Sofia Attelind: Genetic and clinical risk factors for adverse drug reactions: Pharmacogenomic and pharmacoepidemiological studies of bleeding and thrombosis

Abstract

Background There is considerable interindividual variation in drug response and the risk of adverse drug reactions. This variation may be due to several factors, including genetic predisposition and clinical characteristics.

Aim To use pharmacogenomic and pharmacoepidemiological approaches to identify risk factors for the adverse reactions thrombosis and bleeding during treatment with direct oral anticoagulants (DOACs), and venous thromboembolism (VTE) following Covid-19 vaccination.

Methods Study I examined how genetic variation influences the pharmacokinetics of apixaban by analysing data from a pivotal clinical trial using both a genome-wide association study (GWAS) and candidate gene analyses. Study II evaluated a methodology for identifying clinical risk factors for DOAC-induced bleeding using a pharmacovigilance database. In Study III, a GWAS was conducted in patients who experienced bleeding during DOAC therapy to identify genetic risk factors. Study IV combined a GWAS with pharmacoepidemiological analyses to identify risk factors for developing VTE after Covid-19 vaccination.

Results In Study I, genetic variation in the drug transporter gene ABCG2 was associated with the pharmacokinetics of apixaban. However, the effect of ABCG2 on drug exposure was modest and not associated with bleeding or thromboembolic events. The methodology evaluated in Study II identified several established and some novel potential risk factors for bleeding during DOAC treatment. Study III revealed that genetic variation in the genes BAIAP2L2, CYP3A5, ABCG2, and VWF may be associated with bleeding in DOAC-treated patients. In Study IV, individuals with well-characterised genetic variants in coagulation factor V (Leiden, rs6025) or factor II (prothrombin, rs1799963) exhibited higher risk of VTE within 42 days following Covid-19 vaccination. A large population-based health register study further showed that people diagnosed with these congenital thrombophilias had five times higher risk of VTE within 42 days after vaccination.

Conclusion This thesis highlights the complementary roles of pharmacogenomics and pharmacoepidemiology in post-marketing drug safety surveillance. Although further studies are required, the results contribute important knowledge towards the prevention of adverse drug reactions.