No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

Abstract

European studies have revealed that the ABCB11 c.1331T>C (V444A) polymorphism (rs2287622) C-allele frequency is higher among patients with drug-induced cholestasis. Given the low incidence of this disease, however, this association has not been sufficiently elucidated. We aimed to investigate the significance of this polymorphism in Japanese patients. We determined ABCB11 V444A polymorphism frequencies and HLA genotypes in two independent drug-induced cholestasis cohorts. Expression and taurocholate transport activity of proteins from 444A variants were analyzed using Madin-Darby canine kidney II cells. In cohort 1 (n = 40), the V444A polymorphism C-allele frequency (66%) was lower than that in controls (n = 190, 78%), but this difference was not significant (P = 0.09). In cohort 2 (n = 119), comprising patients with cholestatic (n = 19), hepatocellular (n = 74), and mixed (n = 26) liver injuries, the C-allele frequency was lower among patients with cholestatic liver injury (68%) than among those with hepatocellular (75%) or mixed liver injury (83%), although this difference was not significant. In cohort 1, HLA-A*0201 was observed more frequently in patients (22%) than in controls [11%; P = 0.003; odds ratio, 2.4 (95% confidence interval, 1.4-4.0)]. Taurocholate transport activity of 444A-encoded protein was significantly lower than that of 444V-encoded protein (81% of 444V, P < 0.05) because of the reduced protein stability. In conclusion, ABCB11 444A had slightly reduced transport activity, but it did not contribute to the occurrence of drug-induced cholestasis in Japanese patients. Therefore, genetic susceptibility to acquired cholestasis may differ considerably by ethnicity.

Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort

“…Previous studies have identified a common BSEP polymorphism V44A (1331T > C, rs2287622) as genetic risk factor for DILI in Caucasian1011 In the present study, we tested the same SNP in Chinese patients, however, no significant association was found between rs2287622 polymorphism and the development of DILI, which was similar to the study conducted in Japan13. Since genetic associations were ethnicity-specific and drug-specific, the association of ABCB11 rs2287622 genetic variations and DILI should be investigated in other populations and other drugs.…”

Inter-individual differences in the susceptibility of primary human hepatocytes towards drug-induced cholestasis are compound and time dependent

“…However, conflicting reports exist (87) and additional studies in larger and varied populations are needed to validate these findings.…”

Effect of a Common Genetic Variant (p.V444A) in the Bile Salt Export Pump on the Inhibition of Bile Acid Transport by Cholestatic Medications

“…19 Similar findings also were reported in European and Caucasian populations, 29 however, no statistically significant association was reported in studies conducted in Chinese and Japanese cohorts. 21,35 The 444A variant of BSEP also has been identified as a risk factor for the development of ICP, with the variant being more frequent in ICP patients when compared to pregnant controls. 8,20,36 Dixon et al reported an increased risk of ICP in subjects with the 444A variant, especially those who were homozygous for this BSEP variant.…”

“…8,20 However, a similar study in a Japanese population found no association of cholestasis with this variant. 21 Studies to explain the mechanistic basis for this increased susceptibility to acquired cholestatic syndromes have been unsuccessful. The expression of the variant BSEP is slightly lower in both liver tissue 22 and in transfected systems.…”

“…The expression of the variant BSEP is slightly lower in both liver tissue 22 and in transfected systems. 21,23,24 However, this variant is extremely common, with an allele frequency of 53% in African-Americans, 57% in European Americans, 23 and 74% or higher in Mainland Chinese and other Asian populations. 25,26 Thus, any clinically impactful changes in transporter expression of variant BSEP would place a large portion of the population at risk for DILI and ICP, which is not consistent with clinical observations.…”