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

Authors

C Mary Schooling, CUNY School of Public HealthFollow
J. V. Huang, University of Hong Kong
J. V. Zhao, University of Hong Kong
M.K. Kwok, University of Hong Kong
S. L. Au Yeung, University of Hong Kong
S. L. Lin, University of Hong Kong

Document Type

Article

Publication Date

1-31-2018

Abstract

Background: Development 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.Newtreatments aremost 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. Methods: Genes associatedwith IHDwere obtained fromthe 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. Results:Weidentified 173 autosomal genes associatedwith IHDand 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. Conclusions: Closer alignment of IHD treatments with genetically validated physiological targets may represent a major opportunity for combating a leading cause of globalmorbidity andmortality through repurposing existing interventions.

Comments

This article was originally published in EBioMedicine, available at https://doi.org/10.1016/j.ebiom.2018.01.015.

This is an open access article under the CC BY-NC-ND license.