Introduction
Intrahepatic cholestasis of pregnancy (ICP) is a reversible pregnancy-specific liver disease, which characterized by pruritus and abnormal liver function, such as elevated liver enzymes and increased the serum total bile acids (TBA) (≥ 10 μmol/L), appeared in the second and third trimester of the pregnancy and resolved completely after delivery in the early postpartum period.1 The incidence of ICP disease reported between 0.1% and 15.6% depending on geographical differences.1, 2 ICP has associated with the adverse fetal outcomes, including spontaneous preterm birth, respiratory distress, low Apgar scores, fetal distress and fetal death.3-7 It is noted that approximately 2%-4% of ICP pregnancies are affected by fetal mortality.8, 9 And the level of TBA increased the risk of fetal morbidity and stillbirth.10-12Therefore, untangling the genetic mechanisms of ICP and is associated with the fetal complications is very important.
The abnormal synthesis, metabolism transport, secretion and excretion of bile acids may lead to ICP disease.13 Therefore, the etiology contributing to the development of ICP disease is complex that depend on multiple factors, including hormonal, genetic and environmental backgrounds.14Familial clustering analysis in pedigree studies, showed a high incidence in mothers and sisters of patients with ICP, implicating that a genetic predisposition for the condition.15-18 Among which, the gene mutations in the hepatocellular transporters of bile salts playing a pivotal role in the pathogenesis of ICP.19
Bile salts transport is the key physiological function of ATP-binding cassette (ABC) membrane proteins covered seven distinct members: ABCA, ABCB, ABCC, ABCD, ABCE, ABCF and ABCG. Of these genes, ABCB4 ,ABCB11 and ABCC2 are functional known genes having an effect on the development of ICP. Except for ABCB4 , ABCB11and ABCC2 genes, the role of other ABC transporters’ genes seems to less study. By taking advantage of the high-throughput genotyping technologies in a larger scale population, WES approach that combined genotype data for all patients has proved to be far more efficient to anchor all mutations for the target gene at once. In particular, the method can greatly accelerate to screen for new potential pathogenicity sites of all the mutations. Therefore, examining exonic variants across ICP disease groups likely augments the excavation of novel loci. However, until now, to our best knowledge, there have no reports of use of WES to identify the genetic variants in the ABC series genes of bile acids transporter for ICP disease.
Given this background, we hypothesized that the genetic variation in ABC transporters confers susceptibility to ICP. Therefore, we performed WES to investigate extensively the presence of mutations, especially for the discovery of new functional variants, of ABC series genes involved in bile acids transport in 151 patients with ICP disease and related them to the clinical data and pregnancy outcomes.