Identification of gene expression signature for cigarette smoke exposure response—from man to mouse

Abstract

<jats:p> Gene expression profiling data can be used in toxicology to assess both the level and impact of toxicant exposure, aligned with a vision of 21st century toxicology. Here, we present a whole blood-derived gene signature that can distinguish current smokers from either nonsmokers or former smokers with high specificity and sensitivity. Such a signature that can be measured in a surrogate tissue (whole blood) may help in monitoring smoking exposure as well as discontinuation of exposure when the primarily impacted tissue (e.g., lung) is not readily accessible. The signature consisted of LRRN3, SASH1, PALLD, RGL1, TNFRSF17, CDKN1C, IGJ, RRM2, ID3, SERPING1, and FUCA1. Several members of this signature have been previously described in the context of smoking. The signature translated well across species and could distinguish mice that were exposed to cigarette smoke from ones exposed to air only or had been withdrawn from cigarette smoke exposure. Finally, the small signature of only 11 genes could be converted into a polymerase chain reaction-based assay that could serve as a marker to monitor compliance with a smoking abstinence protocol. </jats:p>

The sbv IMPROVER Systems Toxicology computational challenge: Identification of human and species-independent blood response markers as predictors of smoking exposure and cessation status

“…These genes overlapped remarkably with genes present in previously published blood-based smoking gene signatures derived from the same datasets, constituting an independent confirmation of a signature proposed by Martin et al [27] and signatures from a meta-analysis of six studies that included a total of 10,233 subjects [50]. Many genes of the consensus signature are reported to undergo differential regulation at the mRNA and/or DNA methylation level following exposure to cigarette smoke (references in Supplementary table 7).…”

“…This finding confirmed that smoke has a prominent effect that propagates in blood cells distal to lungs, the primary site of exposure [20, 27]. Best-performing teams succeeded in (i) developing inductive models able to predict the class of new independent individual samples with high levels of performance (AUPR ≥0.93 for SC1 and SC2), and (ii) extracting parsimonious signatures that did not exceed 40 genes.…”

“…These results may also be useful for assessing the exposure response to the new generation of non-combustible tobacco products with the potential to reduce individual risk. Applying a human blood-based smoking exposure response gene signature previously identified [27], Martin et al demonstrated that samples from conventional cigarette smokers who switched to a THS2.2 shifted away from the S group and classified closer to the NCS group after only 5 days of switching [49]. These results were independently confirmed by the crowd in the context of this challenge [31].…”

“…Therefore, the identification of specific markers of response to smoking or cessation in whole blood cells may be an important way to monitor the exposure status of an individual subject. In general, blood-based signatures for smoking exposure that have been reported in the literature share very few genes [25–27]. Most pre-clinical toxicological in vivo studies are conducted in rodents, adding a degree of complexity when applying the results to humans.…”

Meta-analysis of Gene Expression Microarray Datasets in Chronic Obstructive Pulmonary Disease

“…The 71 search results were further filtered to include datasets where the age, sex and smoking 72 status of the samples were reported ( Fig 1B). We found 3 datasets from GEO 73 (GSE42057 [21], GSE71220 [22], GSE54837 [23]) and 1 from AE (E-MTAB-5278 [24]) 74 that met our search criteria ( Table 1 and Fig 1B). We conducted an additional search 75 on GEO and AE to find healthy subjects with their smoking history reported to balance 76 our control subjects with our COPD subjects.…”