1 6691 140 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2 1590  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 1591  42 DNA METHYLATION PROFILING IN PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH COPD. BACKGROUND: EPIGENETICS CHANGES HAVE BEEN SHOWN TO BE AFFECTED BY CIGARETTE SMOKING. CIGARETTE SMOKE (CS)-MEDIATED DNA METHYLATION CAN POTENTIALLY AFFECT SEVERAL CELLULAR AND PATHOPHYSIOLOGICAL PROCESSES, ACUTE EXACERBATIONS, AND COMORBIDITY IN THE LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE SOUGHT TO DETERMINE WHETHER GENOME-WIDE LUNG DNA METHYLATION PROFILES OF SMOKERS AND PATIENTS WITH COPD WERE SIGNIFICANTLY DIFFERENT FROM NON-SMOKERS. WE ISOLATED DNA FROM PARENCHYMAL LUNG TISSUES OF PATIENTS INCLUDING EIGHT LIFELONG NON-SMOKERS, EIGHT CURRENT SMOKERS, AND EIGHT PATIENTS WITH COPD AND ANALYZED THE SAMPLES USING ILLUMINA'S INFINIUM HUMANMETHYLATION450 BEADCHIP. RESULTS: OUR DATA REVEALED THAT THE DIFFERENTIALLY METHYLATED GENES WERE RELATED TO TOP CANONICAL PATHWAYS (E.G., G BETA GAMMA SIGNALING, MECHANISMS OF CANCER, AND NNOS SIGNALING IN NEURONS), DISEASE AND DISORDERS (ORGANISMAL INJURY AND ABNORMALITIES, CANCER, AND RESPIRATORY DISEASE), AND MOLECULAR AND CELLULAR FUNCTIONS (CELL DEATH AND SURVIVAL, CELLULAR ASSEMBLY AND ORGANIZATION, CELLULAR FUNCTION AND MAINTENANCE) IN PATIENTS WITH COPD. THE GENOME-WIDE DNA METHYLATION ANALYSIS IDENTIFIED SUGGESTIVE GENES, SUCH AS NOS1AP, TNFAIP2, BID, GABRB1, ATXN7, AND THOC7 WITH DNA METHYLATION CHANGES IN COPD LUNG TISSUES THAT WERE FURTHER VALIDATED BY PYROSEQUENCING. PYROSEQUENCING VALIDATION CONFIRMED HYPER-METHYLATION IN SMOKERS AND PATIENTS WITH COPD AS COMPARED TO NON-SMOKERS. HOWEVER, WE DID NOT DETECT SIGNIFICANT DIFFERENCES IN DNA METHYLATION FOR TNFAIP2, ATXN7, AND THOC7 GENES IN SMOKERS AND COPD GROUPS DESPITE THE CHANGES OBSERVED IN THE GENOME-WIDE ANALYSIS. CONCLUSIONS: OUR STUDY SUGGESTS THAT DNA METHYLATION IN SUGGESTIVE GENES, SUCH AS NOS1AP, BID, AND GABRB1 MAY BE USED AS EPIGENETIC SIGNATURES IN SMOKERS AND PATIENTS WITH COPD IF THE SAME IS VALIDATED IN A LARGER COHORT. FUTURE STUDIES ARE REQUIRED TO CORRELATE DNA METHYLATION STATUS WITH TRANSCRIPTOMICS OF SELECTIVE GENES IDENTIFIED IN THIS STUDY AND ELUCIDATE THEIR ROLE AND INVOLVEMENT IN THE PROGRESSION OF COPD AND ITS EXACERBATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4 2631  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  348  47 ALTERED DNA METHYLATION IS ASSOCIATED WITH ABERRANT GENE EXPRESSION IN PARENCHYMAL BUT NOT AIRWAY FIBROBLASTS ISOLATED FROM INDIVIDUALS WITH COPD. