Early-onset emphysema in a large French-Canadian family: a genetic investigation.

BACKGROUND: Inherited mutations in SERPINA1 coding for the alpha-1 antitrypsin (A1AT) protein is the only well established cause of hereditary emphysema. We aimed to identify the genetic ecause of early-onset emphysema in a five-generation French-Canadian family free of A1AT deficiency. METHODS: Between Dec 1, 2014, and April 1, 2017, we investigated 63 individuals from a single pedigree, including 55 with DNA available. Whole-exome sequencing was done in a convenience sample of 14 individuals (nine with unambiguous expression of the typical form of emphysema observed in this family). We filtered rare non-synonymous variants that were predicted to be damaging to identify a single mutation in a biologically relevant gene shared among all affected individuals. We assessed segregation with the disease in additional family members who were not evaluated by whole-exome sequencing. The effect of the candidate variant on protein function was evaluated in vitro. mRNA and protein expression of the candidate gene was assessed in lung samples from unrelated individuals (n=80) with and without emphysema who underwent surgery for lung cancer at our institution. FINDINGS: A rare in-silico-predicted damaging variant (Ala455Thr) was identified in the protein tyrosine phosphatase non-receptor type 6 (PTPN6) gene, also known as SHP-1, an important negative regulator of immune processes. 20 (95%) of 21 family members with computed tomography-confirmed emphysema were heterozygotes for the Ala455Thr mutation. No Thr455 homozygotes were identified. Emphysema or reduced diffusion capacity was observed in all heterozygotes with a history of smoking. Incomplete penetrance of the mutation and variable degrees of emphysema were observed in never smokers. The Ala455Thr mutation in SHP-1 caused a reduction in phosphatase activity in vitro, confirming the loss-of-function effect of the mutation. mRNA and protein expression of PTPN6 were upregulated in smokers, but were not associated with emphysema or severity of airflow limitation. INTERPRETATION: An inherited variant in the gene PTPN6 is responsible for early-onset emphysema in this family. To our knowledge, this is the second form of hereditary emphysema since the discovery of A1AT deficiency in the 1960s, representing a breakthrough in understanding the genetics and pathogenesis of emphysema. FUNDING: Fonds sur les maladies respiratoires J.-D. Bégin-P.-H. Lavoie de l'Université Laval, Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec, CIHR/GSK research Chair on COPD at Université Laval, and the Canadian Institutes of Health Research.

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

BACKGROUND: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. METHODS: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. RESULTS: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. CONCLUSIONS: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

The DNA repair transcriptome in severe COPD.

Inadequate DNA repair is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the mechanisms that underlie inadequate DNA repair in COPD are poorly understood. We applied an integrative genomic approach to identify DNA repair genes and pathways associated with COPD severity.We measured the transcriptomic changes of 419 genes involved in DNA repair and DNA damage tolerance that occur with severe COPD in three independent cohorts (n=1129). Differentially expressed genes were confirmed with RNA sequencing and used for patient clustering. Clinical and genome-wide transcriptomic differences were assessed following cluster identification. We complemented this analysis by performing gene set enrichment analysis, Z-score and weighted gene correlation network analysis to identify transcriptomic patterns of DNA repair pathways associated with clinical measurements of COPD severity.We found 15 genes involved in DNA repair and DNA damage tolerance to be differentially expressed in severe COPD. K-means clustering of COPD cases based on this 15-gene signature identified three patient clusters with significant differences in clinical characteristics and global transcriptomic profiles. Increasing COPD severity was associated with downregulation of the nucleotide excision repair pathway.Systematic analysis of the lung tissue transcriptome of individuals with severe COPD identified DNA repair responses associated with disease severity that may underlie COPD pathogenesis.

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations.

