TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.
OBJECTIVE
Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD.


METHODS
A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied.


RESULTS
The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A.


CONCLUSIONS
This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.
Thiébaut
R
R
INSERM, U843, Hôpital Robert Debré, Université Paris Diderot, Paris, France.
Kotti
S
S
Jung
C
C
Merlin
F
F
Colombel
J F
JF
Lemann
M
M
Almer
S
S
Tysk
C
C
O'Morain
M
M
Gassull
M
M
Binder
V
V
Finkel
Y
Y
Pascoe
L
L
Hugot
J-P
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics*; D044465:White People / Q000235:genetics*; D055815:Young Adult
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15