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A HETEROGENEOUS DISEASE OF THE LUNGS THAT IS CURRENTLY THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. GENETIC FACTORS ACCOUNT FOR ONLY A SMALL AMOUNT OF COPD RISK, BUT EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HAVE THE POTENTIAL TO MEDIATE THE INTERACTIONS BETWEEN AN INDIVIDUAL'S GENETICS AND ENVIRONMENTAL EXPOSURE. DNA METHYLATION IS HIGHLY CELL TYPE-SPECIFIC, AND INDIVIDUAL CELL TYPE STUDIES OF DNA METHYLATION IN COPD ARE SPARSE. FIBROBLASTS ARE PRESENT WITHIN THE AIRWAY AND PARENCHYMA OF THE LUNG AND CONTRIBUTE TO THE ABERRANT DEPOSITION OF EXTRACELLULAR MATRIX IN COPD. NO ASSESSMENT OR COMPARISON OF GENOME-WIDE DNA METHYLATION PROFILES IN THE AIRWAY AND PARENCHYMAL FIBROBLASTS FROM INDIVIDUALS WITH AND WITHOUT COPD HAS BEEN UNDERTAKEN. THESE DATA PROVIDE VALUABLE INSIGHT INTO THE MOLECULAR MECHANISMS CONTRIBUTING TO COPD AND THE DIFFERING PATHOLOGIES OF SMALL AIRWAYS DISEASE AND EMPHYSEMA IN COPD. METHODS: GENOME-WIDE DNA METHYLATION WAS EVALUATED AT OVER 485,000 CPG SITES USING THE ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY IN THE AIRWAY (NON-COPD N = 8, COPD N = 7) AND PARENCHYMAL FIBROBLASTS (NON-COPD N = 17, COPD N = 29) ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD. TARGETED GENE EXPRESSION WAS ASSESSED BY QPCR IN MATCHED RNA SAMPLES. RESULTS: DIFFERENTIALLY METHYLATED DNA REGIONS WERE IDENTIFIED BETWEEN CELLS ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD IN BOTH AIRWAY AND PARENCHYMAL FIBROBLASTS. ONLY IN PARENCHYMAL FIBROBLASTS WAS DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH DIFFERENTIAL GENE EXPRESSION. A SECOND ANALYSIS OF DIFFERENTIAL DNA METHYLATION VARIABILITY IDENTIFIED 359 INDIVIDUAL DIFFERENTIALLY VARIABLE CPG SITES IN PARENCHYMAL FIBROBLASTS. NO DIFFERENTIALLY VARIABLE CPG SITES WERE IDENTIFIED IN THE AIRWAY FIBROBLASTS. FIVE DIFFERENTIALLY VARIABLE-METHYLATED CPG SITES, ASSOCIATED WITH THREE GENES, WERE SUBSEQUENTLY ASSESSED FOR GENE EXPRESSION DIFFERENCES. TWO GENES (OAT AND GRIK2) DISPLAYED SIGNIFICANTLY INCREASED GENE EXPRESSION IN CELLS ISOLATED FROM INDIVIDUALS WITH COPD. CONCLUSIONS: DIFFERENTIAL AND VARIABLE DNA METHYLATION WAS ASSOCIATED WITH COPD STATUS IN THE PARENCHYMAL FIBROBLASTS BUT NOT AIRWAY FIBROBLASTS. ABERRANT DNA METHYLATION WAS ASSOCIATED WITH ALTERED GENE EXPRESSION IMPARTING BIOLOGICAL FUNCTION TO DNA METHYLATION CHANGES. CHANGES IN DNA METHYLATION ARE THEREFORE IMPLICATED IN THE MOLECULAR MECHANISMS UNDERLYING COPD PATHOGENESIS AND MAY REPRESENT NOVEL THERAPEUTIC TARGETS.	2018	

6 1519  34 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7 1528  42 DNA METHYLATION CHANGES IN REGIONAL LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES. A NUMBER OF PULMONARY DISEASES OCCUR WITH UPPER LOBE PREDOMINANCE, INCLUDING CYSTIC FIBROSIS AND SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IN THE HEALTHY LUNG, SEVERAL PHYSIOLOGIC AND METABOLIC FACTORS EXHIBIT DISPARITY WHEN COMPARING THE UPPER LOBE OF THE LUNG TO LOWER LOBE, INCLUDING DIFFERENCES IN OXYGENATION, VENTILATION, LYMPHATIC FLOW, PH, AND BLOOD FLOW. IN THIS STUDY, WE ASKED WHETHER THESE REGIONAL DIFFERENCES IN THE LUNG ARE ASSOCIATED WITH DNA METHYLATION CHANGES IN LUNG MACROPHAGES THAT COULD POTENTIALLY LEAD TO ALTERED CELL RESPONSIVENESS UPON SUBSEQUENT ENVIRONMENTAL CHALLENGE. ALL ANALYSES WERE PERFORMED USING PRIMARY LUNG MACROPHAGES COLLECTED VIA BRONCHOALVEOLAR LAVAGE FROM HEALTHY HUMAN SUBJECTS WITH