(861.2) Implication of New identified Nicotine regulated genes in diabetic cardiomyopathy

Poster Board Number: E165

Yajing Wang (Thomas Jefferson University), Jing Zhao (Shanxi Medical University), Jianli Zhao (Thomas Jefferson University), Yaoli Xie (Shanxi Medical University), Caihong Liu (Shanxi Medical University), Wayne Bond Lau (Thomas Jefferson University), Bernard Lopez (Thomas Jefferson University), Theodore Christopher (Thomas Jefferson University), Xinliang Ma (Thomas Jefferson University)

Objectives: There is a paradox of nicotine and diabetes in patients with cardiomyopathy. Although great progress has been made in understanding the pathogenesis, it is urgent to clarify the in-depth mechanism and identify new therapeutic targets for preventing diabetic cardiomyopathy (DCM) in smoker.

Methods: Human gene expression profiles in DCM (GSE4745 and GSE99203) corrected by SVA algorithm were analyzed and then “limma” packet gene screening was performed. By constructing the related co-expression WGCNA network of DCM, combined with the analysis of Metascape pathway, the correlation of module and genes with DCM was determined. Furthermore, the Drug bank and STRING databases were used to screen nicotine targets and expand the gene network. The hub gene was identified by crossing the targets with DCM, which was obtained by WGCNA analysis. r-packet “clusterprofiler” was used for GO analysis and KEGG pathway analysis. Then, the network of hub genes affecting DCM and the interaction diagram of core target related pathways that influence DCM is constructed by using the Cytoscape software. The relationship between hub genes was analyzed by using “corrplot”, “vioplot” packages and cibersort algorithm, and the potential mechanism of hub genes affecting DCM progress was further explored. To explore the relationship between the targets in the process of DCM, ROC curve of diagnostic efficacy was drawn with “pROC” package. Finally, a miRNA-mRNA regulatory network including hub genes was further constructed by Targetscan. The regulatory network of transcription factors of hub genes was constructed from TRRUST database.

Results: 3 gene modules were detected by WGCNA analysis, blue (202), grey (31) and turquoise (397), among which turquoise module had the highest correlation with DCM (cor =0.87, P = (3e −10)). The genes rich in monocarboxylic acid and sulfur compound metabolic processes in response to extracellular stimulus were identified. The top 13 nicotine-related are targeted. The intersection of 113 target genes and turquoise module gene were screened out. There are the two hub genes involved Iron (III) ion response and retinoic acid biosynthetic process, involving Tryptophan Metabolism and Ovarian steroidogenesis pathways. The AUC values of the two hub genes are Cyp1a1(AUC: 0.769 (0.580 - 0.958)) and Chrnb4(AUC: 0.707 (0.511 - 0.902)) and both genes are strongly correlated with immune cell response. A total of 40 miRNA-mRNA pairs, including 35 miRNAs and 2 mRNAs, were predicted by Targetscan. Three Cyp1a1 transcription factors were predicted by TRRUST database.

Conclusion: We demonstrated that two genes, Chrnb4 and Ccyp1a11, are the potential genes involved in nicotine modulating DCM, and these two genes may regulate DCM’s immune response through miRNA-mRNA mode. It provides new potential targets for preventing DCM in smoking population.

This work was supported by awards from the National Institutes of Health (HL-96686, X. Ma/Y. Wang, MPI; HL-123404, X. Ma; HL158612, Y. Wang) and the American Heart Association (20TPA35490095, Y. Wang).