Analysis of CYP27A1 mutations in Han Chinese women with intrahepatic cholestasis of pregnancy

Abstract

Objective

To explore the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene mutations in Chinese women with intrahepatic cholestasis of pregnancy (ICP) and the correlation between CYP27A gene mutations and BA (bile acid) level changes.

Methods

In this study, the entire coding region of the CYP27A1 gene was sequenced in 151 Han Chinese women with ICP and 1029 matched samples, and the pathogenicity of identified CYP27A1 gene mutations was judged through evolutionary conservation analysis, computational analysis and protein structure modeling. Finally, we verified the relationship between gene mutations and total serum bile acid (TBA) and cholesterol (CHOL) levels through experiments in cell culture.

Results

We identified five heterozygous CYP27A1 missense mutations in five ICP samples. Three online tools, Polyphen-2, MutationTaster and SIFT, predicted that the five CYP27A1 mutations were pathogenic. Furthermore, all five mutations caused marked protein structural changes. Experiments in cells showed that the intracellular and medium levels of TBA in the mutant groups were lower than those in the wild-type group, while the CHOL levels were higher in all mutants except for the R158H mutant.

Conclusions

CYP27A1 mutations are associated with the levels of TBA and CHOL, suggesting that CYP27A1 mutations contribute to abnormal total cholesterol and BA levels, which leads to ICP.

Keywords:

• CYP27A1
• mutations
• intrahepatic cholestasis of pregnancy
• bile acids

Acknowledgements

The authors want to express our gratitude to the patients who participated in this study.

Ethic approval

The present study followed the tenets of the Helsinki Declaration, ethics approval was approved by the Institutional Review Board of Maternal and Child Health Affiliated Hospital of Nanchang University in China, and each participating woman gave informed consent.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was financially supported by the Science and Technology Project of Jiangxi Province [grant nos. 20192BBG70003, 20202BABL216010 and 20203BBGL73130] and the Science and Technology Plan of Jiangxi Provincial Health Commission [grant no. 202130763].