NORMAL PULMONARY FUNCTION. EPIGENOME-WIDE DNA METHYLATION WAS EXAMINED VIA INFINIUM METHYLATIONEPIC (850K) ARRAY AND VALIDATED BY TARGETED NEXT-GENERATION BISULFITE SEQUENCING. WE OBSERVED 95 CPG LOCI WITH SIGNIFICANT DIFFERENTIAL METHYLATION IN LUNG MACROPHAGES, COMPARING UPPER LOBE TO LOWER LOBE (ALL FALSE DISCOVERY RATE < 0.05). SEVERAL OF THESE GENES, INCLUDING CLIP4, HSH2D, NR4A1, SNX10, AND TYK2, HAVE BEEN IMPLICATED AS PARTICIPANTS IN INFLAMMATORY/IMMUNE-RELATED BIOLOGICAL PROCESSES. FUNCTIONALLY, WE IDENTIFIED PHENOTYPIC DIFFERENCES IN OXYGEN USE, COMPARING UPPER VERSUS LOWER LUNG MACROPHAGES. OUR RESULTS SUPPORT A HYPOTHESIS THAT EPIGENETIC CHANGES, SPECIFICALLY DNA METHYLATION, AT A MULTITUDE OF GENE LOCI IN LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES REGIONALLY IN LUNG.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8 5638  47 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9 1551  42 DNA METHYLATION IS GLOBALLY DISRUPTED AND ASSOCIATED WITH EXPRESSION CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE SMALL AIRWAYS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT IS HIGHLY DISRUPTED IN RESPONSE TO CIGARETTE SMOKE AND INVOLVED IN A WIDE SPECTRUM OF MALIGNANT AND NONMALIGNANT DISEASES, BUT SURPRISINGLY NOT PREVIOUSLY ASSESSED IN SMALL AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SMALL AIRWAYS ARE THE PRIMARY SITES OF AIRFLOW OBSTRUCTION IN COPD. WE SOUGHT TO DETERMINE WHETHER DNA METHYLATION PATTERNS ARE DISRUPTED IN SMALL AIRWAY EPITHELIA OF PATIENTS WITH COPD, AND EVALUATE WHETHER CHANGES IN GENE EXPRESSION ARE ASSOCIATED WITH THESE DISRUPTIONS. GENOME-WIDE METHYLATION AND GENE EXPRESSION ANALYSIS WERE PERFORMED ON SMALL AIRWAY EPITHELIAL DNA AND RNA OBTAINED FROM THE SAME PATIENT DURING BRONCHOSCOPY, USING ILLUMINA'S INFINIUM HM27 AND AFFYMETRIX'S GENECHIP HUMAN GENE 1.0 ST ARRAYS. TO CONTROL FOR KNOWN EFFECTS OF CIGARETTE SMOKING ON DNA METHYLATION, METHYLATION AND GENE EXPRESSION PROFILES WERE COMPARED BETWEEN FORMER SMOKERS WITH AND WITHOUT COPD MATCHED FOR AGE, PACK-YEARS, AND YEARS OF SMOKING CESSATION. OUR RESULTS INDICATE THAT ABERRANT DNA METHYLATION IS (1) A GENOME-WIDE PHENOMENON IN SMALL AIRWAYS OF PATIENTS WITH COPD, AND (2) ASSOCIATED WITH ALTERED EXPRESSION OF GENES AND PATHWAYS IMPORTANT TO COPD, SUCH AS THE NF-E2-RELATED FACTOR 2 OXIDATIVE RESPONSE PATHWAY. DNA METHYLATION IS LIKELY AN IMPORTANT MECHANISM CONTRIBUTING TO MODULATION OF GENES IMPORTANT TO COPD PATHOLOGY. BECAUSE THESE METHYLATION EVENTS MAY UNDERLIE DISEASE-SPECIFIC GENE EXPRESSION CHANGES, THEIR CHARACTERIZATION IS A CRITICAL FIRST STEP TOWARD THE DEVELOPMENT OF EPIGENETIC MARKERS AND AN OPPORTUNITY FOR DEVELOPING NOVEL EPIGENETIC THERAPEUTIC INTERVENTIONS FOR COPD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 6083  45 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11 1739  36 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12   57  44 A GENOME-WIDE ASSOCIATION STUDY OF QUANTITATIVE COMPUTED TOMOGRAPHIC EMPHYSEMA IN KOREAN POPULATIONS. EMPHYSEMA IS AN IMPORTANT FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). GENETIC FACTORS LIKELY AFFECT EMPHYSEMA PATHOGENESIS, BUT THIS QUESTION HAS PREDOMINANTLY BEEN STUDIED IN THOSE OF EUROPEAN ANCESTRY. IN THIS STUDY, WE SOUGHT TO DETERMINE GENETIC COMPONENTS OF EMPHYSEMA SEVERITY AND CHARACTERIZE THE POTENTIAL FUNCTION OF THE ASSOCIATED LOCI IN KOREAN POPULATION. