The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction.
OBJECTIVE
The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort.


METHODS
A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available.


RESULTS
A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P </= 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively).


CONCLUSIONS
The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4.
Pierik
Marie
M
Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. Marieke.Pierik@uz.kuleuven.ac.be
Yang
Huiying
H
Barmada
Michael M
MM
Cavanaugh
Juleen A
JA
Annese
Vito
V
Brant
Steven R
SR
Cho
Judy H
JH
Duerr
Richard H
RH
Hugot
Jean-Pierre
JP
McGovern
Dermot P
DP
Paavola-Sakki
Paulina
P
Radford-Smith
Graham L
GL
Pavli
P
P
Silverberg
Mark S
MS
Schreiber
Stephan
S
Taylor
Kent D
KD
Vlietinck
Robert
R
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002883:Chromosomes, Human, Pair 14; D015331:Cohort Studies; D004777:Environment; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D040641:Quantitative Trait Loci; D035781:Siblings; D012907:Smoking / Q000009:adverse effects*