Association between Toll-like receptor 4 and inflammatory bowel disease.
BACKGROUND
The human Toll-like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family-based controls.


METHODS
In 781 IBD cases and 315 controls, genotyping was performed forAsp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD).


RESULTS
The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset > or = 40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found.


CONCLUSIONS
Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.
Oostenbrug
Liekele E
LE
Department of Gastroenterology and Hepatology, University of Groningen Medical Center, Groningen, The Netherlands. l.e.oostenbrug@inter.nl.net
Drenth
Joost P H
JP
de Jong
Dirk J
DJ
Nolte
Ilja M
IM
Oosterom
Elvira
E
van Dullemen
Hendrik M
HM
van der Linde
Klaas
K
te Meerman
Gerard J
GJ
van der Steege
Gerrit
G
Kleibeuker
Jan H
JH
Jansen
Peter L M
PL
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D018895:Microsatellite Repeats; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors