Conventional and genetic factors influencing responses to cardiovascular medication

Abstract

Individual responses to medication may differ for genetic and non-genetic reasons, but the scientific evidence is limited, including on clinical outcomes. This thesis aims to study genetic and conventional factors affecting clinical responses to common cardiovascular drugs such as lipid lowering statins and antihypertensive calcium channel blockers, using genetic information in UK Biobank large cohort data linked to primary and secondary care records. Previously, the SLCO1B1*5 genetic variant had conflicting evidence on statin-related myopathy, with little data available on key clinical outcomes over long follow-ups or on outcomes stratified by sex. I found SLCO1B1*5 had larger effects on cholesterol and treatment duration in women than in men, and had no effect on myopathy in 65,000 patients. I also used genotype data from whole exome sequencing to identify other pharmacogentic variants in SLCO1B1, and found that genotype-guided treatment might reduce GP-diagnosed muscle symptoms in statin patients by 18% in SLCO1B1*15 carriers and 10% for SLCO1B1*20. I also identified 2 rare variants increasing LDL, and gain of function variants improving outcomes. The Pharmacogenomics Knowledge Base had weak level clinical evidence (3-4 of 4) for pharmacogenetic variants affecting dihydropiridine CCB response. I found 5 of 23 reported variants were associated with GP-data outcomes e.g. for a variant in RYR3, and observed higher rates of heart failure in 32,000 GP-prescribed CCBs patients. I performed polygenic score analysis to determine patient characteristics affecting CCB response, as evidence from classical observational studies was inconclusive. I combined it with pharmacogenetic effects as a novel analysis in hypertension genetics; results showed adiposity and lipoprotein A scores compounded pharmacogenetic effects. Considering factors studied when prescribing could improve clinical outcomes, and have wider applications for optimizing prescribing of other medications, especially as genome-wide genotype data becomes more widely available in routine clinical practice. This PhD provided clinical evidence in pharmacogenetics of studied common cardiovascular preventative medicines in a large-scale community cohort.