Association of Single Nucleotide Polymorphisms of the Bile Salt Export Pump Gene with Intrahepatic Cholestasis of Pregnancy

Ml, Eloranta; Häkli, Tanja; Hiltunen, Mikko; Helisalmi, Seppo; Punnonen, Kari; Heinonen, Seppo

doi:10.1080/00365520310000807

Cited by 69 publications

(5 citation statements)

References 26 publications

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“…In this study, we used a candidate sequencing approach to identify mutations with a potentially large impact on protein function. Separate studies have also taken a population genetics approach using candidate single nucleotide polymorphisms and/or tagging SNPs in an attempt to identify common variants that contribute to overall risk 31 , 38 , 52 , 53 . Common variants that make a much smaller contribution to disease risk in ICP populations have been identified at the ABCB4 and ABCB11 loci (in particular rs2109505 ( ABCB4 ) and rs2287622/rs7577650 ( ABCB11 ) 28 , 31 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy

Dixon

Sambrotta

Chambers

et al. 2017

Sci Rep

113

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Intrahepatic cholestasis of pregnancy (ICP) affects 1/140 UK pregnancies; with pruritus, hepatic impairment and elevated serum bile acids. Severe disease is complicated by spontaneous preterm delivery and stillbirth. Previous studies have reported mutations in hepatocellular transporters (ABCB4, ABCB11). High throughput sequencing in 147 patients was performed in the transporters ABCB4, ABCB11, ATP8B1, ABCC2 and tight junction protein 2 (TJP2). Twenty-six potentially damaging variants were identified with the following predicted protein changes: Twelve ABCB4 mutations - Arg47Gln, Met113Val, Glu161Gly, Thr175Ala, Glu528Glyfs*6, Arg590Gln, Ala601Ser, Glu884Ter, Gly722Ala, Tyr775Met (x2), Trp854Ter. Four potential ABCB11 mutations - Glu297Gly (x3) and a donor splice site mutation (intron 19). Five potential ATP8B1 mutations - Asn45Thr (x3), and two others, Glu114Gln and Lys203Glu. Two ABCC2 mutations - Glu1352Ala and a duplication (exons 24 and 25). Three potential mutations were identified in TJP2; Thr62Met (x2) and Thr626Ser. No patient harboured more than one mutation. All were heterozygous. An additional 545 cases were screened for the potential recurrent mutations of ATP8B1 (Asn45Thr) and TJP2 (Thr62Met) identifying three further occurrences of Asn45Thr. This study has expanded known mutations in ABCB4 and ABCB11 and identified roles in ICP for mutations in ATP8B1 and ABCC2. Possible novel mutations in TJP2 were also discovered.

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Section: Discussionmentioning

confidence: 99%

An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy

Dixon

Sambrotta

Chambers

et al. 2017

Sci Rep

113

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“…Zollner et al [32] found that, compared to controls, basolateral uptake systems (NTCP, OATP2) were reduced and BSEP and MRP2 were preserved, while MDR1, MDR3, and the basolateral efflux pump MRP3 were increased in PBC. Recent studies suggested that additional mutations in ABCB11 may be associated with various disease processes such as benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), and risk for drug-induced cholestasis (DC) [33–36]. …”

Section: Discussionmentioning

confidence: 99%

The Association between Bile Salt Export Pump Single-Nucleotide Polymorphisms and Primary Biliary Cirrhosis Susceptibility and Ursodeoxycholic Acid Response

Chen

Zhou

et al. 2014

Disease Markers

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Background. Primary biliary cirrhosis (PBC) is a chronic and progressive cholestasis liver disease. Bile salt export pump (BSEP) is the predominant bile salt efflux system of hepatocytes. BSEP gene has been attached great importance in the susceptibility of PBC and the response rate of ursodeoxycholic acid (UDCA) treatment of PBC patients. Methods. In this study, TaqMan assay was used to genotype four variants of BSEP, and the Barcelona criteria were used for evaluating the response rate of UDCA treatment. Results. Variant A allele of BSEP rs473351 (dominant model, OR = 2.063; 95% CI, 1.254–3.393; P = 0.004) was highly associated with PBC susceptibility. On the contrary, variant A allele of BSEP rs2287618 (dominant model, OR = 0.617; 95% CI, 0.411–0.928; P = 0.020) provided a protective role and Barcelona evaluation criterion indicated that the frequency of variant allele at BSEP rs2287618 was significantly decreased in UDCA-responsive PBC patients (P = 0.021). Conclusion. These results suggested that BSEP rs473351 was closely associated with the susceptibility of PBC and if people with BSEP rs2287618 were diagnosed as PBC, the UDCA treatment was not satisfactory. Larger studies with mixed ethnicity subjects and stratified by clinical and subclinical characteristics are needed to validate our findings.

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“…Thus, these cells are also frequently used for evaluation of drug-induced expression of metabolism and transport proteins. While enhanced expression of BSEP does not lead to a severe adverse effect on the liver, reduced expression of this transporter has been linked closely to PFIC and other cholestatic conditions [76, 131, 132]. Previously, we have shown that dual inhibition and repression of BSEP is often associated with severe clinically reported DILI, suggesting that in addition to functional inhibition, repression of BSEP expression may play an important role in DIC [93].…”

Section: In Vitro Strategies To Assess Dicmentioning

confidence: 99%

A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis

Garzel

Zhang

Huang

et al. 2019

CDM

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Background: Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally, DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition, but rather are associated with alternative mechanisms. Methods: We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed publications over the past two decades or so. Results: We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC. Conclusion: Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC including 3D cell cultures and computational modeling.

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Association of Single Nucleotide Polymorphisms of the Bile Salt Export Pump Gene with Intrahepatic Cholestasis of Pregnancy

Abstract: The use of two intragenic SNPs in both single locus and haplotype analyses of association suggests that the BSEP gene is a susceptibility gene in intrahepatic cholestasis of pregnancy.

Cited by 69 publications

References 26 publications

An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy

An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy

The Association between Bile Salt Export Pump Single-Nucleotide Polymorphisms and Primary Biliary Cirrhosis Susceptibility and Ursodeoxycholic Acid Response

A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis

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