Whole-exome sequencing identifies the novel mutations in the ABC
transporters’ genes are associated with intrahepatic cholestasis of
pregnancy disease: a case-control study
Abstract
Objectives To identify the novel pathogenic genetic variants associated
with intrahepatic cholestasis of pregnancy (ICP) disease by whole-exome
sequencing (WES) approach. Design WES the DNA, and conduct association
between genetic variants and total bile acids. Setting Jiangxi. Samples
151 ICP patients. Methods DNA samples from 151 ICP patients were
subjected to WES. Rare novel exonic variants (minor allele frequencies:
MAF < 1%) were performed for subsequent analysis. Main
outcome measures Association of genetic variants with ICP and other
clinical disorders. Results We detected 42 were novel. We classified
these loci as four panels according to the prediction results, of which,
7 novel possible pathogenic mutations were identified which located in
the known functional genes including ABCB4, ABCB11 and ABCC2 for first
reported in damaging group. Besides, compare to reference, ABCC2
Ser1342Tyr modified protein structure showed a slight change in the
chemical bond lengths of ATP-ligand binding amino acid side chains. And
in placental tissue, the expression level of ABCC2 gene in ICP patients
was significantly higher than healthy pregnant women. Moreover, the
patients with two mutations in ABC family genes have higher average
value of TBA, AST, DBIL, CHOL, TG and HDL compared to the patients which
have one mutation, no mutation in ICP and local controls. Conclusion Our
results provide new insights into the genetic architecture of ICP
disease. They may contribute to genetic diagnose of ICP disease, and
provide new treatment for ICP patients. Keywords WES, TBA, ABC
transporters’ genes, novel variants, ICP, ABCC2 gene, Ser1342Tyr
mutation