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

Roman Müllenbach,Marcin Krawczyk,Christoph Sarrazin,Frank Lammert,Susanne N Weber,Frank Grünhage,Vincent Zimmer

doi:10.1186/1471-230x-12-63

Roman Müllenbach, Marcin Krawczyk + Show 5 more

Open Access

https://doi.org/10.1186/1471-230x-12-63

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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.

Highlights

The 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
T > C variant does not increase the risk of liver fibrosis or cirrhosis in chronic hepatitis C patients To assess a potential impact of the ABCB11 c.1331 risk genotype [CC] on cirrhosis, we performed univariate and multivariate logistic regression analyses
The only factor significantly associated with the presence of cirrhosis in multivariate analysis was the age of the patients (P = 0.006) (Table 3)

Summary

Introduction

The 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. It is estimated that there are 5 million carriers in Europe, and up to 500.000 chronically HCV-infected people in Germany [1] These individuals are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma [2,3]. This study and the follow-up by Marcolongo et al in an Italian population [15] illustrate the feasibility of genetic risk assessment for cirrhosis prediction. They accentuate the need to identify additional genetic factors that contribute towards HCV susceptibility and subsequent fibrotic progression. A comprehensive map of cirrhosis-associated variants might permit verification of interacting and modifying loci in selected patient groups, which would in turn improve the predictive values of polygenic cirrhosis risk scores

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