A factorial Mendelian randomization study to systematically prioritize genetic targets for the treatment of cardiovascular disease

Abstract

Importance New drugs which provide benefit alongside statin mono-therapy are warranted to reduce risk of cardiovascular disease. Objective To systematically evaluate the genetically predicted effects of 8,851 genes and cardiovascular disease risk factors using data from the UK Biobank and subsequently prioritize their potential to reduce cardiovascular disease in addition to statin therapy. Design, Setting, and Participants A factorial Mendelian randomization study using individual level data from the UK Biobank study. This population-based cohort includes a total of 502,602 individuals aged between 40 and 96 years old at baseline who were recruited between 2006 to 2010. Exposures Genetic variants robustly associated with the expression of target genes in whole blood (based on P<5x10-08) were used to construct gene scores using findings from the eQTLGen consortium (n=31,684). Main Outcomes and Measures Genetically predicted effects for each of the 8,851 genes were firstly evaluated with 5 measured outcomes from the UK Biobank in turn (body mass index, diastolic blood pressure, systolic blood pressure, low-density lipoproteins and triglycerides). Effects surviving multiple comparisons from this initial analysis were subsequently analyzed using factorial Mendelian randomization to evaluate evidence of an additive beneficial effect on cardiovascular disease risk compared to a HMGCR genetic score acting as a proxy for statin inhibition. Finally, a phenome-wide analysis was undertaken to evaluate predicted effects between prioritized targets and 570 outcomes in the UK Biobank to highlight potential adverse side-effects. Results 377 genetically predicted effects on cardiovascular disease risk factors were identified by Mendelian randomization (based on P<1.13x10-6). Of the 68 druggable genes, 20 candidate genes were predicted to lower cardiovascular disease risk in combination with statin treatment (P<7.35x10-4). Genes such as FDFT1 were predicted to have added benefit with statin therapy (OR=0.93; 95% CI, 0.91-0.95; P=2.21x10-10) but are unlikely to make safe targets due to their predicted effects on adverse side effects. In contrast, PRKCE provided evidence of a putative added benefit in combination with statins (OR=0.94; CI, 0.91-0.96; P=1.72x10-9) with no predicted adverse effects. Conclusions and Relevance Through the application of a systematic factorial Mendelian randomization analysis, we have prioritized (and deprioritized) potential drug targets predicted to reduce cardiovascular disease risk in addition to statin therapy.

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