1  3027 110 GENETICS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE WITH MULTIFACTORIAL BACKGROUND, BASED ON THE INTERACTION OF ENVIRONMENTAL AND GENETIC FACTORS. ENVIRONMENTAL FACTORS ARE CLEARLY RELATED TO THE DEVELOPMENT OF THE DISEASE. HOWEVER, FAMILY AND TWIN STUDIES SUGGESTED GENETICS FACTORS TO BE ONE OF THE IMPORTANT DETERMINANTS FOR THE DEVELOPMENT OF COPD. DIFFERENT APPROACHES HAVE BEEN USED TO IDENTIFY GENES OF INTEREST. GENOMEWIDE LINKAGE ANALYSIS FOUND AREAS OF INTEREST ON DIFFERENT CHROMOSOMES, WITH SOME GENES LOCATED IN THIS REGIONS BEING IDENTIFIED AND REPLICATED AS SUSCEPTIBILITY GENES. NUMEROUS OF CANDIDATE GENES THAT COULD BE LINKED TO DISEASE PATHOGENESIS HAVE BEEN IMPLICATED IN COPD GENETICS. HOWEVER, THE CANDIDATE GENE APPROACH IS OFTEN LIMITED BY INCONSISTENT RESULTS IN OTHER STUDY POPULATIONS. RECENTLY, A COMBINATION OF DIFFERENT METHODS IS USED GIVING MORE EVIDENCE FOR SOME CANDIDATE GENES, INCLUDING TGFBETA-1, SURFACTANT, SERPINE2 AND MICROSOMAL EPOXIDE HYDROLASE. IN THE FUTURE ONGOING EXACT PHENOTYPE DEFINITION, COMBINATION OF SEVERAL APPROACHES, GENOME-WIDE ASSOCIATION STUDIES AND ANIMAL MODEL GENETICS WILL LEAD TO NEW INSIGHTS INTO THE GENETICS OF COPD, WITH EPIGENETIC FACTORS NEEDS TO BE FURTHER INVESTIGATED AND CONSIDERED IN CONCERT WITH GENETIC FINDINGS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  5595  30 ROLES OF GENETIC PREDISPOSITION IN THE SEX BIAS OF PULMONARY PATHOPHYSIOLOGY, AS A FUNCTION OF ESTROGENS : SEX MATTERS IN THE PREVALENCE OF LUNG DISEASES. IN ADDITION TO STUDIES FOCUSED ON ESTROGEN MEDIATION OF SEX-DIFFERENT REGULATION OF SYSTEMIC CIRCULATIONS, THERE IS NOW INCREASING CLINICAL RELEVANCE AND RESEARCH INTERESTS IN THE PULMONARY CIRCULATION, IN TERMS OF SEX DIFFERENCES IN THE MORBIDITY AND MORTALITY OF LUNG DISEASES SUCH AS INHERENT-, ALLERGIC- AND INFLAMMATORY-BASED EVENTS. THUS, FEMALE PREDISPOSITION TO PULMONARY ARTERY HYPERTENSION (PAH) IS AN INEVITABLE TOPIC. TO BETTER UNDERSTAND THE NATURE OF SEXUAL DIFFERENTIATION IN THE PULMONARY CIRCULATION, AND HOW HERITABLE FACTORS, IN VIVO- AND/OR IN VITRO-ALTERED ESTROGEN CIRCUMSTANCES AND CHANGES IN THE LIVE ENVIRONMENT WORK IN CONCERT TO DISCERN THE SEX BIAS, THIS CHAPTER REVIEWS PULMONARY EVENTS CHARACTERIZED BY SEX-DIFFERENT FEATURES, CONCOMITANT WITH EXPLORATION OF HOW ALTERATIONS OF GENETIC EXPRESSION AND ESTROGEN METABOLISMS TRIGGER THE FEMALE-PREDOMINANT PATHOLOGICAL SIGNALING. WE ADDRESS THE FOLLOWING: PAH (SECT.7.2) IS CHARACTERIZED AS AN ESTROGENIC PROMOTION OF ITS INCIDENCE (SECT. 7.2.2), AS A FUNCTION OF SPECIFIC GERMLINE MUTATIONS, AND AS AN ESTROGEN-ELICITED PROTECTION OF ITS PROGNOSIS (SECT.7.2.1). MORE DETAIL IS PROVIDED TO INTRODUCE A LESS RECOGNIZED GENE OF EPHX2 THAT ENCODES SOLUBLE EPOXIDE HYDROLASE (SEH) TO DEGRADE EPOXYEICOSATRIENIC ACIDS (EETS). AS A SUSCEPTIBLE TARGET OF ESTROGEN, EPHX2/SEH EXPRESSION IS DOWNREGULATED BY AN ESTROGEN-DEPENDENT EPIGENETIC MECHANISM. INCREASES IN PULMONARY EETS THEN EVOKE A POTENTIATION OF PAH GENERATION, BUT MITIGATION OF ITS PROGRESSION, A PHENOMENON SIMILAR TO THE ESTROGEN-PARADOX REGULATION OF PAH. ADDITIONALLY, THE FEMALE SUSCEPTIBILITY TO CHRONIC OBSTRUCTIVE PULMONARY DISEASES (SECT. 7.3) AND ASTHMA (SECT.7.4), BUT LESS PREFERENCE TO COVID-19 (SECT. 7.5), AND ROLES OF ESTROGEN IN THEIR PATHOGENESES ARE BRIEFLY DISCUSSED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3  3824  31 INVESTIGATING THE EPIGENETIC EFFECTS OF A PROTOTYPE SMOKE-DERIVED CARCINOGEN IN HUMAN CELLS. GLOBAL LOSS OF DNA METHYLATION AND LOCUS/GENE-SPECIFIC GAIN OF DNA METHYLATION ARE TWO DISTINCT HALLMARKS OF CARCINOGENESIS. ABERRANT DNA METHYLATION IS IMPLICATED IN SMOKING-RELATED LUNG CANCER. IN THIS STUDY, WE HAVE COMPREHENSIVELY INVESTIGATED THE MODULATION OF DNA METHYLATION CONSEQUENT TO CHRONIC EXPOSURE TO A PROTOTYPE SMOKE-DERIVED CARCINOGEN, BENZO[A]PYRENE DIOL EPOXIDE (B[A]PDE), IN GENOMIC REGIONS OF SIGNIFICANCE IN LUNG CANCER, IN NORMAL