Causal genes of chronic obstructive pulmonary disease (COPD) remain elusive. The current study aims at integrating genome-wide association studies (GWAS) and lung expression quantitative trait loci (eQTL) data to map COPD candidate causal genes and gain biological insights into the recently discovered COPD susceptibility loci. Two complementary genomic datasets on COPD were studied. First, the lung eQTL dataset which included whole-genome gene expression and genotyping data from 1038 individuals. Second, the largest COPD GWAS to date from the International COPD Genetics Consortium (ICGC) with 13 710 cases and 38 062 controls. Methods that integrated GWAS with eQTL signals including transcriptome-wide association study (TWAS), colocalization and Mendelian randomization-based (SMR) approaches were used to map causality genes, i.e. genes with the strongest evidence of being the functional effector at specific loci. These methods were applied at the genome-wide level and at COPD risk loci derived from the GWAS literature. Replication was performed using lung data from GTEx. We collated 129 non-overlapping risk loci for COPD from the GWAS literature. At the genome-wide scale, 12 new COPD candidate genes/loci were revealed and six replicated in GTEx including CAMK2A, DMPK, MYO15A, TNFRSF10A, BTN3A2 and TRBV30. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci and 23 of them were replicated in GTEx. Mapping candidate causal genes in lung tissue represents an important contribution to the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.

A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis.

Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues (n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS (P = 1.53 × 10-10) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options.

Lung cancer susceptibility genetic variants modulate HOXB2 expression in the lung.

The HOX genes are transcription factors that are expressed in coordinated spatiotemporal patterns to ensure normal development. Ectopic expression may instead lead to the development and progression of tumors. Genetic polymorphisms in the regions of four HOX gene clusters were tested for association with lung cancer in 420 cases and 3,151 controls. The effect of these variants on lung gene expression (expression quantitative trait loci, eQTL) was tested in a discovery set of 409 non-tumor lung samples and validated in two lung eQTL replication sets (n = 287 and 342). The expression levels of HOXB2 were evaluated at the mRNA and protein levels by quantitative real-time PCR and immunohistochemistry in paired tumor and non-tumor lung tissue samples. The most significant SNP associated with lung cancer in the HOXB cluster was rs10853100 located upstream of the HOXB cluster. HOXB2 was the top eQTL-regulated gene with several polymorphisms associated with its mRNA expression levels in lung tissue. This includes the lung cancer SNP rs10853100 that was significantly associated with HOXB2 expression (P=3.39E-7). In the lung eQTL discovery and replication sets, the lung cancer risk allele (T) for rs10853100 was associated with lower HOXB2 expression levels. In paired normal-tumor samples, HOXB2 mRNA and protein levels were significantly reduced in tumors when compared to non-tumor lung tissues. Genetic variants in the HOXB cluster may confer susceptibility to lung cancer by modulating the expression of HOXB2 in the lung.

Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse.

BACKGROUND: A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. METHODS: DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico. RESULTS: p.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases. CONCLUSION: This study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease.

BACKGROUND: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD. METHODS: Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking. Cases and controls were selected from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. RESULTS: In total, 37 genetic variants showed association with COPD (p < 0.05, uncorrected). Several variants previously discovered to be associated with COPD from genetic genome-wide analysis studies were replicated using our sample. Two high-risk variants were followed-up for functional characterization in a large eQTL mapping study of 1,111 human lung specimens. The C allele of a synonymous variant, rs8040868, predicting a p.(S45=) in the gene for cholinergic receptor nicotinic alpha 3 (CHRNA3) was associated with COPD (p = 8.8 x 10-3). This association remained (p = 0.003 and OR = 1.4, 95 % CI 1.1-1.7) when analysing all available cases and controls in OLIN (n = 1,534). The rs8040868 variant is in linkage disequilibrium with rs16969968 previously associated with COPD and altered expression of the CHRNA5 gene. A follow-up analysis for detection of expression quantitative trait loci revealed that rs8040868-C was found to be significantly associated with a decreased expression of the nearby gene cholinergic receptor, nicotinic, alpha 5 (CHRNA5) in lung tissue. CONCLUSION: Our data replicate previous result suggesting CHRNA5 as a candidate gene for COPD and rs8040868 as a risk variant for the development of COPD in the Swedish population.

