The role of p.Val444Ala variant in the ABCB11 gene and susceptibility to biliary atresia in Vietnamese patients

Abstract

Biliary atresia (BA) is the most serious type of obstructive cholangiopathy that occurs in infants. BA can be the cause of death in children under 2 years if untreated early. However, the etiology of the disease is not known. BA is considered to be the result of the destruction of the bile duct system including the accumulation of bile acids. The bile salt export pump, a transporter protein encoded by the ABCB11 gene, plays the main role in the exportation and accumulation of bile acids. The p.Val444Ala variant in this gene is known to be associated with many cholestatic diseases. However, to date no study have been performed to evaluate the association of this variant with susceptibility to the risk of BA. In this study, we aimed to identify the frequency of p.Val444Ala variant and the risk of BA in Vietnamese patients.The polymerase chain reaction (PCR)-restriction fragment length polymorphism method was used to determine the frequency of alleles c.1331T>C (p.Val444Ala, rs2287622) in the ABCB11 gene in 266 Vietnamese patients with BA and 150 healthy people. The gene segment containing the variant was amplified by PCR with specific primers, after that the PCR products were cut by HaeIII restriction enzyme and analyzed on agarose gel to determine the genotypes. The frequency of alleles was assessed statistically to determine the association between these alleles and the risk of disease in patients.In our study, the frequency of alleles c.1331T>C (p.Val444Ala, rs2287622) in the ABCB11 gene was investigated the first time in the patients with BA. The results showed that CC and TC genotypes were significantly different between BA patients and healthy people (P < .01), and the C allele was associated with an increased risk of BA (odds ratio = 2.47; 95% confidence interval: 1.84-3.32; P < .01). The initial results of clinical, biochemical, and genetic analysis in our study suggested that the p.Val444Ala variant in the ABCB11 gene may be a susceptibility factor for the disease in Vietnamese patients with BA. These results provided new insights into the role of this ABCB11 variant in the pathogenesis of BA.Abbreviations: BA = biliary atresia, BSEP = bile salt export pump, CI = confidence interval, DNA = deoxyribonucleic acid, HPE = hepatoportoenterostomy, OR = odds ratio, PCR = polymerase chain reaction, PFIC = progressive familial intrahepatic cholestasis.

Rare sequence variants associated with the risk of non‐syndromic biliary atresia

“…We examined the frequencies of 60 known BA‐related SNPs in the patient and control groups. These SNPs were selected based on the previous reports 5–28 . We confirmed that the identified SNPs were in Hardy–Weinberg equilibrium.…”

“…To date, candidate gene approaches, genome‐wide association studies, and whole exome sequencing (WES) detected 60 single‐nucleotide polymorphisms (SNPs) and 75 genes associated with the risk for non‐syndromic BA 5–28 . For example, WES by Gürünlüoğlu et al.…”

Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia

“…Susceptible genes are selected according to the following criteria: (1) SNPs are significantly correlated with BA cohort; (2) It is verified by multiple cohorts or animal disease models; (3) its biological function is closely related to the four aspects described in our review. Some genes, such as IL18, CD14, NOTCH2 and so on, are only reported by one cohort are not in text but in Table 1 (34)(35)(36)(37)40). Genes that may be susceptible genes but have not yet been found BA are selected according to the following criteria: (1) Abnormal expression in BA specimens; (2) Demonstrated by animal disease models; (3) Their biological function is closely related to the four aspects described in our review.…”

A structural and mechanistic model for BSEP dysfunction in PFIC2 cholestatic disease

“…Nonsense and frameshift mutations give rise to the most severe and earliest onset forms, while missense mutations, depending on their level of dysfunction, drive varying degrees of severity 12 . Beyond monogenic disorders, emerging evidence links BSEP dysfunction to the pathogenesis of multifactorial liver diseases such as drug-induced liver injury 13,14 , biliary atresia 15 , primary intrahepatic stones 16 , and MASH (formerly NASH) [17][18][19] .…”