Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection.
OBJECTIVE
Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with the original polymorphisms.


METHODS
We carried out dense genotyping and association testing of additional SNPs in each of the 7 regions in Caucasian case control samples.


RESULTS
We identified several SNPs in the toll-like receptor 4 (TLR4) and syntaxin binding protein 5-like (STXBP5L) loci that were associated with fibrosis risk independently of the original significant SNPs. Haplotypes consisting of these SNPs in TLR4 and STXBP5L were strongly associated with fibrosis risk (global P=3.04 x 10(-5) and 4.49 x 10(-6), respectively).


CONCLUSIONS
Multiple variants in TLR4 and STXBP5L genes modulate risk of liver fibrosis. These findings are of relevance for understanding the pathogenesis of HCV-induced liver disease in Caucasians and may be extended to other ethnicities as well.
Li
Yonghong
Y
Celera Corporation, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA. yonghong.li@celera.com
Chang
Monica
M
Abar
Olivia
O
Garcia
Veronica
V
Rowland
Charles
C
Catanese
Joseph
J
Ross
David
D
Broder
Samuel
S
Shiffman
Mitchell
M
Cheung
Ramsey
R
Wright
Teresa
T
Friedman
Scott L
SL
Sninsky
John
J
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D044465:White People / Q000235:genetics*
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; C492527:STXBP5L protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4