Identification of Gender-Specific Genetic Variants in Patients With Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) is the most frequent congenital heart defect and has a male predominance of 3 to 1. A large proportion of patients develop valvular and aortic complications. Despite the high prevalence of BAV, its cause and genetic origins remain elusive. The goal of this study was to identify genetic variants associated with BAV. Nine genes previously associated with BAV (NOTCH1, AXIN1, EGFR, ENG, GATA5, NKX2-5, NOS3, PDIA2, and TGFBR2) were sequenced in 48 patients with BAV using the Ion Torrent Personal Genome Machine. Pathogenicity of genetic variants was evaluated with the Combined Annotation Dependent Depletion framework. A selection of 89 variants identified by sequencing or in previous BAV genetic studies was genotyped, and allele frequencies were compared in 323 patients with BAV confirmed at surgery and 584 controls. Analyses were also performed by gender. Nine novel and 19 potentially pathogenic variants were identified by next-generation sequencing and confirmed by Sanger sequencing, but they were not associated with BAV in the case-control population. A significant association was observed between an in silico-predicted benign EGFR intronic variant (rs17290301) and BAV. Analyses performed by gender revealed different variants associated with BAV in men (EGFR rs533525993 and TEX26 rs12857479) and women (NOTCH1 rs61751489, TGFBR2 rs1155705, and NKX2-5 rs2277923). In conclusion, these results constitute the first association between EGFR genetic variants and BAV in humans and support a possible role of gender-specific polymorphisms in the development of BAV.

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.

BACKGROUND: Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS. METHODS AND RESULTS: A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P<5×10(-6) in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P=5.33×10(-5)). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene. CONCLUSIONS: This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C, belonging to the calcium signaling pathway.

Polymorphisms associated with expression of BPIFA1/BPIFB1 and lung disease severity in cystic fibrosis.

BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are putative innate immune molecules expressed in the upper airways. Because of their hypothesized roles in airway defense, these molecules may contribute to lung disease severity in cystic fibrosis (CF). We interrogated BPIFA1/BPIFB1 single-nucleotide polymorphisms in data from an association study of CF modifier genes and found an association of the G allele of rs1078761 with increased lung disease severity (P = 2.71 × 10(-4)). We hypothesized that the G allele of rs1078761 is associated with decreased expression of BPIFA1 and/or BPIFB1. Genome-wide lung gene expression and genotyping data from 1,111 individuals with lung disease, including 51 patients with CF, were tested for associations between genotype and BPIFA1 and BPIFB1 gene expression levels. Findings were validated by quantitative PCR in a subset of 77 individuals. Western blotting was used to measure BPIFA1 and BPIFB1 protein levels in 93 lung and 101 saliva samples. The G allele of rs1078761 was significantly associated with decreased mRNA levels of BPIFA1 (P = 4.08 × 10(-15)) and BPIFB1 (P = 0.0314). These findings were confirmed with quantitative PCR and Western blotting. We conclude that the G allele of rs1078761 may be detrimental to lung function in CF owing to decreased levels of BPIFA1 and BPIFB1.

Influences of gestational obesity on associations between genotypes and gene expression levels in offspring following maternal gastrointestinal bypass surgery for obesity.

METHODS: Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis. RESULTS: Significant interactions (p ≤ 1.22 x 10(-12)) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways. CONCLUSION: We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism.

Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung.

