Author + information
- Annapoorna Subhash Kinia,b,
- Khader Shameera,b,
- Yuliya Vengrenyuka,b,
- Benjamin Glicksberga,b,
- Kipp Johnsona,b,
- Aparna Divaraniyaa,b,
- Ben Readheada,b,
- Meerarani Purushothamana,b,
- Brian Kidda,b,
- Samin Sharmaa,b,
- Jagat Narulaa,b and
- Joel Dudleya,b
Background: Reanalysis of clinical trial data can enable discovery of new disease-associated genes, including potential drug targets. Characterizing new genes and pathways is essential for developing therapies to augment statins, especially in statin therapy non-responders. Multiple factors influence statin tolerance and response in cardiovascular patients including pharmacogenetics, age, comorbidities, and side effect profiles. In this study, we characterized genes discovered in the YELLOW-II trial of intensive statin therapy with rosuvastatin 40mg. Results from YELLOW-II trial provided several insights including the relation of serial changes in plaque morphology of obstructive non-culprit lesions to cholesterol efflux capacity and transcriptomic perturbations in response to high-dose statin therapy over 8-12 weeks.
Methods: The YELLOW-II trial was designed to understand transcriptomic and biochemical features associated with reduction in atherosclerotic plaque, lipids, and vascular inflammation through statin therapy. We analyzed transcriptome signatures of 85 patients using limma and generated coexpression networks using WGCNA to identify potentially novel drug targets. Genes without prior functional roles were prioritized as putative drug targets.
Results: Microarray analysis of PBMC transcriptome detected 117 differentially expressed genes at follow-up compared to baseline with 39 genes downregulated and 78 genes upregulated. Five genes have limited biochemical data and encode functional domains that may be targeted as alternative lipid lowering therapies: two TMEM gene family members (TMEM135 and TMEM51) and three open reading frames (C15ORF39, C17ORF87 and C12ORF35). Translational bioinformatics profiling reveals these genes could be potential drug targets.
Conclusions: We identified five novel genes that are potential targets for alternate lipid lowering therapies. Target-based drug repositioning and chemogenomic evaluations are in progress to characterize small molecules to modulate the expression of these genes.
Moderated Poster Contributions
Interventional Cardiology Moderated Poster Theater, Poster Hall, Hall C
Friday, March 17, 2017, 4:15 p.m.-4:25 p.m.
Session Title: The Inside View: Learning From Intracoronary Imaging
Abstract Category: 25. Interventional Cardiology: Translation and Pre-clinical Research
Presentation Number: 1175M-07
- 2017 American College of Cardiology Foundation