HUMAN CELLS. WE HAVE USED A PULLDOWN ASSAY FOR ENRICHMENT OF THE CPG METHYLATED FRACTION OF CELLULAR DNA COMBINED WITH MICROARRAY PLATFORMS, FOLLOWED BY EXTENSIVE VALIDATION THROUGH CONVENTIONAL BISULFITE-BASED ANALYSIS. HERE, WE DEMONSTRATE STRIKINGLY SIMILAR PATTERNS OF DNA METHYLATION IN NON-TRANSFORMED B[A]PDE-TREATED CELLS VS CONTROL USING HIGH-THROUGHPUT MICROARRAY-BASED DNA METHYLATION PROFILING CONFIRMED BY CONVENTIONAL BISULFITE-BASED DNA METHYLATION ANALYSIS. THE ABSENCE OF ABERRANT DNA METHYLATION IN OUR MODEL SYSTEM WITHIN A TIMEFRAME THAT PRECEDES CELLULAR TRANSFORMATION SUGGESTS THAT FOLLOWING CARCINOGEN EXPOSURE, OTHER AS YET UNKNOWN FACTORS (SECONDARY TO CARCINOGEN TREATMENT) MAY HELP INITIATE GLOBAL LOSS OF DNA METHYLATION AND REGION-SPECIFIC GAIN OF DNA METHYLATION, WHICH CAN, IN TURN, CONTRIBUTE TO LUNG CANCER DEVELOPMENT. UNVEILING THE INITIATING EVENTS THAT CAUSE ABERRANT DNA METHYLATION IN LUNG CANCER HAS TREMENDOUS PUBLIC HEALTH RELEVANCE, AS IT CAN HELP DEFINE FUTURE STRATEGIES FOR EARLY DETECTION AND PREVENTION OF THIS HIGHLY LETHAL DISEASE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  6691  35 VARIABLE DNA METHYLATION IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG FUNCTION. RATIONALE: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ASSOCIATED WITH LOCAL (LUNG) AND SYSTEMIC (BLOOD) INFLAMMATION AND MANIFESTATIONS. DNA METHYLATION IS AN IMPORTANT REGULATOR OF GENE TRANSCRIPTION, AND GLOBAL AND SPECIFIC GENE METHYLATION MARKS MAY VARY WITH CIGARETTE SMOKE EXPOSURE. OBJECTIVES: TO PERFORM A COMPREHENSIVE ASSESSMENT OF METHYLATION MARKS IN DNA FROM SUBJECTS WELL PHENOTYPED FOR NONNEOPLASTIC LUNG DISEASE. METHODS: WE CONDUCTED ARRAY-BASED METHYLATION SCREENS, USING A TEST-REPLICATION APPROACH, IN TWO FAMILY-BASED COHORTS (N = 1,085 AND 369 SUBJECTS). MEASUREMENTS AND MAIN RESULTS: WE OBSERVED 349 CPG SITES SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE AND SEVERITY OF COPD IN BOTH COHORTS. SEVENTY PERCENT OF THE ASSOCIATED CPG SITES WERE OUTSIDE OF CPG ISLANDS, WITH THE MAJORITY OF CPG SITES RELATIVELY HYPOMETHYLATED. GENE ONTOLOGY ANALYSIS BASED ON THESE 349 CPGS (330 GENES) SUGGESTED THE INVOLVEMENT OF A NUMBER OF GENES RESPONSIBLE FOR IMMUNE AND INFLAMMATORY SYSTEM PATHWAYS, RESPONSES TO STRESS AND EXTERNAL STIMULI, AS WELL AS WOUND HEALING AND COAGULATION CASCADES. INTERESTINGLY, OUR OBSERVATIONS INCLUDE SIGNIFICANT, REPLICABLE ASSOCIATIONS BETWEEN SERPINA1 HYPOMETHYLATION AND COPD AND LOWER AVERAGE LUNG FUNCTION PHENOTYPES (COMBINED P VALUES: COPD, 1.5 X 10(-23); FEV(1)/FVC, 1.5 X 10(-35); FEV(1), 2.2 X 10(-40)). CONCLUSIONS: GENETIC AND EPIGENETIC PATHWAYS MAY BOTH CONTRIBUTE TO COPD. MANY OF THE TOP ASSOCIATIONS BETWEEN COPD AND DNA METHYLATION OCCUR IN BIOLOGICALLY PLAUSIBLE PATHWAYS. THIS LARGE-SCALE ANALYSIS SUGGESTS THAT DNA METHYLATION MAY BE A BIOMARKER OF COPD AND MAY HIGHLIGHT NEW PATHWAYS OF COPD PATHOGENESIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  2628  29 EPIGENOME-WIDE ASSOCIATION STUDY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG FUNCTION IN KOREANS. AIM: TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND REGIONS (DMRS) IN RELATION TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG FUNCTION TRAITS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF COPD AND SPIROMETRIC PARAMETERS, INCLUDING FORCED EXPIRATORY VOLUME IN 1 S (FEV1), FORCED VITAL CAPACITY (FVC) AND FEV1/FVC, IN BLOOD DNA USING THE INFINIUM HUMANMETHYLATION450 (N = 100, A KOREAN COPD COHORT). RESULTS: WE FOUND ONE SIGNIFICANT DMP (CG03559389, DIP2C) AND 104 SIGNIFICANT DMRS AFTER MULTIPLE-TESTING CORRECTION. OF THESE, 34 DMRS MAPPED TO GENES DIFFERENTIAL EXPRESSED WITH RESPECT TO THE SAME TRAIT. FIVE OF THE GENES WERE ASSOCIATED WITH MORE THAN TWO TRAITS: CTU2, USP36, ZNF516, KLK10 AND CPT1B. CONCLUSION: WE IDENTIFIED NOVEL DIFFERENTIAL METHYLATION LOCI RELATED TO COPD AND LUNG FUNCTION IN BLOOD DNA IN KOREANS AND CONFIRMED