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MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage.

ABSTRACT: BACKGROUND:Cigarette smoking increases risk for multiple diseases. MicroRNAs regulate gene expression and may play a role in smoking-induced target organ damage. We sought to describe a microRNA signature of cigarette smoking and relate it to smoking-associated clinical phenotypes, gene expression, and lung inflammatory signaling. METHODS AND RESULTS:Expression profiling of 283 microRNAs was conducted on whole blood-derived RNA from 5023 Framingham Heart Study participants (54.0% women; mean age, 55±13 years) using TaqMan assays and high-throughput reverse transcription quantitative polymerase chain reaction. Associations of microRNA expression with smoking status and associations of smoking-related microRNAs with inflammatory biomarkers and pulmonary function were tested with linear mixed effects models. We identified a 6-microRNA signature of smoking. Five of the 6 smoking-related microRNAs 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 microRNA signature of cigarette smoking revealed enrichment for immune-related pathways. Smoking-associated microRNAs altered expression of selected inflammatory mediators in cell culture gain-of-function assays. CONCLUSIONS:We characterized a novel microRNA signature of cigarette smoking. The top microRNAs 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 microRNAs and are consistent with the hypothesis that smoking-associated microRNAs serve as mediators of smoking-induced inflammation and target organ damage. These findings call for further mechanistic studies to explore the diagnostic and therapeutic use of smoking-related microRNAs.

SUBMITTER: Willinger CM

PROVIDER: S-EPMC5683429 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage.

Willinger Christine M CM Rong Jian J Tanriverdi Kahraman K Courchesne Paul L PL Huan Tianxiao T Wasserman Gregory A GA Lin Honghuang H Dupuis Josée J Joehanes Roby R Jones Matthew R MR Chen George G Benjamin Emelia J EJ O'Connor George T GT Mizgerd Joseph P JP Freedman Jane E JE Larson Martin G MG Levy Daniel D

Circulation. Cardiovascular genetics 20171001 5

<h4>Background</h4>Cigarette smoking increases risk for multiple diseases. MicroRNAs regulate gene expression and may play a role in smoking-induced target organ damage. We sought to describe a microRNA signature of cigarette smoking and relate it to smoking-associated clinical phenotypes, gene expression, and lung inflammatory signaling.<h4>Methods and results</h4>Expression profiling of 283 microRNAs was conducted on whole blood-derived RNA from 5023 Framingham Heart Study participants (54.0% ...[more]

PMID: 29030400

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Project description:IntroductionAcademic achievement (AA) is associated with smoking rates. Can we determine the degree to which this relationship is likely a causal one?MethodsWe predict smoking in male conscripts (mean age 18.2) assessed from 1984 to 1991 (N = 233 248) and pregnant females (mean age 27.7) receiving prenatal care 1972-1990 (N = 494 995) from AA assessed in all students at 16. Instrumental variable (IV) analyses used the instrument month-of-birth as in each school year, older children have high AA. Co-relative analyses used AA-smoking associations in the population, cousins and siblings to predict the AA-smoking relationship in MZ twins, thereby controlling for familial confounding.ResultsIn males, higher AA was associated with a substantial decrease in risk for smoking (odds ratio [OR] [95% confidence intervals [CIs]] per standard deviation [SD] = 0.41 [0.40-0.41]) while the parallel figures obtain from our IV and co-relative analyses were 0.47 (0.39-0.57) and 0.51 (0.43-0.60), respectively. In females, these figures for pre-pregnancy smoking were, respectively, 0.39 (0.39-0.39), 0.50 (0.46-0.54) and 0.54 (0.51-0.58). Results for heavy versus light smoking suggested a causal effect but were inconsistent across methods. However, among females smoking prior to pregnancy, AA predicted a reduced risk for continued smoking with ORs for uncontrolled, IV, and co-relative analyses equaling, respectively, were 0.54 (0.53-0.55) 0.68 (0.56-0.82) and 0.78 (0.66-0.91), respectively.ConclusionsTwo different methods produced consistent evidence that higher AA has a causal effect on reducing smoking rates and increasing cessation rates in smoking pregnant females. Improving AA may result in meaningful gains in population health through reduced smoking.ImplicationsThis study provides consistent evidence across two different methods that high AA is causally related to reduced rates of smoking and increasing rates of smoking cessation among pregnant women. Our results suggest that interventions that improve educational achievement in adolescence would reduce tobacco consumption, thereby improving public health.

Dataset Information

MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage.

Publications

MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage.

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