Abstract
BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world’s largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
Highlights
Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets
In sum, by integrating genetic and electronic medical record data, and leveraging one of the world’s largest human RNA-sequence datasets (STARNET), we identified known and novel cardiovascular disease (CVD)-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation
LoF-harboring genes associated with CVD traits in BioMe Genotyping and imputed data from 11,212 individuals of the BioMe Biobank were used to identify a total of 2818 LoFs in 2143 different genes (Methods; Additional file 1: Figure S1; Additional file 1: Figure S2A)
Summary
Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. In the recent published FOURIER trial, the PCSK9 inhibitor Evolocumab used in conjunction with background of statin therapy was shown to significantly reduce the risk of cardiovascular events as well as levels of plasma LDL cholesterol [5]. In another example, LoF mutations in NPC1L1, encoding a transporter involved in the absorption of dietary cholesterol, are associated with reduced incidence of CHD [6], and a small-molecule inhibitor of NPC1L1, ezetimibe, was found to both lower plasma LDL levels and reduce the risk of CHD events [7]. Retrospective analysis shows that for novel targets with human genetic validation, the rate of success in clinical development is increased twofold [11]
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