PREVIOUS FINDINGS IN NON-ASIANS. EPIGENETIC MODIFICATION COULD CONTRIBUTE TO THE ETIOLOGY OF THESE PHENOTYPES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  2737  31 EXPOSING A DEADLY ALLIANCE: NOVEL INSIGHTS INTO THE BIOLOGICAL LINKS BETWEEN COPD AND LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE AND IS EXPECTED TO BECOME THE THIRD LEADING CAUSE OF DEATH IN 2020. COPD IS CHARACTERIZED BY PROGRESSIVE AIRFLOW LIMITATION, DUE TO A COMBINATION OF CHRONIC INFLAMMATION AND REMODELING OF THE SMALL AIRWAYS (BRONCHIOLITIS) AND LOSS OF ELASTIC RECOIL CAUSED BY DESTRUCTION OF THE ALVEOLAR WALLS (EMPHYSEMA). LUNG CANCER IS THE MOST IMPORTANT CAUSE OF CANCER-RELATED DEATH IN THE WORLD. (CIGARETTE) SMOKING IS THE PRINCIPAL CULPRIT CAUSING BOTH COPD AND LUNG CANCER; IN ADDITION, EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE, BIOMASS FUEL SMOKE, COAL SMOKE AND OUTDOOR AIR POLLUTION HAVE ALSO BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF BOTH DISEASES. IMPORTANTLY, SMOKERS WITH COPD--DEFINED AS EITHER NOT FULLY REVERSIBLE AIRFLOW LIMITATION OR EMPHYSEMA--HAVE A TWO- TO FOUR-FOLD INCREASED RISK TO DEVELOP LUNG CANCER. IN THIS REVIEW, WE HIGHLIGHT SEVERAL OF THE GENETIC, EPIGENETIC AND INFLAMMATORY MECHANISMS, WHICH LINK COPD AND CARCINOGENESIS IN THE LUNGS. ELUCIDATING THE BIOLOGICAL PATHWAYS AND NETWORKS, WHICH UNDERLIE THE INCREASED SUSCEPTIBILITY OF LUNG CANCER IN PATIENTS WITH COPD, HAS IMPORTANT IMPLICATIONS FOR SCREENING, PREVENTION, DIAGNOSIS AND TREATMENT OF THESE TWO DEVASTATING PULMONARY DISEASES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  1590  36 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8  3420  34 HUMAN LUNG DNA METHYLATION QUANTITATIVE TRAIT LOCI COLOCALIZE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE GENOME-WIDE ASSOCIATION LOCI. RATIONALE: AS THE THIRD LEADING CAUSE OF DEATH IN THE UNITED STATES, THE IMPACT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) MAKES IDENTIFICATION OF ITS MOLECULAR MECHANISMS OF GREAT IMPORTANCE. GENOME-WIDE ASSOCIATION STUDIES (GWASS) HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS ASSOCIATED WITH COPD. HOWEVER, GENETIC VARIATION ONLY EXPLAINS A SMALL FRACTION OF THE SUSCEPTIBILITY TO COPD, AND SUB-GENOME-WIDE SIGNIFICANT LOCI MAY PLAY A ROLE IN PATHOGENESIS. OBJECTIVES: REGULATORY ANNOTATION WITH EPIGENETIC EVIDENCE MAY GIVE PRIORITY FOR FURTHER INVESTIGATION, PARTICULARLY FOR GWAS ASSOCIATIONS IN NONCODING REGIONS. WE PERFORMED INTEGRATIVE GENOMICS ANALYSES USING DNA METHYLATION PROFILING AND GENOME-WIDE SNP GENOTYPING FROM LUNG TISSUE SAMPLES FROM 90 SUBJECTS WITH COPD AND 36 CONTROL SUBJECTS. METHODS: WE PERFORMED METHYLATION QUANTITATIVE TRAIT LOCI (MQTL) ANALYSES, TESTING FOR SNPS ASSOCIATED WITH PERCENT DNA METHYLATION AND ASSESSED THE COLOCALIZATION OF THESE RESULTS WITH PREVIOUS COPD GWAS FINDINGS USING BAYESIAN METHODS IN THE R PACKAGE COLOC TO HIGHLIGHT POTENTIAL REGULATORY FEATURES OF THE LOCI. MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED 942,068 UNIQUE SNPS AND 33,996 UNIQUE CPG SITES AMONG THE SIGNIFICANT (5% FALSE DISCOVERY RATE) CIS-MQTL RESULTS. THE GENOME-WIDE SIGNIFICANT AND SUBTHRESHOLD (P < 10(-4)) GWAS SNPS WERE ENRICHED IN THE SIGNIFICANT MQTL SNPS (HYPERGEOMETRIC TEST P < 0.00001). WE OBSERVED ENRICHMENT FOR SITES LOCATED IN CPG SHORES AND SHELVES, BUT NOT CPG ISLANDS. USING BAYESIAN COLOCALIZATION, WE IDENTIFIED LOCI IN REGIONS NEAR KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, AND IL27. CONCLUSIONS: COLOCALIZATION OF MQTL AND GWAS LOCI PROVIDES REGULATORY CHARACTERIZATION OF SIGNIFICANT AND SUBTHRESHOLD GWAS FINDINGS, SUPPORTING A ROLE FOR GENETIC CONTROL OF METHYLATION IN COPD PATHOGENESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  2631  43 EPIGENOME-WIDE ASSOCIATION STUDY OF WHOLE BLOOD GENE EXPRESSION IN FRAMINGHAM HEART STUDY PARTICIPANTS PROVIDES MOLECULAR INSIGHT INTO THE POTENTIAL ROLE OF CHRNA5 IN CIGARETTE SMOKING-RELATED