Combination of QTL and GWAS to uncover the role of phosphodiesterases in ischemic heart disease

BackgroundPhosphodiesterases (PDEs) are regarded as important therapeutic targets for multiple diseases, and the cardiovascular benefits of several PDE inhibitors have received extensive interests. ObjectivesTo explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian Randomization (MR) approach. MethodsThe expression of genes encoding PDEs was used to proxy the level of PDEs, and available quantitative trait loci of gene expression and DNA methylation (eQTLs and mQTLs) for each target gene were identified as the genetic instruments. Coronary heart disease (CHD) and myocardial infarction (MI) were the outcomes. Summary-data-based MR method was used to generate the estimates and two-step MR analysis was applied to investigate the mediation of metabolic traits. ResultsMR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A=1.22,95% CI=1.06-1.40; ORPDE8A=1.26,95% CI=1.07-1.49) and MI (ORPDE5A=1.27,95% CI=1.09-1.48; ORPDE8A=1.24,95% CI=1.04-1.48). Especially, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR=1.17,95% CI=1.05-1.32) and MI (OR=1.15,95% CI=1.02-1.30). Besides, the methylation level of 12 CpG sites showed a relation with CHD or MI via affecting PDE5A expression. The observed association between PDE5A expression and outcomes were partly mediated by blood pressure and LDL cholesterol, and the association with MI were mostly mediated by CHD (Proportion-mediated: 78.84%). ConclusionsThis study provided genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, especially in preventing patients with CHD from developing MI.