Main findings
This study is the first to use whole-exome sequencing technology to
uncover potential novel pathogenic mutations in ABC family genes
involved in bile acid transport. In all, we identified 42 new loci
covering 44 ABC genes in 151 patients which were diagnosed with ICP
disease.
Strengths andlimitations
The present study has 4 major strengths: first, following the advent of
WES technology, which has proved to be efficient to unearth sequence
variation across the MAF spectrum in
obstetric and gynecological
diseases.22,
23 Using this method, we successfully
identified novel candidate pathogenicity loci with known functional
genes ABCB4 , ABCB11 and ABCC2 . In addition to these
three genes, we also dig some novel variations in other ABC series
genes. Our results investigated the genetic mutations of the first
WES-identified ABC family genes associated with ICP disease. Second, to
date, no studies have unraveled the genetic mutations in ABC genes of
hepatic disease among pregnancy women from a relatively large scale of
nationally representative sample (n=151) in China. Moreover, the
clinical data of these patients are relatively complete, providing data
support for association analysis between mutations and clinical data and
subsequent functional verification. Finally, combine WES and clinical
data, it is in favor of deciphering of molecular mechanism of ICP
disease.
Certainly, our study also have limitations. First, WES approach needs to
more sample size to target the low-frequency and rare variants.
Otherwise, it may lead to miss some valuable variants. Moreover, it also
bring out inaccuracy MAF of rare variants. However, the strict exclusion
conditions guaranteed the selection of the defined cohort, such as
employing the MAF in the databases, 151 ICP cases and 1029 controls
derived from locals and combined with predicted tools. Second, the
samples in this study were all derived from Jiangxi Province, which lack
of geographic diversity, may limit the applicability of the generality
of these results. However, this study is still valuable since the high
incidence (~ 1%~3%) of ICP in Jiangxi.
Finally, the causality between these potential pathogenic candidate loci
and ICP disease needs to be verified by validation functional
experiments.