LUNG DISEASES. BACKGROUND: DNA METHYLATION IS A KEY EPIGENETIC MODIFICATION THAT CAN DIRECTLY AFFECT GENE REGULATION. DNA METHYLATION IS HIGHLY INFLUENCED BY ENVIRONMENTAL FACTORS SUCH AS CIGARETTE SMOKING, WHICH IS CAUSALLY RELATED TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. TO DATE, THERE HAVE BEEN FEW LARGE-SCALE, COMBINED ANALYSES OF DNA METHYLATION AND GENE EXPRESSION AND THEIR INTERRELATIONS WITH LUNG DISEASES. RESULTS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF WHOLE BLOOD GENE EXPRESSION IN ~ 6000 INDIVIDUALS FROM FOUR COHORTS. WE DISCOVERED AND REPLICATED NUMEROUS CPGS ASSOCIATED WITH THE EXPRESSION OF CIS GENES WITHIN 500 KB OF EACH CPG, WITH 148 TO 1,741 CIS CPG-TRANSCRIPT PAIRS IDENTIFIED ACROSS COHORTS. WE FOUND THAT THE CLOSER A CPG RESIDED TO A TRANSCRIPTION START SITE, THE LARGER ITS EFFECT SIZE, AND THAT 36% OF CIS CPG-TRANSCRIPT PAIRS SHARE THE SAME CAUSAL GENETIC VARIANT. MENDELIAN RANDOMIZATION ANALYSES REVEALED THAT HYPOMETHYLATION AND LOWER EXPRESSION OF CHRNA5, WHICH ENCODES A SMOKING-RELATED NICOTINIC RECEPTOR, ARE CAUSALLY LINKED TO INCREASED RISK OF COPD AND LUNG CANCER. THIS PUTATIVELY CAUSAL RELATIONSHIP WAS FURTHER VALIDATED IN LUNG TISSUE DATA. CONCLUSIONS: OUR RESULTS PROVIDE A LARGE AND COMPREHENSIVE ASSOCIATION STUDY OF WHOLE BLOOD DNA METHYLATION WITH GENE EXPRESSION. EXPRESSION PLATFORM DIFFERENCES RATHER THAN POPULATION DIFFERENCES ARE CRITICAL TO THE REPLICATION OF CIS CPG-TRANSCRIPT PAIRS. THE LOW REPRODUCIBILITY OF TRANS CPG-TRANSCRIPT PAIRS SUGGESTS THAT DNA METHYLATION REGULATES NEARBY RATHER THAN REMOTE GENE EXPRESSION. THE PUTATIVELY CAUSAL ROLES OF METHYLATION AND EXPRESSION OF CHRNA5 IN RELATION TO COPD AND LUNG CANCER PROVIDE EVIDENCE FOR A MECHANISTIC LINK BETWEEN PATTERNS OF SMOKING-RELATED EPIGENETIC VARIATION AND LUNG DISEASES, AND HIGHLIGHT POTENTIAL THERAPEUTIC TARGETS FOR LUNG DISEASES AND SMOKING CESSATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  4025  33 LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE: NEEDS AND OPPORTUNITIES FOR INTEGRATED RESEARCH. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE LEADING CAUSES OF MORBIDITY AND MORTALITY IN THE UNITED STATES AND WORLDWIDE. THEY SHARE A COMMON ENVIRONMENTAL RISK FACTOR IN CIGARETTE SMOKE EXPOSURE AND A GENETIC PREDISPOSITION REPRESENTED BY THE INCIDENCE OF THESE DISEASES IN ONLY A FRACTION OF SMOKERS. THE PRESENCE OF COPD INCREASES THE RISK OF LUNG CANCER UP TO 4.5-FOLD. TO INVESTIGATE COMMONALITIES IN DISEASE MECHANISMS AND PERSPECTIVES FOR DISEASE CHEMOPREVENTION, THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) AND THE NATIONAL CANCER INSTITUTE (NCI) HELD A WORKSHOP. THE PARTICIPANTS IDENTIFIED FOUR RESEARCH OBJECTIVES: 1) CLARIFY COMMON EPIDEMIOLOGICAL CHARACTERISTICS OF LUNG CANCER AND COPD; 2) IDENTIFY SHARED GENETIC AND EPIGENETIC RISK FACTORS; 3) IDENTIFY AND VALIDATE BIOMARKERS, MOLECULAR SIGNATURES, AND IMAGING-DERIVED MEASUREMENTS OF EACH DISEASE; AND 4) DETERMINE COMMON AND DISPARATE PATHOGENETIC MECHANISMS. THESE OBJECTIVES SHOULD BE REACHED VIA FOUR RESEARCH APPROACHES: 1) IDENTIFY, PUBLICIZE, AND ENABLE THE EVALUATION AND ANALYSIS OF EXISTING DATASETS AND REPOSITORIES OF BIOSPECIMENS; 2) OBTAIN PHENOTYPIC AND OUTCOME DATA AND BIOSPECIMENS FROM LARGE STUDIES OF SUBJECTS WITH AND/OR AT RISK FOR COPD AND LUNG CANCER; 3) DEVELOP AND USE ANIMAL AND OTHER PRECLINICAL MODELS TO INVESTIGATE PATHOGENETIC LINKS BETWEEN THE DISEASES; AND 4) CONDUCT EARLY-PHASE CLINICAL TRIALS OF POTENTIAL CHEMOPREVENTIVE AGENTS. TO FOSTER MUCH NEEDED RESEARCH INTERACTIONS, TWO FINAL RECOMMENDATIONS WERE MADE BY THE PARTICIPANTS: 1) INCORPORATE BASELINE PHENOTYPING AND OUTCOME MEASURES FOR BOTH DISEASES IN FUTURE LONGITUDINAL STUDIES OF EACH DISEASE AND 2) EXPAND COLLABORATIVE EFFORTS BETWEEN THE NCI AND NHLBI.