A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population

Abstract

BackgroundThe human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T > C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-α2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T > C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients.MethodsABCB11 c.1331 T > C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness.ResultsHomo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T > C genotype and increased liver stiffness.ConclusionsOur data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T > C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.

Intrahepatic cholestasis in common chronic liver diseases

“…A common variant (p.A444V) of the hepatocanalicular BSEP (ABCB11) is associated with significant reduction in response rates for patients infected with HCV genotypes 2 and 3 compared with wild‐type carriers; a weaker association was found for genotype 1 . Consistent with these findings, two other studies showed that this variant was associated with HCV positivity in 206 and 649 patients, respectively. These data suggest that decreased BSEP expression in patients harbouring the p.A444V variant may lead to increased intracellular bile acid levels, which in turn may enhance viral replication via FXR.…”

Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population

“…Measuring liver stiffness with TE is an effective, non-invasive, reproducible and currently well-established method to assess liver fibrosis [28,46,47]. Several studies have previously described associations between genetic variants and various liver diseases, using transient elastography as phenotype [48][49][50][51][52][53][54][55][56]. We used a cut-off of 8.0 kPa for clinically relevant liver fibrosis, as proposed and validated in previous community-based studies [26,27].…”

Host Genetic Variants in the Pathogenesis of Hepatitis C

“…In a study of 649 HCV-infected patients and 413 controls, risk allele C carriers were overrepresented, but liver stiffness was not associated according to ABCB11 1331 genetic variants [96]. No significant association between ABCB11 polymorphism and prevalence of cirrhosis either in patients with nonalcoholic fatty liver disease (NASH) [89] or in a population with alcoholic liver disease [97] could be identified.…”