Candidate gene and pathway analyses identifying genetic variations associated with prasugrel pharmacokinetics and pharmacodynamics

Abstract

Aim: We aimed to investigate the genetic polymorphisms and pharmacogenetic variability associated with the pharmacodynamics (PD) and pharmacokinetics (PK) of prasugrel, in healthy Han Chinese subjects.

Patients & methods: Healthy, native, Han Chinese subjects (n = 36) aged 18 to 45 years with unknown genotypes were included. All subjects received a loading dose (LD) on day 1 and a maintenance dose (MD) from day 2 until day 11. Candidate gene association and gene-set analysis of biological pathways related to prasugrel and platelet activity were analyzed.

Results: 28 SNPs of 17 candidate genes previously associated with prasugrel or platelet activity were selected after a literature search. In the 30 mg LD groups (n = 24), ITGA2-rs28095 was found to be significantly associated with the P2Y12 reaction unit (PRU) value at 24 h after the LD (p = 0.015). 165 study genes related to platelet activation-related processes and prasugrel activity were selected from the MSigDB database, including curated gene sets from KEGG, Bio Carta, and Gene Cards. 14 SNPs of 9 genes were found to be significantly correlated both at 24 h and 12 days after LD: ADAMTSL1, PRKCA, ITPR2, P2RY12, P2RY14, PLCB4, PRKG1, ADCY1, and LYN. Seven SNPs of 6 protein-coding genes associated with area under the concentration-time curve (AUC0-tlast) were significantly identified among the 47 selected genes, including ADAMTSL1, CD36, P2RY1, PCSK9, PON1, and SCD.

Conclusion: These results show that genetic variation affects the PK and PD of prasugrel in normal individuals. Further studies with larger sample sizes are required to explore whether the SNPs are associated only with prasugrel activity or also with cardiovascular events and all-cause mortality.

Keywords: Candidate gene; Pathway; Prasugrel.