Evaluating Genotype-Treatment Interactions for High-Risk Medications in British General Practice: Evidence from UK Biobank

Background: Pharmacogenetics has the potential to optimise drug therapy and reduce adverse drug effects (ADEs) by tailoring treatment to a patient's genotype, particularly for chronic disorders managed in general practice (GP). However, the adoption of pharmacogenetics in GP remains slow. Aim: This study aimed to evaluate the reproducibility of previously reported associations between genomic variants and medically important adverse drug effects (MIADEs) associated with high-risk medications in GP. Design and setting: A retrospective study using data from the UK Biobank (UKBB), a population-based cohort of over 500,000 community-based participants. Method: We identified high-risk medications prescribed in GP by linking serious ADEs from the Yellow Card database with English GP prescription data. These high-risk medications were then cross-examined with genomic variants associated with MIADEs from the Pharmacogenomics Knowledgebase (PharmGKB), to select variant-drug pairs for investigation within the UKBB. Results: From 78 high-risk medications prescribed in GP and 56 PharmGKB annotations linked to MIADE risk, SLCO1B1 rs4149056 was the only variant with guideline-based prescribing recommendations. This variant, along with others of lower evidence levels, was analysed in the UKBB. No genotype-treatment interaction was observed for SLCO1B1 rs4149056 and statin-related muscle toxicity. Similarly, no interactions were detected for the remaining variants in either secondary or exploratory analyses. Conclusion: No statistically significant genotype-treatment interactions were observed for MIADE risk associated with high-risk medications in GP. However, the limited predictive value of the assessed variants may reflect underlying phenotypic imprecision and methodological limitations. Hence, further research is needed to validate these results.