A common polymorphism in theABCB11gene is associated with advanced fibrosis in hepatitis C but not in non-alcoholic fatty liver disease

Abstract

Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) μmol/l compared with 3.5 (1-61) μmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.

Bile Acids Specifically Increase Hepatitis C Virus RNA-Replication

“…However, since drug resistant variants are rapidly selected during monotherapy [4], these drugs complement but do not replace the previous IFN-based regimen. HCV patients that have high serum levels of BAs respond poorly to IFN therapy [5] and are more prone to develop hepatic fibrosis [6]. BAs therefore were suggested to play an important role in pathogenesis and therapy response of HCV [7], [8].…”

A preliminary investigation on single nucleotide polymorphism rs2287622 of bile salt export pump gene in patients with chronic hepatitis C virus infection in Hunan, China

“…Europeans researches suggested that the polymorphism of BSEP V444A might be associated with the HCV infection development, liver fibrosis progression and long-term treatment response [8–11]. The few studies needed to be further supported by researches on extended population.…”

“…In recent years, researches on different related genetic variants have been published [4–11]. Since 2009, single nucleotide polymorphisms (SNPs) of the interleukin-28B gene have been identified as accurate predictors for therapy response and spontaneous clearance of HCV infection [4, 5].…”

“…Since 2011, several European researches have underscored associations between a certain SNP, V444A (HGVS name: NM_003742.2: c.1331 T > C; ref SNP: rs2287622) in exon 13 of the hepatobiliary bile salt export pump (BSEP) gene, and the risk of HCV infection, progression of liver fibrosis and even the virological response during anti-HCV therapy [8–11]. But their findings need to be validated by investigation on extended population, especially on population of different races.…”

Nuclear Receptor Variants in Liver Disease

“…Viral replication efficiency has been linked to variations in cellular bile salt concentrations using the HCV replicon system [61]. Of note, variants of the human bile salt that export pump ABCB11 might be associated with sustained virological response [62] and progression towards liver cirrhosis [63]. In vitro experiments using HCV replicon-harboring cells have shown that the impact of bile salts on HCV replication might be through the action of FXR rather than a direct effect of bile salts themselves [64].…”