The common bile salt transporter polymorphism ABCB11C.1331T>C is associated with HCV infection but not with increased liver stiffness in a german cohort: Mechanistical implications

The hepatocanalicular bile salt export pump BSEP (ABCB11) is the central transporter of bile acids from hepatocytes into bile canaliculi. Homozygous inactivations cause progressive familial cholestasis type 2 (PFIC2) resulting in end-stage liver disease, fibrosis and cirrhosis. The frequent sequence variant ABCB11 c.1331T>C (p.V444A) has been associated with different serum bile acid levels. Homozygosity for the [C]-allele causes a threefold increase in the risk of developing intrahepatic cholestasis of pregnancy (ICP). The aim of our study was to investigate a potential correlation between ABCB11c.1331T>C and liver stiffness in a cohort of German patients with HCV infection ABCB11 c.1331T>C was genotyped in 723 HCV-infected patients and uninfected controls (n=413). Liver stiffness was measured in 556 patients by transient elastograpy. Allele distribution was significantly different in HCV-patients compared to uninfected controls (p=0.04). Carriers of the risk allele [C] have a 1.5-fold likelihood of being HCV positive than patients with homozygous [T]-allele (p=0.02). No association was detected between the ABCB11 c.1331T>C polymorphism and liver stiffness (p=0.3) The risk allele [C] is associated with lower activity of the bile salt export pump. This may cause increased bile acid concentrations inside hepatocytes. Bile acids increase viral replication in vitro. Lack of association with liver stiffness might point towards a different underlying mechanism: Bile acids are tightly linked with cholesterol and lipid metabolism. High serum cholesterol levels have been associated with sustained SVR in patients treated with PEG-interferon and ribavirin. HCV replication is associated with lipid droplets. Metabolomic analyses showed a significant increase in cholesterol and free fatty acid levels in HCV-infected cells, with cholesterol and free fatty acid levels more than a third higher in HCV-infected cells.

Table1: Genotype distribution and associated risk ratio of ABCB11c.1331T>C in German patients

ABCB11p.V444A (c.1331T>C) genotypes/alleles	patients (n=720)	controls (n=413)
TT	102 (14%)	82 (20%)
TC	357 (50%)	195 (47%)
CC	261 (36%)	136 (33%)
T	561 (39%)	359 (43%)
C	879 (61%)	467 (57%)

Risk allele „C“	Relative risk	95% confidence interval	P
C ↔ T	1,204	[1,013–1,433]	0,036
CC ↔ TC+TT	1,543	[1,080–2,205]	0,017
CC + CT ↔ TT	1,501	[1,090–2,067]	0,012
TC ↔ TT	1,472	[1,049–2,066]	0,025

HCV - bile acids - fibrosis - genetics - infection - predisposition