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[This article belongs to Volume - 54, Issue - 2]

Abstract :

Cigarette smoking increases risk for multiple diseases. MicroRNAs (miRNAs) regulate gene expression and may play a role in smoking-induced target organ damage. We sought to describe a miRNA signature of cigarette smoking and relate it to smoking-associated clinical phenotypes, gene expression, and lung inflammatory signaling. Expression profiling of 283 miRNAs was conducted on whole blood-derived RNA from 5,023 Framingham Heart Study participants (54.0% women, mean age 55±13 years) using TaqMan assays and high-throughput RT-qPCR. Associations of miRNA expression with smoking status and associations of smoking-related miRNAs with inflammatory biomarkers and pulmonary function were tested with linear mixed-effects models. We identified a six-miRNA signature of smoking. Five of the six smoking-related miRNAs were associated with serum levels of C-reactive protein or interleukin-6; miR-1180 was associated with pulmonary function measures at a marginally significant level. Bioinformatic evaluation of smoking-associated genes coexpressed with the miRNA signature of cigarette smoking revealed enrichment for immune-related pathways. Smoking-associated miRNAs altered expression of select inflammatory mediators in cell culture gain-of-function assays. We characterized a novel miRNA signature of cigarette smoking. The top miRNAs were associated with systemic inflammatory markers and reduced pulmonary function, correlated with expression of genes involved in immune function, and were sufficient to modulate inflammatory signaling. Our results highlight smoking-associated miRNAs and are consistent with the hypothesis that smoking-associated miRNAs serve as mediators of smoking-induced inflammation and target organ damage. These findings call for further mechanistic studies to explore the diagnostic and therapeutic utility of smoking-related miRNAs.