Pharmacogenomics and Pharmacokinetics of Aspirin in Preeclampsia Prevention

Abstract

Background: It has become evident that some women develop preeclampsia despite aspirin. This study aimed to examine how such aspirin nonresponsiveness develops in high-risk preeclampsia pregnancies by exploring the role of genetic polymorphisms and aspirin metabolism.

Methods: The study involved pregnant women who developed preeclampsia despite low-dose aspirin and those who did not. First, we conducted a pharmacogenomic association study exploring the association of potential genetic variants with aspirin nonresponsiveness. Next, we analyzed the rate of enzymatic aspirin hydrolysis in maternal plasma. The extent of placental exposure to acetylsalicylic acid and its bioactive metabolites, that is, salicylic acid and gentisic acid, was determined by liquid chromatography-mass spectrometry. The expressions of placental AMEs (aspirin metabolizing enzymes), that is, GLYAT (glycine-N-acyltransferase), UGT1A6 (UDP glucuronosyltransferase family 1 member A6), CYP2E1 (cytochrome P450 family 2 subfamily E member 1), and NAT2 (N-acetyltransferase 2) were analyzed by quantitative reverse transcription polymerase chain reaction, immunohistochemistry staining, and enzyme-linked immunosorbent assay. Finally, the effects of AMEs were further studied on HTR-8/SVneo (an immortalized human trophoblast cell line derived from first-trimester placenta) and hPCTB (human primary cytotrophoblast) cells.

Results: Our genetic study showed that single-nucleotide polymorphisms (SNPs) of genes involved in aspirin pharmacokinetics and pharmacodynamics were not associated with aspirin nonresponsiveness in preeclampsia. Rates of aspirin hydrolysis in maternal plasma and the concentrations of acetylsalicylic acid, salicylic acid, and gentisic acid in the placenta did not differ between aspirin-responsive and aspirin-nonresponsive women. Intriguingly, GLYAT was significantly upregulated in the aspirin-nonresponsive placenta and associated with aspirin nonresponsiveness. This overexpression of GLYAT was found to diminish the proangiogenic, anti-inflammatory, and antisenescence effects of salicylic acid in HTR-8/SVneo and hPCTB cells.

Conclusions: Our study revealed that maternal genetic factors and plasma aspirin hydrolysis are not among the decisive factors in determining the effectiveness of low-dose aspirin in preventing preeclampsia among high-risk women. Instead, placental GLYAT appears to play a key role by limiting the effect of salicylic acid in the placenta.

Keywords: aspirin; hypertension; pharmacogenetics; placenta; pre-eclampsia; pregnancy.