Polymorphic Variants of Selected Genes Regulating Bile Acid Homeostasis in Women with Intrahepatic Cholestasis of Pregnancy

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the onset of pruritus and elevated serum transaminases and bile acids (BA). The key enzyme in BA synthesis is CYP7A1, and its functions are regulated by various nuclear receptors. The goal of this study is to evaluate the association between CYP7A1, NR1H1, RXRA, and PPARA gene variants and risk of ICP. Five single nucleotide variants (SNVs), rs3808607 (CYP7A1), rs56163822 (NR1H4), rs1800206 (PPARA), rs749759, and rs11381416 (NR2B1), were genotyped in a group of 96 ICP and 211 controls. The T allele of the CYP7A1 (rs3808607) variant may be a protective factor against ICP risk (OR = 0.697, 95% CI: 0.495-0.981, p = 0.038). Genetic model analysis showed that rs3808607 was associated with decreased risk of ICP under dominant (OR = 0.55, 95% CI: 0.32-3.16, p = 0.032, AIC = 380.9) and log-additive models (OR = 0.71, 95% CI: 0.51-1.00, p = 0.046, AIC = 381.4). The A insertion in the rs11381416 NR2B1 variant was associated with the degree of elevation in the liver function tests TBA (34.3 vs. 18.8 μmol/L, p = 0.002), ALT (397.0 vs. 213.0 IU/L, p = 0.017), and AST (186.0 vs. 114.4 IU/L, p = 0.032) in ICP women. Results indicate an association between the CYP7A1 rs3808607 and the risk of ICP and the association of the rs11381416 of the NR2B1 receptor with higher values of liver function tests in women with ICP. A better understanding of the cooperation of proteins involved in BA metabolism may have important therapeutic implications in ICP and other hepatobiliary diseases.

Keywords: genes regulating bile acid homeostasis; intrahepatic cholestasis; polymorphic variants; pregnancy.

Figure 1

The main relationships between proteins encoded by genes analyzed in the work. Bile acids (BA) are produced in the liver from cholesterol by CYP7A1 and secreted into the gallbladder. From the ileum, they are reabsorbed in enterocytes, where they activate FXR, which stimulates transcription of the FGF19 gene. The FGF19 protein is secreted into the portal circulation and in the liver binds itself to the receptor FGFR4 to reduce CYP7A1 expression. Bile acids synthesis in the liver is also regulated by FXR, which transcriptionally increases SHP protein expression, which reduces CYP7A1 expression. PPARA competes with FXR for the RXRA receptor and may downregulate SHP expression. Abbreviations: BA, bile acids; FA, fatty acids; CYP7A1, cholesterol 7alpha-monooxygenase; FGF, fibroblast growth factor; FGFR4, fibroblast growth factor receptor 4; FXRA, farnesoid X receptor alpha; NTCP, Na⁺-taurocholate cotransporting polypeptide; PPARA, peroxisome proliferator-activated receptor alpha; RXRA, retinoid X receptor alpha; SHP, small heterodimer partner; 9cRA, 9-cis retinoic acid.

Figure 2

The gestational time of onset of intrahepatic cholestasis symptoms.

Figure 3

Box plots showing the distribution of data on gestational age at delivery, neonatal weight, and placental weight by the time of ICP symptoms onset.

Figure 4

ALT, AST and TBA serum levels between NR2B1 (RXRA) rs11381416 alleles in ICP women (ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBA, total bile acids).

Figure 5

The network of the genes we studied (CYP7A1, NR1H4, PPARA, RXRA) and their closest functional partners. The plot was from the STRING (Search Tool for the Retrieval of Interacting Genes) database (http://string-db.org/—accessed on 2 October 2024).