Martinelli Ana, Knapp Susanne, Anstee Quentin, Worku Mulugeta, Tommasi Anna, Zucoloto Sergio, Goldin Robert, Thursz Mark
Department of Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
J Gastroenterol Hepatol. 2008 Sep;23(9):1403-9. doi: 10.1111/j.1440-1746.2007.05220.x. Epub 2007 Nov 14.
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.
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.
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.
In conclusion, these findings suggest that PAR-1 receptor polymorphisms influence the progression of liver fibrosis.
组织损伤会导致凝血激活及凝血酶生成。已证实抑制凝血酶受体蛋白酶激活受体1（PAR-1）可减轻动物肝纤维化。本研究旨在评估PAR-1基因多态性对慢性丙型肝炎患者肝纤维化速率（RF）的影响。
研究的多态性包括：翻译起始位点上游1426 bp处的C>T转换（-1426C/T）、-506位点前5'-CGGCCGCGGGAAG-3'序列的13 bp重复（-506I/D）以及外显子2起始位点上游14 bp的内含子序列（IVS）中的A>T颠换（IVS-14A/T）。共研究了287名欧洲患者和90名巴西患者。
1426C/T多态性：在欧洲人中，TT基因型患者的RF有升高趋势（P = 0.06），CC基因型与肝纤维化进展缓慢相关（P = 0.03）。在男性中，TT基因型患者的RF显著高于CT基因型（P = 0.003）和CC基因型（P = 0.007）。TT基因型与肝纤维化快速进展显著相关（P = 0.04）。这在一个独立的巴西人群队列中得到证实，其中TT基因型患者的RF高于CC基因型（P = 0.03）。-506I/D分析显示，在这两个人群中，不同基因型之间的RF及肝纤维化进展缓慢/快速分布无差异。IVS-14A/T分析显示基因型之间无差异。
总之，这些发现提示PAR-1受体多态性影响肝纤维化的进展。