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  1443  25 DIFFERENTIAL RESPONSES OF HEALTHY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4). WHILE THE KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS IS STILL INCOMPLETE, DETAILED IN VITRO STUDIES ARE HIGHLY NEEDED. WITH THE AIM OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS AND BETTER INTEGRATING A NUMBER OF FACTORS RELATED TO PRE-EXISTING CHRONIC PULMONARY INFLAMMATORY, WE SOUGHT TO DEVELOP PRIMARY CULTURES OF NORMAL HUMAN BRONCHIAL EPITHELIAL (NHBE) CELLS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED HUMAN BRONCHIAL EPITHELIAL (DHBE) CELLS, GROWN AT THE AIR-LIQUID INTERFACE. PAN-CYTOKERATIN AND MUC5AC IMMUNOSTAINING CONFIRMED THE SPECIFIC CELL-TYPES OF BOTH THESE HEALTHY AND DISEASED CELL MODELS AND SHOWED THEY ARE CLOSED TO HUMAN BRONCHIAL EPITHELIA. THEREAFTER, HEALTHY AND DISEASED CELLS WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4) AT THE NON-CYTOTOXIC CONCENTRATION OF 5 MUG/CM(2). THE DIFFERENCES BETWEEN THE OXIDATIVE AND INFLAMMATORY STATES IN NON-EXPOSED NHBE AND COPD-DHBE CELLS INDICATED THAT DISEASED CELLS CONSERVED THEIR SPECIFIC PHYSIOPATHOLOGICAL CHARACTERISTICS. INCREASES IN BOTH OXIDATIVE DAMAGE AND CYTOKINE SECRETION WERE REPORTED IN REPEATEDLY EXPOSED NHBE CELLS AND PARTICULARLY IN COPD-DHBE CELLS. DISEASED CELLS REPEATEDLY EXPOSED HAD LOWER CAPACITIES TO METABOLIZE THE ORGANIC CHEMICALS-COATED ONTO THE AIR-POLLUTION-DERIVED PM(4), SUCH AS BENZO[A]PYRENE (B[A]P), BUT SHOWED HIGHER SENSIBILITY TO THE FORMATION OF OH-B[A]P DNA ADDUCTS, BECAUSE THEIR DISEASED STATE POSSIBLY AFFECTED THEIR DEFENSES. DIFFERENTIAL PROFILES OF EPIGENETIC HALLMARKS (I.E., GLOBAL DNA HYPOMETHYLATION, P16 PROMOTER HYPERMETHYLATION, TELOMERE LENGTH SHORTENING, TELOMERASE ACTIVATION, AND HISTONE H3 MODIFICATIONS) OCCURRED IN REPEATEDLY EXPOSED NHBE AND PARTICULARLY IN COPD-DHBE CELLS. TAKEN TOGETHER, THESE RESULTS CLOSELY SUPPORTED THE HIGHEST RESPONSIVENESS OF COPD-DHBE CELLS TO A REPEATED EXPOSURE TO AIR POLLUTION-DERIVED PM(4). THE USE OF THESE INNOVATIVE IN VITRO EXPOSURE SYSTEMS SUCH AS NHBE AND COPD-DHBE CELLS COULD THEREFORE BE CONSIDER AS A VERY USEFUL AND POWERFUL PROMISING TOOL IN THE FIELD OF THE RESPIRATORY TOXICOLOGY, TAKING INTO ACCOUNT SENSITIVE INDIVIDUALS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  6440  29 THERAPEUTIC APPROACHES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) EXACERBATIONS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE PULMONARY DISORDER UNDERPINNED BY POORLY REVERSIBLE AIRFLOW RESULTING FROM CHRONIC BRONCHITIS OR EMPHYSEMA. THE PREVALENCE AND MORTALITY OF COPD CONTINUE TO INCREASE. PHARMACOTHERAPY FOR PATIENTS WITH COPD HAS INCLUDED ANTIBIOTICS, BRONCHODILATORS, AND ANTI-INFLAMMATORY CORTICOSTEROIDS (BUT WITH LITTLE SUCCESS). ORAL DISEASES HAVE LONG BEEN ESTABLISHED AS CLINICAL RISK FACTORS FOR DEVELOPING RESPIRATORY DISEASES. THE ESTABLISHMENT OF A VERY SIMILAR MICROBIOME IN THE MOUTH AND THE LUNG CONFIRMS THE ORAL-LUNG CONNECTION. THE ASPIRATION OF PATHOGENIC MICROBES FROM THE ORAL CAVITY HAS BEEN IMPLICATED IN SEVERAL RESPIRATORY DISEASES, INCLUDING PNEUMONIA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS REVIEW FOCUSES ON CURRENT AND FUTURE PHARMACOTHERAPEUTIC APPROACHES FOR COPD EXACERBATION INCLUDING ANTIMICROBIALS, MUCOREGULATORS, THE USE OF BRONCHODILATORS AND ANTI-INFLAMMATORY DRUGS, MODIFYING EPIGENETIC MARKS, AND MODULATING DYSBIOSIS OF THE MICROBIOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  4744  46 NOVEL INSIGHTS INTO THE GENETICS OF SMOKING BEHAVIOUR, LUNG FUNCTION, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (UK BILEVE): A GENETIC ASSOCIATION STUDY IN UK BIOBANK. BACKGROUND: UNDERSTANDING THE GENETIC BASIS OF AIRFLOW OBSTRUCTION AND SMOKING BEHAVIOUR IS KEY TO DETERMINING THE PATHOPHYSIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE USED UK BIOBANK DATA TO STUDY THE GENETIC CAUSES OF SMOKING BEHAVIOUR AND LUNG HEALTH. METHODS: WE SAMPLED INDIVIDUALS OF EUROPEAN ANCESTRY FROM UK BIOBANK, FROM THE MIDDLE AND EXTREMES OF THE FORCED