Paired transcriptomic analyses of atheromatous and control vessels reveal novel autophagy and immunoregulatory genes in peripheral artery disease

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Abstract Background Peripheral artery disease (PAD), a significant health burden worldwide, affects lower extremities due to atherosclerotic changes in the peripheral vessels. Although mechanisms of PAD have been studied, the molecular milieu of the plaques localized within peripheral arteries in patients are not well understood. Thus, to identify PAD lesion specific gene expression profiles precluding genetic, environmental and dietary biases, we studied the transcriptomic profile of plaque tissues normalized to non-plaque tissues from the same donors. Methods Transcriptomic analysis of 9 paired samples of PAD patients from south Indian population was performed with institutional ethics approval and written consent. Plaque tissues were histologically confirmed. Expression of a select target gene set was done by qPCR from the same tissues. Bioinformatic and network analyses were performed using various statistical tools. Results A total of 296 upregulated, 274 downregulated genes and 186 non-coding RNAs were identified. STAG1, SPCC3, FOXQ1 and E2F3 were key downregulated genes and CD93 was top upregulated gene. Autophagosome assembly, cellular response to UV, cytoskeletal organization, TCR signaling and phosphatase activity were key dysregulated pathways identified in the study. Telomerase regulation and autophagy were identified as novel interacting pathways using network analysis. Plaque tissue was predominantly composed of immune cells and dedifferentiated cell populations indicated by cell specific marker imputed gene expression analysis. Conclusion The current study identifies novel genes, non-coding RNAs, associated regulatory pathways and cell composition of the plaque tissue in PAD patients. The autophagy and immunoregulatory genes may drive novel mechanisms resulting in atheroma. These novel interacting networks and genes have the potential for PAD specific therapeutic applications.

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