Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
Department of Medical Biology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
Orphanet J Rare Dis. 2022 Nov 17;17(1):419. doi: 10.1186/s13023-022-02565-6.
The ATP-binding cassette subfamily B member 4 (ABCB4) gene encodes the hepatic phospholipid transporter. Variants in the ABCB4 gene are associated with various cholestatic phenotypes, some of which progress to liver fibrosis and cirrhosis. The aim of our study was to investigate the role of the cholestasis-associated variant ABCB4 c.711A > T (p.I237I, rs2109505) in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).
Two cohorts of Polish patients took part in this study. The Szczecin cohort comprised 196 patients with PBC (174 females, 38% with cirrhosis) and 135 patients with PSC (39 females, 39% with cirrhosis). The Warsaw cohort consisted of 260 patients with PBC (241 females, 44% with cirrhosis) and 276 patients with PSC (97 females, 33% with cirrhosis). Two control cohorts-150 healthy blood donors and 318 patients without liver disease, were recruited in Szczecin and in Warsaw, respectively. The ABCB4 c.711A > T polymorphism was genotyped using TaqMan assay. In both PBC cohorts, carriers of the risk variant presented more frequently with cirrhosis (Szczecin: OR = 1.841, P = 0.025; Warsaw: OR = 1.528, P = 0.039). The risk allele was associated with increased serum AST, GGT and ALP (all P < 0.05) at inclusion. During the follow-up, patients in both cohorts significantly improved their laboratory results, independently of their ABCB4 c.711A > T genotype (P > 0.05). During 8 ± 4 years follow-up, a total of 22 patients in the Szczecin PBC group developed cirrhosis, and this risk was higher among carriers of the risk variant (OR = 5.65, P = 0.04). In contrast to PBC, we did not detect any association of ABCB4 c.711A > T with a liver phenotype in PSC cohorts.
The frequent pro-cholestatic variant ABCB4 c.711A > T modulates liver injury in PBC, but not in PSC. In particular, carriers of the major allele are at increased risk of progressive liver scarring.
ATP 结合盒亚家族 B 成员 4（ABCB4）基因编码肝磷脂转运蛋白。ABCB4 基因的变异与各种胆汁淤积表型相关，其中一些进展为肝纤维化和肝硬化。本研究的目的是研究胆盐相关变异 ABCB4 c.711A > T（p.I237I，rs2109505）在原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC）患者中的作用。
波兰的两个队列参与了这项研究。什切青队列包括 196 名 PBC 患者（174 名女性，38%患有肝硬化）和 135 名 PSC 患者（39 名女性，39%患有肝硬化）。华沙队列由 260 名 PBC 患者（241 名女性，44%患有肝硬化）和 276 名 PSC 患者（97 名女性，33%患有肝硬化）组成。在什切青和华沙分别招募了 150 名健康献血者和 318 名无肝病患者作为两个对照队列。使用 TaqMan 测定法对 ABCB4 c.711A > T 多态性进行基因分型。在两个 PBC 队列中，携带风险变异的患者更常出现肝硬化（什切青：OR=1.841，P=0.025；华沙：OR=1.528，P=0.039）。风险等位基因与纳入时血清 AST、GGT 和 ALP 的增加相关（均 P<0.05）。在随访期间，两个队列的患者的实验室结果均显著改善，与 ABCB4 c.711A > T 基因型无关（P>0.05）。在 8±4 年的随访期间，什切青 PBC 组共有 22 名患者发展为肝硬化，而携带风险变异的患者风险更高（OR=5.65，P=0.04）。与 PBC 不同，我们没有发现 ABCB4 c.711A > T 与 PSC 队列中的肝脏表型有关。
常见的亲胆盐变异 ABCB4 c.711A > T 可调节 PBC 中的肝损伤，但不能调节 PSC 中的肝损伤。特别是，主要等位基因的携带者发生进行性肝瘢痕形成的风险增加。