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) ON QUANTITATIVE EMPHYSEMA IN SUBJECTS WITH OR WITHOUT COPD FROM TWO KOREAN COPD COHORTS. WE INVESTIGATED THE FUNCTIONAL CONSEQUENCES OF THE LOCI USING EPIGENETIC ANNOTATION AND GENE EXPRESSION DATA. WE ALSO COMPARED OUR GWAS RESULTS WITH AN EPIGENOME-WIDE ASSOCIATION STUDY AND PREVIOUS DIFFERENTIAL GENE EXPRESSION ANALYSIS. IN TOTAL, 548 SUBJECTS (476 [86.9%] MALE) INCLUDING 514 COPD PATIENTS WERE EVALUATED. WE IDENTIFIED ONE GENOME-WIDE SIGNIFICANT SNP (P < 5.0 X 10(-8)), RS117084279, NEAR PIBF1. WE IDENTIFIED AN ADDITIONAL 57 SNPS (P < 5.0 X 10(-6)) ASSOCIATED WITH EMPHYSEMA IN ALL SUBJECTS, AND 106 SNPS (P < 5.0 X 10(-6)) IN COPD PATIENTS. OF THESE CANDIDATE SNPS, 2 (RS12459249, RS11667314) NEAR CYP2A6 WERE EXPRESSION QUANTITATIVE TRAIT LOCI IN LUNG TISSUE AND A SNP (RS11214944) NEAR NNMT WAS AN EXPRESSION QUANTITATIVE TRAIT LOCUS IN WHOLE BLOOD. OF NOTE, RS11214944 WAS IN LINKAGE DISEQUILIBRIUM WITH VARIANTS IN ENHANCER HISTONE MARKS IN LUNG TISSUE. SEVERAL GENES NEAR ADDITIONAL SNPS WERE IDENTIFIED IN OUR PREVIOUS EWAS STUDY WITH NOMINAL LEVEL OF SIGNIFICANCE. WE IDENTIFIED A NOVEL SNP ASSOCIATED WITH QUANTITATIVE EMPHYSEMA ON CT. INCLUDING THE NOVEL SNP, SEVERAL CANDIDATE SNPS IN OUR STUDY MAY PROVIDE CLUES TO THE GENETIC ETIOLOGY OF EMPHYSEMA IN ASIAN POPULATIONS. FURTHER RESEARCH AND VALIDATION OF THE LOCI WILL HELP DETERMINE THE GENETIC FACTORS FOR THE DEVELOPMENT OF EMPHYSEMA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 1607  41 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 1587  39 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15 5883  32 SYSTEMIC AND AIRWAY EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH HEALTH STATUS IN COPD. EPIGENETIC MODIFICATIONS ARE COMMON IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD); HOWEVER, THEIR CLINICAL RELEVANCE IS LARGELY UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH SYMPTOMS AND HEALTH STATUS IN COPD. WE PROFILED THE BLOOD (N = 57) AND AIRWAYS (N = 62) OF COPD PATIENTS FOR DNA METHYLATION (N = 55 PAIRED). THE PATIENTS' HEALTH STATUS WAS ASSESSED USING THE ST. GEORGE'S RESPIRATORY QUESTIONNAIRE (SGRQ). WE CONDUCTED DIFFERENTIAL METHYLATION ANALYSES AND IDENTIFIED PATHWAYS CHARACTERIZED BY EPIGENETIC DISRUPTIONS ASSOCIATED WITH SGRQ SCORES AND ITS INDIVIDUAL DOMAINS. 