Tumor necrosis factor receptor gene polymorphisms in Crohn's disease: association with clinical phenotypes.
OBJECTIVE
Crohn's disease (CD) is a chronic multifactorial disorder with diverse clinical features that are influenced by a heterogeneous set of genetic factors. TNF-alpha/TNF receptor interactions play a pivotal role in the pathogenesis of the inflammatory response. Our purpose was to determine whether single nucleotide polymorphisms (SNPs) in the TNF receptors confer susceptibility to Crohn's disease and whether they are associated with clinical phenotype.


METHODS
A cohort of 205 consecutively identified and unrelated patients with CD and 106 controls were recruited. Subjects were genotyped for polymorphisms in TNFRSF1A (position +36, -609), TNFRSF1B (+196, +1466), along with the three common CARD15 variants and phenotyped for disease behavior. Genotypic and allelic frequencies were compared between CD and controls and a logistic regression model was constructed to determine independent associations with specific clinical phenotypes.


RESULTS
Only the TNFRSF1A +36 and TNFRSF1B +196 SNPs were associated with CD (p= 0.0019 and 0.034, respectively). The TNFRSF1A +36 mutation was negatively associated with stricturing disease phenotype (OR = 0.384; CI = 0.166-0.887). In contrast, the TNFRSF1B +196 was negatively associated with colitis (OR = 0.410; CI = 0.191-0.880). These associations were independent of CARD15 mutation status. Finally, TNFRSF1B +196 was negatively associated with surgery in CARD15 negative patients.


CONCLUSIONS
These data constitute the first report of an association of TNFRSF1A and TNFRSF1B polymorphisms with CD in a Caucasian population and address the role of TNFR mutations in determining clinical heterogeneity in CD.
Waschke
Kevin A
KA
Department of Medicine, Division of Gastroenterology, McGill University Inflammatory Bowel Disease Program, Montreal, Canada.
Villani
Alexandra-Chloe
AC
Vermeire
Severine
S
Dufresne
Line
L
Chen
Tsao-Chun
TC
Bitton
Alain
A
Cohen
Albert
A
Thomson
Alan B R
AB
Wild
Gary E
GE
D000225:Adenine; D000328:Adult; D015331:Cohort Studies; D003092:Colitis / Q000235:genetics / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006147:Guanine; D006801:Humans; D007079:Ileitis / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D006147:Guanine; D000225:Adenine