433-1439
Number of pages7
JournalGut
Volume62
Issue number10
DOIs
StatePublished - Oct 1 2013

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Pouchitis
Colonic Pouches
Ulcerative Colitis
Crohn Disease
Single Nucleotide Polymorphism
Chronic Disease
Phenotype
Sclerosing Cholangitis
Antineutrophil Cytoplasmic Antibodies
Ileostomy
Joint Diseases
Ontario
Genetic Polymorphisms
North America
Genetic Markers
Inflammatory Bowel Diseases
Arthritis
Canada
Saccharomyces cerevisiae
Immunoglobulin G

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Tyler, A. D., Milgrom, R., Stempak, J. M., Xu, W., Brumell, J. H., Muise, A. M., ... Silverberg, M. S. (2013). The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis. Gut, 62(10), 1433-1439. https://doi.org/10.1136/gutjnl-2011-301957
Tyler, Andrea D. ; Milgrom, Raquel ; Stempak, Joanne M. ; Xu, Wei ; Brumell, John Hunter ; Muise, Aleixo M. ; Sehgal, Rishabh ; Cohen, Zane ; Koltun, Walter ; Shen, Bo ; Silverberg, Mark S. / The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis. In: Gut. 2013 ; Vol. 62, No. 10. pp. 1433-1439.
@article{cd839a883ac54fe39c3857e4d6c00857,
title = "The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis",
abstract = "Background: Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common. Objective: To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn's disease-like (CDL) phenotype. Design: 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype. Results: Clinical and genetic data were available on 714 individuals. 487 (68.2{\%}) were classified as NCP, 118 (16.5{\%}) CP and 109 (15.3{\%}) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The NOD2insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10-5). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in NOX3 (rs6557421, rs12661812), DAGLB (rs836518) and NCF4 (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-Saccharomyces cerevisiae antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10-7) for NCP versus CP/CDL and 3.22 (p=4.11×10-8) for NCP versus CDL, respectively. Conclusion: Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.",
author = "Tyler, {Andrea D.} and Raquel Milgrom and Stempak, {Joanne M.} and Wei Xu and Brumell, {John Hunter} and Muise, {Aleixo M.} and Rishabh Sehgal and Zane Cohen and Walter Koltun and Bo Shen and Silverberg, {Mark S.}",
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Tyler, AD, Milgrom, R, Stempak, JM, Xu, W, Brumell, JH, Muise, AM, Sehgal, R, Cohen, Z, Koltun, W, Shen, B & Silverberg, MS 2013, 'The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis', Gut, vol. 62, no. 10, pp. 1433-1439. https://doi.org/10.1136/gutjnl-2011-301957

The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis. / Tyler, Andrea D.; Milgrom, Raquel; Stempak, Joanne M.; Xu, Wei; Brumell, John Hunter; Muise, Aleixo M.; Sehgal, Rishabh; Cohen, Zane; Koltun, Walter; Shen, Bo; Silverberg, Mark S.

In: Gut, Vol. 62, No. 10, 01.10.2013, p. 1433-1439.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis

AU - Tyler, Andrea D.

AU - Milgrom, Raquel

AU - Stempak, Joanne M.

AU - Xu, Wei

AU - Brumell, John Hunter

AU - Muise, Aleixo M.

AU - Sehgal, Rishabh

AU - Cohen, Zane

AU - Koltun, Walter

AU - Shen, Bo

AU - Silverberg, Mark S.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Background: Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common. Objective: To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn's disease-like (CDL) phenotype. Design: 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype. Results: Clinical and genetic data were available on 714 individuals. 487 (68.2%) were classified as NCP, 118 (16.5%) CP and 109 (15.3%) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The NOD2insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10-5). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in NOX3 (rs6557421, rs12661812), DAGLB (rs836518) and NCF4 (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-Saccharomyces cerevisiae antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10-7) for NCP versus CP/CDL and 3.22 (p=4.11×10-8) for NCP versus CDL, respectively. Conclusion: Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.

AB - Background: Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common. Objective: To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn's disease-like (CDL) phenotype. Design: 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype. Results: Clinical and genetic data were available on 714 individuals. 487 (68.2%) were classified as NCP, 118 (16.5%) CP and 109 (15.3%) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The NOD2insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10-5). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in NOX3 (rs6557421, rs12661812), DAGLB (rs836518) and NCF4 (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-Saccharomyces cerevisiae antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10-7) for NCP versus CP/CDL and 3.22 (p=4.11×10-8) for NCP versus CDL, respectively. Conclusion: Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.

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