29,211 AND 5044 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE ASSOCIATED WITH TOTAL SGRQ SCORES IN BLOOD AND AIRWAY SAMPLES, RESPECTIVELY. THE ACTIVITY, IMPACT, AND SYMPTOM DOMAINS WERE ASSOCIATED WITH 9161, 25,689 AND 17,293 DMPS IN BLOOD, RESPECTIVELY; AND 4674, 3730 AND 5063 DMPS IN AIRWAYS, RESPECTIVELY. THERE WAS A SUBSTANTIAL OVERLAP OF DMPS BETWEEN AIRWAY AND BLOOD. DMPS WERE ENRICHED FOR PATHWAYS RELATED TO COMMON CO-MORBIDITIES OF COPD (E.G., AGEING, CANCER AND NEUROLOGICAL) IN BOTH TISSUES. HEALTH STATUS IN COPD IS ASSOCIATED WITH AIRWAY AND SYSTEMIC EPIGENETIC CHANGES ESPECIALLY IN PATHWAYS RELATED TO CO-MORBIDITIES OF COPD. THERE ARE MORE BLOOD DMPS THAN IN THE AIRWAYS SUGGESTING THAT BLOOD EPIGENOME IS A PROMISING SOURCE TO DISCOVER BIOMARKERS FOR CLINICAL OUTCOMES IN COPD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 3954  34 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 2048  33 EPIGENETIC CLUSTERING OF LUNG ADENOCARCINOMAS BASED ON DNA METHYLATION PROFILES IN ADJACENT LUNG TISSUE: ITS CORRELATION WITH SMOKING HISTORY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE AIM OF THIS STUDY WAS TO CLARIFY THE SIGNIFICANCE OF DNA METHYLATION ALTERATIONS DURING LUNG CARCINOGENESIS. INFINIUM ASSAY WAS PERFORMED USING 139 PAIRED SAMPLES OF NON-CANCEROUS LUNG TISSUE (N) AND TUMOROUS TISSUE (T) FROM A LEARNING COHORT OF PATIENTS WITH LUNG ADENOCARCINOMAS (LADCS). FIFTY PAIRED N AND T SAMPLES FROM A VALIDATION COHORT WERE ALSO ANALYZED. DNA METHYLATION ALTERATIONS ON 1,928 PROBES OCCURRED IN N SAMPLES RELATIVE TO NORMAL LUNG TISSUE FROM PATIENTS WITHOUT PRIMARY LUNG TUMORS, AND WERE INHERITED BY, OR STRENGTHENED IN, T SAMPLES. UNSUPERVISED HIERARCHICAL CLUSTERING USING DNA METHYLATION LEVELS IN N SAMPLES ON ALL 26,447 PROBES SUBCLUSTERED PATIENTS INTO CLUSTER I (N = 32), CLUSTER II (N = 35) AND CLUSTER III (N = 72). LADCS IN CLUSTER I DEVELOPED FROM THE INFLAMMATORY BACKGROUND IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN HEAVY SMOKERS AND WERE LOCALLY INVASIVE. MOST PATIENTS IN CLUSTER II WERE NON-SMOKERS AND HAD A FAVORABLE OUTCOME. LADCS IN CLUSTER III DEVELOPED IN LIGHT SMOKERS WERE MOST AGGRESSIVE (FREQUENTLY SHOWING LYMPHATIC AND BLOOD VESSEL INVASION, LYMPH NODE METASTASIS AND AN ADVANCED PATHOLOGICAL STAGE), AND HAD A POOR OUTCOME. DNA METHYLATION LEVELS OF HALLMARK GENES FOR EACH CLUSTER, SUCH AS IRX2, HOXD8, SPARCL1, RGS5 AND EI24, WERE AGAIN CORRELATED WITH CLINICOPATHOLOGICAL CHARACTERISTICS IN THE VALIDATION COHORT. DNA METHYLATION PROFILES REFLECTING CARCINOGENETIC FACTORS SUCH AS SMOKING AND COPD APPEAR TO BE ESTABLISHED IN NON-CANCEROUS LUNG TISSUE FROM PATIENTS WITH LADCS AND MAY DETERMINE THE AGGRESSIVENESS OF TUMORS DEVELOPING IN INDIVIDUAL PATIENTS, AND THUS PATIENT OUTCOME.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18 1909  40 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 1552  47 DNA METHYLATION IS PREDICTIVE OF MORTALITY IN CURRENT AND FORMER SMOKERS. RATIONALE: SMOKING RESULTS IN AT LEAST A DECADE LOWER LIFE EXPECTANCY. MORTALITY AMONG CURRENT SMOKERS IS TWO TO THREE TIMES AS HIGH AS NEVER SMOKERS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION OF THE HUMAN GENOME THAT HAS BEEN ASSOCIATED WITH BOTH CIGARETTE SMOKING AND MORTALITY.OBJECTIVES: WE SOUGHT TO IDENTIFY DNA METHYLATION MARKS IN BLOOD