Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus.
OBJECTIVE
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.
Achkar
Jean-Paul
JP
Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA.
Dassopoulos
Themistocles
T
Silverberg
Mark S
MS
Tuvlin
Jeffrey A
JA
Duerr
Richard H
RH
Brant
Steven R
SR
Siminovitch
Kathy
K
Reddy
Deepa
D
Datta
Lisa W
LW
Bayless
Theodore M
TM
Zhang
Leilei
L
Barmada
M Michael
MM
Rioux
John D
JD
Steinhart
A Hillary
AH
McLeod
Robin S
RS
Griffiths
Anne M
AM
Cohen
Zane
Z
Yang
Huiying
H
Bromfield
Gillian P
GP
Schumm
Phil
P
Hanauer
Stephen B
SB
Cho
Judy H
JH
Nicolae
Dan L
DL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003106:Colon / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008126:Lod Score; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C470090:IBD2 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D029701:Saccharomyces cerevisiae Proteins