Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus

Jean Paul Achkar, Themistocles Dassopoulos, Mark S. Silverberg, Jeffrey A. Tuvlin, Richard H. Duerr, Steven R. Brant, Kathy Siminovitch, Deepa Reddy, Lisa Datta, Theodore M Bayless, Leilei Zhang, M. Michael Barmada, John D. Rioux, A. Hillary Steinhart, Robin S. McLeod, Anne M. Griffiths, Zane Cohen, Huiying Yang, Gillian P. Bromfield, Phil Schumm & 3 others Stephen B. Hanauer, Judy H. Cho, Dan L. Nicolae

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p <0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

Original languageEnglish (US)
Pages (from-to)572-580
Number of pages9
JournalAmerican Journal of Gastroenterology
Volume101
Issue number3
DOIs
StatePublished - Mar 2006

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Genetic Linkage
Ulcerative Colitis
Inflammatory Bowel Diseases
Ileal Diseases
Phenotype
Small Intestine
Colon
Disease Susceptibility
Crohn Disease
Chromosomes
Inflammation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Achkar, J. P., Dassopoulos, T., Silverberg, M. S., Tuvlin, J. A., Duerr, R. H., Brant, S. R., ... Nicolae, D. L. (2006). Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. American Journal of Gastroenterology, 101(3), 572-580. https://doi.org/10.1111/j.1572-0241.2006.00451.x

Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. / Achkar, Jean Paul; Dassopoulos, Themistocles; Silverberg, Mark S.; Tuvlin, Jeffrey A.; Duerr, Richard H.; Brant, Steven R.; Siminovitch, Kathy; Reddy, Deepa; Datta, Lisa; Bayless, Theodore M; Zhang, Leilei; Barmada, M. Michael; Rioux, John D.; Steinhart, A. Hillary; McLeod, Robin S.; Griffiths, Anne M.; Cohen, Zane; Yang, Huiying; Bromfield, Gillian P.; Schumm, Phil; Hanauer, Stephen B.; Cho, Judy H.; Nicolae, Dan L.

In: American Journal of Gastroenterology, Vol. 101, No. 3, 03.2006, p. 572-580.

Research output: Contribution to journalArticle

Achkar, JP, Dassopoulos, T, Silverberg, MS, Tuvlin, JA, Duerr, RH, Brant, SR, Siminovitch, K, Reddy, D, Datta, L, Bayless, TM, Zhang, L, Barmada, MM, Rioux, JD, Steinhart, AH, McLeod, RS, Griffiths, AM, Cohen, Z, Yang, H, Bromfield, GP, Schumm, P, Hanauer, SB, Cho, JH & Nicolae, DL 2006, 'Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus', American Journal of Gastroenterology, vol. 101, no. 3, pp. 572-580. https://doi.org/10.1111/j.1572-0241.2006.00451.x
Achkar, Jean Paul ; Dassopoulos, Themistocles ; Silverberg, Mark S. ; Tuvlin, Jeffrey A. ; Duerr, Richard H. ; Brant, Steven R. ; Siminovitch, Kathy ; Reddy, Deepa ; Datta, Lisa ; Bayless, Theodore M ; Zhang, Leilei ; Barmada, M. Michael ; Rioux, John D. ; Steinhart, A. Hillary ; McLeod, Robin S. ; Griffiths, Anne M. ; Cohen, Zane ; Yang, Huiying ; Bromfield, Gillian P. ; Schumm, Phil ; Hanauer, Stephen B. ; Cho, Judy H. ; Nicolae, Dan L. / Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. In: American Journal of Gastroenterology. 2006 ; Vol. 101, No. 3. pp. 572-580.
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T1 - Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus

AU - Achkar, Jean Paul

AU - Dassopoulos, Themistocles

AU - Silverberg, Mark S.

AU - Tuvlin, Jeffrey A.

AU - Duerr, Richard H.

AU - Brant, Steven R.

AU - Siminovitch, Kathy

AU - Reddy, Deepa

AU - Datta, Lisa

AU - Bayless, Theodore M

AU - Zhang, Leilei

AU - Barmada, M. Michael

AU - Rioux, John D.

AU - Steinhart, A. Hillary

AU - McLeod, Robin S.

AU - Griffiths, Anne M.

AU - Cohen, Zane

AU - Yang, Huiying

AU - Bromfield, Gillian P.

AU - Schumm, Phil

AU - Hanauer, Stephen B.

AU - Cho, Judy H.

AU - Nicolae, Dan L.

PY - 2006/3

Y1 - 2006/3

N2 - OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p <0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

AB - OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p <0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

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