THAT ARE PREDICTIVE OF MORTALITY IN A SUBSET OF THE COPDGENE (GENETIC EPIDEMIOLOGY OF COPD) STUDY, REPRESENTING 101 DEATHS AMONG 667 CURRENT AND FORMER SMOKERS.METHODS: WE ASSAYED GENOME-WIDE DNA METHYLATION IN NON-HISPANIC WHITE SMOKERS WITH AND WITHOUT CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) USING BLOOD SAMPLES FROM THE COPDGENE ENROLLMENT VISIT. WE TESTED WHETHER DNA METHYLATION WAS ASSOCIATED WITH MORTALITY IN MODELS ADJUSTED FOR COPD STATUS, AGE, SEX, CURRENT SMOKING STATUS, AND PACK-YEARS OF CIGARETTE SMOKING. REPLICATION WAS PERFORMED IN A SUBSET OF 231 INDIVIDUALS FROM THE ECLIPSE (EVALUATION OF COPD LONGITUDINALLY TO IDENTIFY PREDICTIVE SURROGATE ENDPOINTS) STUDY.MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED SEVEN CPG SITES ASSOCIATED WITH MORTALITY (FALSE DISCOVERY RATE < 20%) THAT REPLICATED IN THE ECLIPSE COHORT (P < 0.05). NONE OF THESE MARKS WERE ASSOCIATED WITH LONGITUDINAL LUNG FUNCTION DECLINE IN SURVIVORS, SMOKING HISTORY, OR CURRENT SMOKING STATUS. HOWEVER, DIFFERENTIAL METHYLATION OF TWO REPLICATED PIK3CD (PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA) SITES WERE ASSOCIATED WITH LUNG FUNCTION AT ENROLLMENT (P < 0.05). WE ALSO OBSERVED ASSOCIATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION FOR THE PIK3CD SITES.CONCLUSIONS: THIS STUDY IS THE FIRST TO IDENTIFY VARIABLE DNA METHYLATION ASSOCIATED WITH ALL-CAUSE MORTALITY IN SMOKERS WITH AND WITHOUT COPD. EVALUATING PREDICTIVE EPIGENOMIC MARKS OF SMOKERS IN PERIPHERAL BLOOD MAY ALLOW FOR TARGETED RISK STRATIFICATION AND AID IN DELIVERY OF FUTURE TAILORED THERAPEUTIC INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20 3308  35 HIGH-RESOLUTION TRANSCRIPTOMIC AND EPIGENETIC PROFILING IDENTIFIES NOVEL REGULATORS OF COPD. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE STILL WAITING FOR CURATIVE TREATMENTS. CONSIDERING ITS ENVIRONMENTAL CAUSE, WE HYPOTHESIZED THAT COPD WILL BE ASSOCIATED WITH ALTERED EPIGENETIC SIGNALING IN LUNG CELLS. WE GENERATED GENOME-WIDE DNA METHYLATION MAPS AT SINGLE CPG RESOLUTION OF PRIMARY HUMAN LUNG FIBROBLASTS (HLFS) ACROSS COPD STAGES. WE SHOW THAT THE EPIGENETIC LANDSCAPE IS CHANGED EARLY IN COPD, WITH DNA METHYLATION CHANGES OCCURRING PREDOMINANTLY IN REGULATORY REGIONS. RNA SEQUENCING OF MATCHED FIBROBLASTS DEMONSTRATED DYSREGULATION OF GENES INVOLVED IN PROLIFERATION, DNA REPAIR, AND EXTRACELLULAR MATRIX ORGANIZATION. DATA INTEGRATION IDENTIFIED 110 CANDIDATE REGULATORS OF DISEASE PHENOTYPES THAT WERE LINKED TO FIBROBLAST REPAIR PROCESSES USING PHENOTYPIC SCREENS. OUR STUDY PROVIDES HIGH-RESOLUTION MULTI-OMIC MAPS OF HLFS ACROSS COPD STAGES. WE REVEAL NOVEL TRANSCRIPTOMIC AND EPIGENETIC SIGNATURES ASSOCIATED WITH COPD ONSET AND PROGRESSION AND IDENTIFY NEW CANDIDATE REGULATORS INVOLVED IN THE PATHOGENESIS OF CHRONIC LUNG DISEASES. THE PRESENCE OF VARIOUS EPIGENETIC FACTORS AMONG THE CANDIDATES DEMONSTRATES THAT EPIGENETIC REGULATION IN COPD IS AN EXCITING RESEARCH FIELD THAT HOLDS PROMISE FOR NOVEL THERAPEUTIC AVENUES FOR PATIENTS.	2023