Effect of a thrombin receptor (protease-activated receptor 1, PAR-1) gene polymorphism in chronic hepatitis C liver fibrosis.
OBJECTIVE
Tissue injury leads to activation of coagulation and generation of thrombin. Inhibition of thrombin receptor protease-activated receptor 1 (PAR-1) has been shown to reduce liver fibrosis in animals. This study aimed to evaluate the effect of PAR-1 gene polymorphism on rate of liver fibrosis (RF) in chronic hepatitis C.


METHODS
Polymorphisms studied: C > T transition 1426 bp upstream of translation start site (-1426C/T), 13 bp repeat of preceding -506 5'-CGGCCGCGGGAAG-3' sequence (-506I/D), and A > T transversion in intervening sequence (IVS) 14 bp upstream of exon-2 start site (IVS-14A/T). A total of 287 European and 90 Brazilian patients were studied.


RESULTS
1426C/T polymorphism: There was a trend to higher RF in patients with the TT genotype (P = 0.06) and an association between genotype CC and slow fibrosis (P = 0.03) in Europeans. In males, RF was significantly higher in those with the TT genotype compared to CT (P = 0.003) and CC (P = 0.007). There was a significant association between TT and fast fibrosis (P = 0.04). This was confirmed in an independent cohort of Brazilians where RF was higher in TT than in CC (P = 0.03). Analysis of -506I/D showed no difference in RF and distribution of slow/fast fibrosis among different genotypes in both populations. Analysis of IVS-14A/T showed no difference between genotypes.


CONCLUSIONS
In conclusion, these findings suggest that PAR-1 receptor polymorphisms influence the progression of liver fibrosis.
Martinelli
Ana
A
Department of Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil. adlcmart@fmrp.usp.br
Knapp
Susanne
S
Anstee
Quentin
Q
Worku
Mulugeta
M
Tommasi
Anna
A
Zucoloto
Sergio
S
Goldin
Robert
R
Thursz
Mark
M
D000328:Adult; D001938:Brazil; D018450:Disease Progression; D005060:Europe; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000821:virology; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D044463:Receptor, PAR-1 / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
D044463:Receptor, PAR-1