TUCAN (CARD8) genetic variants and inflammatory bowel disease.
OBJECTIVE
The identification of the association between Crohn's disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor kappaB (NFkappaB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFkappaB, making it an excellent candidate gene for gastrointestinal inflammation.


METHODS
Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. A diagnostic panel for CD was constructed using smoking status and TUCAN, NOD2, IBD5, NOD1, and TNFSF15 data.


RESULTS
We demonstrate significant association between a TUCAN SNP and CD (OR 1.35, P = .0083). The association was more pronounced with disease affecting sites other than the colon (odds ratio, 1.52) and NOD2-negative CD (odds ratio, 1.50). Combination of these data with smoking and NOD2, IBD5, NOD1, and TNFSF15 status demonstrated very strong associations with CD and high sensitivities (96.3%), specificities (99.4%), and likelihood ratios (12.8) for CD, although further work will be needed before this model can be translated into direct clinical utility.


CONCLUSIONS
We have shown an association between a likely functional polymorphism in TUCAN and CD. The combination of these data in a genetic panel suggests that clinicians may soon be able to translate genetic advances into direct benefits for patients.
McGovern
Dermot P B
DP
Wellcome Trust Centre for Human Genetics, University of Oxford, Drive, Headington, Oxford OX3 7BN, England, UK. dermot@well.ox.ac.uk
Butler
Helen
H
Ahmad
Tariq
T
Paolucci
Marta
M
van Heel
David A
DA
Negoro
Kenichi
K
Hysi
Pirro
P
Ragoussis
Jiannis
J
Travis
Simon P L
SP
Cardon
Lon R
LR
Jewell
Derek P
DP
D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D003424:Crohn Disease / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005820:Genetic Testing; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics
D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D009363:Neoplasm Proteins; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15