Recent studies identified three genetic loci reproducibly associated with lung cancer in populations of European ancestry, namely 15q25, 5p15 and 6p21. The goals of this study are first to confirm whether these loci are associated with lung cancer in a French Canadian population and second to identify disease-associated single nucleotide polymorphisms (SNPs) influencing messenger RNA (mRNA) expression levels of genes in the lung, that is expression quantitative trait loci (eQTLs). SNPs were genotyped in 420 patients undergoing lung cancer surgery and compared with 3151 controls of European ancestry. Genome-wide gene expression levels in non-tumor lung tissues of the same 420 patients were also measured to identify eQTLs. Significant eQTLs were then followed-up in two replication sets (n = 339 and 363). SNPs found in the three susceptibility loci were associated with lung cancer in the French Canadian population. Strong eQTLs were found on chromosome 15q25 with the expression levels of CHRNA5 (P = 2.23 × 10(-) (22) with rs12907966). The CHRNA5-rs12907966 eQTL was convincingly validated in the two replication sets (P = 3.46 × 10(-) (16) and 2.01 × 10(-) (15)). On 6p21, a trend was observed for rs3131379 to be associated with the expression of APOM (P = 3.58 × 10(-) (4)) and validated in the replication sets (P = 1.11 × 10(-) (8) and 6.84 × 10(-) (4)). On 5p15, no significant eQTLs were found. This study confirmed that chromosomes 15q25, 5p15 and 6p21 harbored susceptibility loci for lung cancer in French Canadians. Most importantly, this study suggests that the risk alleles at 15q25 and 6p21 may mediate their effect by regulating the mRNA expression levels of CHRNA5 and APOM in the lung.

Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction.

BACKGROUND: COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL). OBJECTIVE: To determine causal associations between COPD and lung function-associated single nucleotide polymorphisms (SNPs) and lung tissue gene expression changes in our lung eQTL dataset. METHODS: We evaluated causality between SNPs and gene expression for three COPD phenotypes: FEV(1)% predicted, FEV(1)/FVC and COPD as a categorical variable. Different models were assessed in the three cohorts independently and in a meta-analysis. SNPs associated with a COPD phenotype and gene expression were subjected to causal pathway modelling and manual curation. In silico analyses evaluated functional enrichment of biological pathways among newly identified causal genes. Biologically relevant causal genes were validated in two separate gene expression datasets of lung tissues and bronchial airway brushings. RESULTS: High reliability causal relations were found in SNP-mRNA-phenotype triplets for FEV(1)% predicted (n=169) and FEV(1)/FVC (n=80). Several genes of potential biological relevance for COPD were revealed. eQTL-SNPs upregulating cystatin C (CST3) and CD22 were associated with worse lung function. Signalling pathways enriched with causal genes included xenobiotic metabolism, apoptosis, protease-antiprotease and oxidant-antioxidant balance. CONCLUSIONS: By using integrative genomics and analysing the relationships of COPD phenotypes with SNPs and gene expression in lung tissue, we identified CST3 and CD22 as potential causal genes for airflow obstruction. This study also augmented the understanding of previously described COPD pathways.

Impact of cigarette smoke on the human and mouse lungs: a gene-expression comparison study.

Cigarette smoke is well known for its adverse effects on human health, especially on the lungs. Basic research is essential to identify the mechanisms involved in the development of cigarette smoke-related diseases, but translation of new findings from pre-clinical models to the clinic remains difficult. In the present study, we aimed at comparing the gene expression signature between the lungs of human smokers and mice exposed to cigarette smoke to identify the similarities and differences. Using human and mouse whole-genome gene expression arrays, changes in gene expression, signaling pathways and biological functions were assessed. We found that genes significantly modulated by cigarette smoke in humans were enriched for genes modulated by cigarette smoke in mice, suggesting a similar response of both species. Sixteen smoking-induced genes were in common between humans and mice including six newly reported to be modulated by cigarette smoke. In addition, we identified a new conserved pulmonary response to cigarette smoke in the induction of phospholipid metabolism/degradation pathways. Finally, the majority of biological functions modulated by cigarette smoke in humans were also affected in mice. Altogether, the present study provides information on similarities and differences in lung gene expression response to cigarette smoke that exist between human and mouse. Our results foster the idea that animal models should be used to study the involvement of pathways rather than single genes in human diseases.