Intrahepatic cholestasis: Analysis of genetic variants in an European cohort

Aims: Bile flow is maintained by hepatobiliary ATP-dependent transport proteins. ABCB11 ( BSEP ) exports bile acids, ABCB4 ( MDR3 ) flops phosphatidylcholine and ATP8B1 maintains the correct phospholipid composition of the canalicular membrane. Dysfunction of these proteins, or genes regulating their expression (e.g. farnesoid X receptor, FXR ), can lead to cholestatic disorders (known as BRIC or PFIC). Here we present the results of genetic testing as performed in our tertiary referral centre in the period from 2000–2011. Methods: We genotyped 198 pregnant women (age range 17–46 years) with suspected intrahepatic cholestasis of pregnancy (ICP) and 179 individuals with unexplained non-pregnancy related cholestasis (78 females, age range 13–73 years). We tested the following procholestatic mutations (marked with an asterisk) and polymorphisms: ATP8B1 (p.N45T*, p.E429A*, p.I661T*, p.R952Q), ABCB4 (p.R590Q*, c.787A>T), ABCB11 (p.E297G*, p.A444V, p.D482G*, c.3084A>G), and FXR (c.-1G>T). Results: The major procholestatic mutations were carried by 7 individuals in the ICP cohort (3.5%) and by 10 individuals (5.6%) in the cholestasis cohort. However, none of the patients tested positive for more than one of these mutations. The ABCB4 variant p.R590Q was found in two individuals with cholestasis and five women with ICP. The BRIC1/PFIC1-associated ATP8B1 mutation p.I661T was found in three patients with cholestasis but in none of the ICP cohort. One individual in the ICP cohort and five individuals in the cholestasis cohort were carriers of the ATP8B1 mutation p.N45T. The ABCB11 mutation p.D482G was detected in a single patient. Overall, the prevalence of genetic risk variants in comparison to European controls was markedly increased in both cohorts but was more pronounced in the cholestasis cohort. Conclusions: Our study underscores the feasibility of genetic detection of susceptibility factors for cholestatic disorders both in women with ICP and in patients with unexplained chronic cholestasis. Further studies are needed to detect additional rare mutations that contribute to cholestatic phenotypes in at-risk individuals.