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High-frequency Haplotypes in the X Chromosome Locus TLR8 Are Associated With Both CD and UC in Females

Saruta, Masayuki MD1; Targan, Stephan R. MD1; Mei, Ling MD2; Ippoliti, Andrew F. MD1; Taylor, Kent D. MD2; Rotter, Jerome I. MD2

doi: 10.1002/ibd.20754
Original Article: Original Basic Science Articles

Background: TNF-α and IL-1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15/NOD2. Recently, Toll-like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD.

Methods: Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes.

Results: Both “risk (H4)” and “protective (H1)” TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls (P = 0.02). Fifty-nine percent of CD females had H1 compared with 72% of controls (P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4–0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0–2.2. Thus, the risk for IBD was 4–5 times higher in females with 1 risk haplotype than with the protective/protective diplotype.

Conclusions: TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well.

1Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California

2Medical Genetics Institute, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California

Reprints: Stephan R. Targan, MD, Director, Division of Gastroenterology, Inflammatory Bowel Disease Center and Immunobiology Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles CA 90048


Received for publication August 12 2008; Accepted August 13 2008

Published online 22 October 2008 in Wiley InterScience (

Supported in part by National Institutes of Health (NIH) grant Program Project Grant DK 45763 and the Cedars-Sinai Board of Governors Chair in Medical Genetics (to J.I.R). Genotyping was supported in part by the Cedars-Sinai GCRC genotyping core (M01-RR00425).

Additional Supporting Material may be found in the online version of this article.

© Crohn's & Colitis Foundation of America, Inc.
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