EXPIRATORY VOLUME IN 1 S (FEV1) DISTRIBUTION AMONG HEAVY SMOKERS (MEAN 35 PACK-YEARS) AND NEVER SMOKERS. WE DEVELOPED A CUSTOM ARRAY FOR UK BIOBANK TO PROVIDE OPTIMUM GENOME-WIDE COVERAGE OF COMMON AND LOW-FREQUENCY VARIANTS, DENSE COVERAGE OF GENOMIC REGIONS ALREADY IMPLICATED IN LUNG HEALTH AND DISEASE, AND TO ASSAY RARE CODING VARIANTS RELEVANT TO THE UK POPULATION. WE INVESTIGATED WHETHER THERE WERE SHARED GENETIC CAUSES BETWEEN DIFFERENT PHENOTYPES DEFINED BY EXTREMES OF FEV1. WE ALSO LOOKED FOR NOVEL VARIANTS ASSOCIATED WITH EXTREMES OF FEV1 AND SMOKING BEHAVIOUR AND ASSESSED REGIONS OF THE GENOME THAT HAD ALREADY SHOWN EVIDENCE FOR A ROLE IN LUNG HEALTH AND DISEASE. WE SET GENOME-WIDE SIGNIFICANCE AT P<5 X 10(-8). FINDINGS: UK BIOBANK PARTICIPANTS WERE RECRUITED FROM MARCH 15, 2006, TO JULY 7, 2010. SAMPLE SELECTION FOR THE UK BILEVE STUDY STARTED ON NOV 22, 2012, AND WAS COMPLETED ON DEC 20, 2012. WE SELECTED 50,008 UNIQUE SAMPLES: 10,002 INDIVIDUALS WITH LOW FEV1, 10,000 WITH AVERAGE FEV1, AND 5002 WITH HIGH FEV1 FROM EACH OF THE HEAVY SMOKER AND NEVER SMOKER GROUPS. WE NOTED A SUBSTANTIAL SHARING OF GENETIC CAUSES OF LOW FEV1 BETWEEN HEAVY SMOKERS AND NEVER SMOKERS (P=2.29 X 10(-16)) AND BETWEEN INDIVIDUALS WITH AND WITHOUT DOCTOR-DIAGNOSED ASTHMA (P=6.06 X 10(-11)). WE DISCOVERED SIX NOVEL GENOME-WIDE SIGNIFICANT SIGNALS OF ASSOCIATION WITH EXTREMES OF FEV1, INCLUDING SIGNALS AT FOUR NOVEL LOCI (KANSL1, TSEN54, TET2, AND RBM19/TBX5) AND INDEPENDENT SIGNALS AT TWO PREVIOUSLY REPORTED LOCI (NPNT AND HLA-DQB1/HLA-DQA2). THESE VARIANTS ALSO SHOWED ASSOCIATION WITH COPD, INCLUDING IN INDIVIDUALS WITH NO HISTORY OF SMOKING. THE NUMBER OF COPIES OF A 150 KB REGION CONTAINING THE 5' END OF KANSL1, A GENE THAT IS IMPORTANT FOR EPIGENETIC GENE REGULATION, WAS ASSOCIATED WITH EXTREMES OF FEV1. WE ALSO DISCOVERED FIVE NEW GENOME-WIDE SIGNIFICANT SIGNALS FOR SMOKING BEHAVIOUR, INCLUDING A VARIANT IN NCAM1 (CHROMOSOME 11) AND A VARIANT ON CHROMOSOME 2 (BETWEEN TEX41 AND PABPC1P2) THAT HAS A TRANS EFFECT ON EXPRESSION OF NCAM1 IN BRAIN TISSUE. INTERPRETATION: BY SAMPLING FROM THE EXTREMES OF THE LUNG FUNCTION DISTRIBUTION IN UK BIOBANK, WE IDENTIFIED NOVEL GENETIC CAUSES OF LUNG FUNCTION AND SMOKING BEHAVIOUR. THESE RESULTS PROVIDE NEW INSIGHT INTO THE SPECIFIC MECHANISMS UNDERLYING AIRFLOW OBSTRUCTION, COPD, AND TOBACCO ADDICTION, AND SHOW SUBSTANTIAL SHARED GENETIC ARCHITECTURE UNDERLYING AIRFLOW OBSTRUCTION ACROSS INDIVIDUALS, IRRESPECTIVE OF SMOKING BEHAVIOUR AND OTHER AIRWAY DISEASE. FUNDING: MEDICAL RESEARCH COUNCIL.	2015	

14  1550  28 DNA METHYLATION IS ASSOCIATED WITH AIRFLOW OBSTRUCTION IN PATIENTS LIVING WITH HIV. INTRODUCTION: PEOPLE LIVING WITH HIV (PLWH) SUFFER FROM AGE-RELATED COMORBIDITIES SUCH AS COPD. THE PROCESSES RESPONSIBLE FOR REDUCED LUNG FUNCTION IN PLWH ARE LARGELY UNKNOWN. WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY TO INVESTIGATE WHETHER BLOOD DNA METHYLATION IS ASSOCIATED WITH IMPAIRED LUNG FUNCTION IN PLWH. METHODS: USING BLOOD DNA METHYLATION PROFILES FROM 161 PLWH, WE TESTED THE EFFECT OF METHYLATION ON FEV(1), FEV(1)/FVC RATIO AND FEV(1) DECLINE OVER A MEDIAN OF 5 YEARS. WE EVALUATED THE GLOBAL METHYLATION OF PLWH WITH AIRFLOW OBSTRUCTION BY TESTING THE DIFFERENTIAL METHYLATION OF TRANSPOSABLE ELEMENTS ALU AND LINE-1, A WELL-DESCRIBED MARKER OF EPIGENETIC AGEING. RESULTS: AIRFLOW OBSTRUCTION AS DEFINED BY A FEV(1)/FVC<0.70 WAS ASSOCIATED WITH 1393 DIFFERENTIALLY METHYLATED POSITIONS (DMPS), WHILE 4676 WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION BASED ON THE FEV(1)/FVC<LOWER LIMIT OF NORMAL. THESE DMPS WERE ENRICHED FOR BIOLOGICAL PATHWAYS ASSOCIATED WITH CHRONIC VIRAL INFECTIONS. THE AIRFLOW OBSTRUCTION GROUP WAS GLOBALLY HYPOMETHYLATED COMPARED WITH THOSE WITHOUT AIRFLOW OBSTRUCTION. 