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.