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.