103 AND 7112 DMPS WERE ASSOCIATED WITH FEV(1) AND FEV(1)/FVC, RESPECTIVELY. NO POSITIONS WERE ASSOCIATED WITH FEV(1) DECLINE. CONCLUSION: A LARGE NUMBER OF DMPS WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION AND LUNG FUNCTION IN A UNIQUE COHORT OF PLWH. AIRFLOW OBSTRUCTION IN EVEN RELATIVELY YOUNG PLWH IS ASSOCIATED WITH GLOBAL HYPOMETHYLATION, SUGGESTING ADVANCED EPIGENETIC AGEING COMPARED WITH THOSE WITH NORMAL LUNG FUNCTION. THE DISTURBANCE OF THE EPIGENETIC REGULATION OF KEY GENES NOT PREVIOUSLY IDENTIFIED IN NON-HIV COPD COHORTS COULD EXPLAIN THE UNIQUE RISK OF COPD IN PLWH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  1539  26 DNA METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LUNG DISEASE AFFECTED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. THEREFORE, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS OF COPD HAS ATTRACTED MUCH ATTENTION. AS ONE OF THE THREE EPIGENETIC MECHANISMS, DNA METHYLATION HAS BEEN EXTENSIVELY STUDIED IN COPD. THE PRESENT REVIEW AIMS AT OVERVIEWING THE EFFECT OF DNA METHYLATION ON ETIOLOGY, PATHOGENESIS, PATHOPHYSIOLOGICAL CHANGES, AND COMPLICATIONS OF COPD. THE CLARIFICATION OF ABERRANT METHYLATION OF TARGET GENES, WHICH PLAY IMPORTANT ROLES IN THE INITIATION AND PROGRESSION OF COPD, WILL PROVIDE NEW DISEASE-SPECIFIC BIOMARKER AND TARGETS FOR EARLY DIAGNOSIS AND THERAPY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16   927  30 CHRONIC INFLAMMATION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND LUNG CANCER. PURPOSE OF REVIEW: SMOKING IS A MAJOR RISK FACTOR FOR LUNG CANCER, WHICH IS THE LEADING CAUSE OF CANCER-RELATED DEATHS BOTH IN THE USA AND WORLDWIDE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND EMPHYSEMA ARE COMORBID CONDITIONS OFTEN FOUND IN LUNG CANCER PATIENTS. THE INFLAMMATORY PATHWAYS THAT LINK CHRONIC OBSTRUCTIVE PULMONARY DISEASE, EMPHYSEMA, AND LUNG CANCER LIKELY INVOLVE GENETIC AND EPIGENETIC MODULATIONS DUE TO CHRONIC TISSUE INJURY AND ABNORMAL TUMOR IMMUNITY IN SUSCEPTIBLE HOSTS. RECENT FINDINGS: CHRONIC AIRWAY INFLAMMATION CONTRIBUTES TO ALTERATIONS IN THE BRONCHIAL EPITHELIUM AND LUNG MICROENVIRONMENT, PROVOKING A MILIEU CONDUCIVE TO PULMONARY CARCINOGENESIS. FOR EXAMPLE, INFLAMMATION-INDUCIBLE CYCLOOXYGENASE-2 IS UPREGULATED IN NONSMALL CELL LUNG CANCER AND ALSO PLAYS AN IMPORTANT ROLE IN PROMOTING EPITHELIAL-TO-MESENCHYMAL TRANSITION. GENETIC CHANGES IN THE AIRWAY EPITHELIUM OF SMOKERS MAY HELP PREDICT OR IDENTIFY INDIVIDUALS AT RISK FOR LUNG CANCER. FINALLY, RADIOGRAPHIC FINDINGS OF EMPHYSEMA HAVE BEEN ESTABLISHED AS INDEPENDENT RISK FACTORS FOR LUNG CANCER. SUMMARY: THE RELATIONSHIPS BETWEEN INFLAMMATION, AIRFLOW OBSTRUCTION, AND LUNG CANCER ARE COMPLEX. DEREGULATED INFLAMMATION IS COMPLICIT IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER, BUT THE OVERLAP OF SIGNALING EVENTS IS NOT YET FULLY UNDERSTOOD. TOBACCO EXPOSURE IS AN IMPORTANT RISK FACTOR THAT CONFERS LONG-TERM RISK OF LUNG DISEASE. DIAGNOSTIC SENSITIVITY OF DETECTING LUNG CANCER MAY IMPROVE WITH THE UTILIZATION OF GENETIC PROFILING IN COMBINATION WITH PATHOLOGIC EVALUATION OF AIRWAY EPITHELIUM. ADDITIONAL RESEARCH IS REQUIRED TO UNDERSTAND THE ROLE OF EPITHELIAL-TO-MESENCHYMAL TRANSITION IN CHRONIC INFLAMMATORY LUNG DISEASES AND LUNG CARCINOGENESIS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17   970  30 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER: COMMON PATHWAYS FOR PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER COMPRISE THE LEADING CAUSES OF LUNG DISEASE-RELATED MORTALITY WORLDWIDE. EXPOSURE TO TOBACCO SMOKE IS A MUTUAL AETIOLOGY UNDERLYING THE TWO DISEASES, ACCOUNTING FOR ALMOST 90% OF CASES. THERE IS ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF IMMUNE DYSFUNCTION, THE LUNG MICROBIOME, EXTRACELLULAR VESICLES AND UNDERLYING GENETIC SUSCEPTIBILITY IN THE DEVELOPMENT OF COPD AND LUNG CANCER. FURTHER, EPIGENETIC FACTORS, INVOLVING DNA METHYLATION AND MICRORNA EXPRESSION, HAVE BEEN IMPLICATED IN BOTH DISEASES. CHRONIC INFLAMMATION IS A KEY FEATURE OF COPD AND COULD BE A POTENTIAL DRIVER OF LUNG CANCER DEVELOPMENT. USING NEXT