Search

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. [ABSTRACT FROM AUTHOR]

Objectives: Preeclampsia (PE) and fetal growth restriction (FGR) have abnormal placental implantation and endothelial dysfunction in common. However, their etiologies are not well understood. Both heat shock protein 70 (Hsp70) and nitric oxide (NO) are suggested to play a major role in the regulation of maternal and fetoplacental hemodynamics. In this study, the association of PE with FGR and Hsp70 or NO was analyzed.Methods: A total of 30 cases of PE, 25 cases of PE complicated with FGR and 50 cases of normal pregnant women were chose, and PE and normal animal models were constructed. Subsequently, the levels of Hsp70 and NO in serum and placental tissues of humans and animals were measured and compared. Further, rats were injected with pLV-NC-shRNA, pLV-Hsp70-shRNA, pLV-EFIa-NC, and pLV-EFIa-Hsp70, respectively, the weight of each conceptus, number of pups, fetal crown to tail length, total weight of the placenta/fetus unit, and the content of NO were analyzed.Results: The expression of Hsp70 in serum and placental tissues of PE complicated with or without FGR group was increased, whereas the content of NO was decreased compared to the normal group. The fetal weight (FW) of the Hsp70 targeted suppression group was higher than the other two groups, whereas the placental weight (PW) was reversed. Also, NO synthase (NOS) expression was decreased in the Hsp70 over-expression group.Conclusions: We speculated that the enhancement of Hsp70 might be related to the development of PE combined with FGR through inhibiting the synthesis of NOS. [ABSTRACT FROM AUTHOR]

Objectives: To research the associations between fructose-bisphosphate aldolase B (ALDOB) gene polymorphisms and intrahepatic cholestasis of pregnancy (ICP) risk., Material and Methods: Whole-genome sequencing (WGS) was performed to detect ALDOB polymorphisms. Five web-available tools were employed to predict the effect of the site variant on the protein. Protein structure comparisons between the reference and ALDOB-modified samples were performed by SWISS-MODEL and Chimera 1.14rc, respectively., Results: We identified 28 genetic variants in the ALDOB gene. When the cut-off value of minor allele frequency (MAF) of loci was 0.001 in four databases, five missense variants, including rs747604233, rs759204107, rs758242037, rs371526091 and rs77718928, were reserved for subsequent analysis. These variants were absent from the 1029 control individuals. The influence of all five variants on protein function was predicted to be damaging by the abovementioned five prediction software programs. Bioinformatics analysis demonstrated that these five missense variants were highly conserved among vertebrates. Compared to the wild-type protein structure, all five mutated protein structures showed a slight change in the chemical bond lengths of the enzyme activity domains. The combined clinical data indicate that the variant group had a significantly older age (p = 0.038), a higher level of indirect bilirubin (IDBIL, p = 0.033), and lower counts of white blood cells (WBCs, p = 7.38E-05) and platelets (PLTs, p = 0.018) than the wild-type group., Conclusions: This is the first study to examine the associations between ALDOB polymorphisms and ICP disease in 249 Chinese patients with ICP. Our present study expands the understanding of the pathogenesis of ICP.