Genetic polymorphism in cyclooxygenase‐2 promoter affects hepatic inflammation and fibrosis in patients with chronic hepatitis C

Abstract

Cyclooxygenase (COX)-2 is involved in inflammation, anti-apoptosis and carcinogenesis. The -1195GG genotype of single nucleotide polymorphism (SNP) in COX-2 promoter was associated with low platelet counts in patients with chronic hepatitis C. Polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (rs738409 C>G) have been reported to be associated with cirrhosis, and the major genotype of SNPs near interleukin (IL)28B are related to viral clearance. The present study was designed to assess the contribution of these SNPs to disease progression in patients with chronic hepatitis C. The study enrolled 220 Japanese patients with chronic hepatitis C. Three SNPs, -1195 COX-2, PNPLA3 and IL28B (rs8099917), were genotyped in order to analyze their association with hepatic fibrosis and inflammation. The -1195GG genotype in COX-2 was associated with advanced fibrosis and higher levels of inflammation in the liver tissues. The major genotype of IL28B was also associated with advanced fibrosis, but the polymorphism of PNPLA3 was neither associated with fibrosis nor inflammation. Multivariate analysis showed that -1195GG in COX-2 is an independent factor associated with advanced fibrosis, while the major genotype of IL28B and HCV genotype 2 were other independent factors. In conclusion, the -1195GG genotype in COX-2 is a genetic marker for liver disease progression, while the PNPLA3 genotypes are not associated with disease progression in Japanese patients with chronic hepatitis C.

Predictive impact of polymorphism of PNPLA3 on HCC development after interferon therapy in Japanese patients with chronic hepatitis C

“…Liver steatosis, inflammation, insulin resistance, and excessive body composition may accelerate HCC development. Among those factors, we could find none significantly associated with the SNP genotype of PNPLA3 as previously reported (Miyashita et al 2012; Kotronen et al 2009). …”

“…A recent genome-wide association study for Japanese patients with non-alcoholic fatty liver disease by Kawaguchi et al revealed that the risk variant of PNPLA3 148 M is significantly associated with non-alcoholic steatohepatitis, but did not show significant differences in liver steatosis or fibrosis among the patients with non-alcoholic fatty liver disease (Kawaguchi et al 2012). Miyashita et al studied the associations of the SNP genotype of PNPLA3 with liver fibrosis and inflammation for Japanese patients with chronic hepatitis C, without significant associations in the results (Miyashita et al 2012). Takeuchi et al reported that the SNP genotype of PNPLA3 might not affect HCC prognosis in Japanese patients with hepatitis B virus, HCV, or non-alcoholic fatty liver diseases (Takeuchi et al 2013).…”

PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients

“…PNPLA3 polymorphisms have also been reported to be associated with hepatic steatosis, fibrosis, treatment response, and carcinogenesis in CHC (Valenti et al 2011 ; Trepo et al 2011 ; Cai et al 2011 ; Valenti et al 2012 ; Clark et al 2012 ; Dunn et al 2014 ; Ezzikouri et al 2014 ; Moritou et al 2013 ; Zampino et al 2013 ; Trepo et al 2014 ; Sato et al 2013 ). However, several reports have not found an association of PNPLA3 polymorphisms with fibrosis and carcinogenesis in CHC (Trepo et al 2011 ; Nischalke et al 2011 ; Rembeck et al 2012 ; Miyashita et al 2012 ; Takeuchi et al 2013 ; Nakamura et al 2013 ; Guyot et al 2013 ).…”

Constitutive activation of AMPK α1 in vascular endothelium promotes high‐fat diet‐induced fatty liver injury: role of COX‐2 induction

“…The expression levels of COX-2 are extremely low in normal liver tissues, but up-regulated under pathological conditions such as acute liver failure (Demirel et al, 2012), hepatic fibrosis and cirrhosis (Kwon et al, 2012), as well as hepatocarcinogenesis (Giannitrapani et al, 2009). Genetic polymorphism of COX-2 has been linked with liver disease progression in human (Miyashita et al, 2012). Both clinical and animal studies demonstrate that selective inhibition of COX-2 attenuates liver dysfunctions associated with hepatic inflammation, fibrosis, cirrhosis and cancer (Planaguma et al, 2005;Breinig et al, 2007;Tu et al, 2007;Hsieh et al, 2009;Paik et al, 2009).…”