GENERATION TECHNOLOGIES, FURTHER STUDIES INVESTIGATING THE GENOMICS, EPIGENETICS AND GENE-ENVIRONMENT INTERACTION IN KEY MOLECULAR PATHWAYS WILL CONTINUE TO ELUCIDATE THE PATHOGENIC MECHANISMS UNDERLYING THE DEVELOPMENT OF COPD AND LUNG CANCER, AND CONTRIBUTE TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PROGNOSTIC TOOLS FOR EARLY INTERVENTION AND PERSONALISED THERAPEUTIC STRATEGIES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  2940  34 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  1143  33 CONCISE REVIEW: CLINICAL PROSPECTS FOR TREATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITH REGENERATIVE APPROACHES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS BECOMING A MAJOR CAUSE OF DEATH WORLDWIDE. COPD IS CHARACTERIZED BY A PROGRESSIVE AND NOT FULLY REVERSIBLE AIRFLOW LIMITATION CAUSED BY CHRONIC SMALL AIRWAY DISEASE AND LUNG PARENCHYMAL DESTRUCTION. CLINICALLY AVAILABLE DRUGS IMPROVE AIRFLOW OBSTRUCTION AND RESPIRATORY SYMPTOMS BUT CANNOT CURE THE DISEASE. SLOWING THE PROGRESSIVE LUNG DESTRUCTION OR REBUILDING THE DESTROYED LUNG STRUCTURE IS A PROMISING STRATEGY TO CURE COPD. IN CONTRAST TO SMALL ANIMAL MODELS, PHARMACOLOGICAL LUNG REGENERATION IS DIFFICULT IN HUMAN COPD. MATURATION, AGING, AND SENESCENCE IN COPD LUNG CELLS, INCLUDING ENDOGENOUS STEM CELLS, MAY AFFECT THE REGENERATIVE CAPACITY FOLLOWING PHARMACOLOGICAL THERAPY. THE LUNG IS A COMPLEX ORGAN COMPOSED OF MORE THAN 40 DIFFERENT CELL TYPES; THEREFORE, DETAILED ANALYSES, SUCH AS EPIGENETIC MODIFICATION ANALYSIS, IN EACH SPECIFIC CELL TYPE HAVE NOT BEEN PERFORMED IN LUNGS WITH COPD. RECENTLY, A METHOD FOR THE DIRECT ISOLATION OF INDIVIDUAL CELL TYPES FROM HUMAN LUNG HAS BEEN DEVELOPED, AND FINGERPRINTS OF EACH CELL TYPE IN COPD LUNGS CAN BE ANALYZED. RESEARCH USING THIS TECHNIQUE COMBINED WITH THE RECENTLY DISCOVERED LUNG ENDOGENOUS STEM-PROGENITOR POPULATIONS WILL GIVE A BETTER UNDERSTANDING ABOUT THE FATE OF COPD LUNG CELLS AND PROVIDE A FUTURE FOR CELL-BASED THERAPY TO TREAT THIS INTRACTABLE DISEASE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20  5299  42 PROTEIN INTERACTION NETWORKS PROVIDE INSIGHT INTO FETAL ORIGINS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LEADING CAUSE OF DEATH IN ADULTS THAT MAY HAVE ORIGINS IN EARLY LUNG DEVELOPMENT. IT IS A COMPLEX DISEASE, INFLUENCED BY MULTIPLE FACTORS INCLUDING GENETIC VARIANTS AND ENVIRONMENTAL FACTORS. MATERNAL SMOKING DURING PREGNANCY MAY INFLUENCE THE RISK FOR DISEASES DURING ADULTHOOD, POTENTIALLY THROUGH EPIGENETIC MODIFICATIONS INCLUDING METHYLATION. METHODS: IN THIS WORK, WE EXPLORE THE FETAL ORIGINS OF COPD BY UTILIZING LUNG DNA METHYLATION MARKS ASSOCIATED WITH IN UTERO SMOKE (IUS) EXPOSURE, AND EVALUATE THE NETWORK RELATIONSHIPS BETWEEN METHYLOMIC AND TRANSCRIPTOMIC SIGNATURES ASSOCIATED WITH ADULT LUNG TISSUE FROM FORMER SMOKERS WITH AND WITHOUT COPD. TO IDENTIFY POTENTIAL PATHOBIOLOGICAL MECHANISMS THAT MAY LINK FETAL LUNG, SMOKE EXPOSURE AND ADULT LUNG DISEASE, WE STUDY THE INTERACTIONS (PHYSICAL AND FUNCTIONAL) OF IDENTIFIED GENES USING PROTEIN-PROTEIN INTERACTION NETWORKS. RESULTS: WE BUILD IUS-EXPOSURE AND COPD MODULES, WHICH IDENTIFY CONNECTED SUBNETWORKS LINKING FETAL LUNG SMOKE EXPOSURE TO ADULT COPD. STUDYING THE RELATIONSHIPS AND CONNECTIVITY AMONG THE DIFFERENT MODULES FOR FETAL SMOKE EXPOSURE AND ADULT COPD, WE IDENTIFY ENRICHED PATHWAYS, INCLUDING THE AGE-RAGE AND FOCAL ADHESION PATHWAYS. CONCLUSIONS: THE MODULES IDENTIFIED IN OUR ANALYSIS ADD NEW AND POTENTIALLY IMPORTANT INSIGHTS TO UNDERSTANDING THE EARLY LIFE MOLECULAR PERTURBATIONS RELATED TO THE PATHOGENESIS OF COPD. WE IDENTIFY AGE-RAGE AND FOCAL ADHESION AS TWO BIOLOGICALLY PLAUSIBLE PATHWAYS THAT MAY REVEAL LUNG DEVELOPMENTAL CONTRIBUTIONS TO COPD. WE WERE NOT ONLY ABLE TO IDENTIFY MEANINGFUL MODULES BUT WERE ALSO ABLE TO STUDY INTERCONNECTIONS BETWEEN SMOKE EXPOSURE AND LUNG DISEASE, AUGMENTING OUR KNOWLEDGE ABOUT THE FETAL ORIGINS OF COPD.	2022