Disconnect Between Genes Associated With Ischemic Heart Disease and Targets of Ischemic Heart Disease Treatments.

backgroundDevelopment of pharmacological treatments to mitigate ischemic heart disease (IHD) has encompassed disappointing results and expensive failures, which has discouraged investment in new approaches to prevention and control. New treatments are most likely to be successful if they act on genetically validated targets. We assessed whether existing pharmacological treatments for IHD reduction are acting on genetically validated targets and whether all such targets for IHD are currently being exploited.

methodsGenes associated with IHD were obtained from the loci of single nucleotide polymorphisms reported in either of two recent genome wide association studies supplemented by a gene-based analysis (accounting for linkage disequilibrium) of CARDIoGRAMplusC4D 1000 Genomes, a large IHD case (n=60,801)-control (n=123,504) study. Treatments targeting the products of these IHD genes and genes with products targeted by current IHD treatments were obtained from Kyoto Encyclopedia of Genes and Genomes and Drugbank. Cohen's kappa was used to assess agreement.

resultsWe identified 173 autosomal genes associated with IHD and 236 autosomal genes with products targeted by current IHD treatments, only 8 genes (PCSK9, EDNRA, PLG, LPL, CXCL12, LRP1, CETP and ADORA2A) overlapped, i.e. were both associated with IHD and had products targeted by current IHD treatments. The Cohen's kappa was 0.03. Interventions related to another 29 IHD genes exist, including dietary factors, environmental exposures and existing treatments for other indications.

conclusionsCloser alignment of IHD treatments with genetically validated physiological targets may represent a major opportunity for combating a leading cause of global morbidity and mortality through repurposing existing interventions.