1 57 142 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 2 1590 41 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 44 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 6190 46 THE IMPACT OF METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ON ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES. BACKGROUND: METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ARE THE GENETIC VARIANTS THAT MAY AFFECT THE DNA METHYLATION PATTERNS OF CPG SITES. HOWEVER, THEIR ROLES IN INFLUENCING THE DISTURBANCES OF SMOKING-RELATED EPIGENETIC CHANGES HAVE NOT BEEN WELL ESTABLISHED. THIS STUDY WAS CONDUCTED TO ADDRESS WHETHER MQTLS EXIST IN THE VICINITY OF SMOKING-RELATED CPG SITES (+/- 50 KB) AND TO EXAMINE THEIR ASSOCIATIONS WITH SMOKING EXPOSURE AND ALL-CAUSE MORTALITY IN OLDER ADULTS. RESULTS: WE OBTAINED DNA METHYLATION PROFILES IN WHOLE BLOOD SAMPLES BY ILLUMINA INFINIUM HUMAN METHYLATION 450 BEADCHIP ARRAY OF TWO INDEPENDENT SUBSAMPLES OF THE ESTHER STUDY (DISCOVERY SET, N = 581; VALIDATION SET, N = 368) AND THEIR CORRESPONDING GENOTYPING DATA USING THE ILLUMINA INFINIUM ONCOARRAY BEADCHIP. AFTER CORRECTION FOR MULTIPLE TESTING (FDR), WE SUCCESSFULLY IDENTIFIED THAT 70 OUT OF 151 PREVIOUSLY REPORTED SMOKING-RELATED CPG SITES WERE SIGNIFICANTLY ASSOCIATED WITH 192 SNPS WITHIN THE 50 KB SEARCH WINDOW OF EACH LOCUS. THE 192 MQTLS SIGNIFICANTLY INFLUENCED THE ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES, WITH PERCENTAGE CHANGES RANGING FROM 0.01 TO 18.96%, ESPECIALLY FOR THE WEAKLY/MODERATELY SMOKING-RELATED CPG SITES. HOWEVER, THESE IDENTIFIED MQTLS WERE NOT DIRECTLY ASSOCIATED WITH ACTIVE SMOKING EXPOSURE OR ALL-CAUSE MORTALITY. CONCLUSIONS: OUR FINDINGS CLEARLY DEMONSTRATED THAT IF NOT DEALT WITH PROPERLY, THE MQTLS MIGHT IMPAIR THE POWER OF EPIGENETIC-BASED MODELS OF SMOKING EXPOSURE TO A CERTAIN EXTENT. IN ADDITION, SUCH GENETIC VARIANTS COULD BE THE KEY FACTOR TO DISTINGUISH BETWEEN THE HERITABLE AND SMOKING-INDUCED IMPACT ON EPIGENOME DISPARITIES. THESE MQTLS ARE OF SPECIAL IMPORTANCE WHEN DNA METHYLATION MARKERS MEASURED BY ILLUMINA INFINIUM ASSAY ARE USED FOR ANY COMPARATIVE POPULATION STUDIES RELATED TO SMOKING-RELATED CANCERS AND CHRONIC DISEASES. 2017 5 1607 33 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 6 6691 44 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 7 2620 45 EPIGENOME-WIDE ASSOCIATION DATA IMPLICATES DNA METHYLATION-MEDIATED GENETIC RISK IN PSORIASIS. BACKGROUND: PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPROLIFERATION AND ALTERED KERATINOCYTE DIFFERENTIATION AND INFLAMMATION AND IS CAUSED BY THE INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. PREVIOUS STUDIES HAVE REVEALED THAT DNA METHYLATION (DNAM) AND GENETIC MAKERS ARE CLOSELY ASSOCIATED WITH PSORIASIS, AND STRONG EVIDENCES HAVE SHOWN THAT DNAM CAN BE CONTROLLED BY GENETIC FACTORS, WHICH ATTRACTED US TO EVALUATE THE RELATIONSHIP AMONG DNAM, GENETIC MAKERS, AND DISEASE STATUS. METHODS: WE UTILIZED THE GENOME-WIDE METHYLATION DATA OF PSORIATIC SKIN (PP, N = 114) AND UNAFFECTED CONTROL SKIN (NN, N = 62) TISSUE SAMPLES IN OUR PREVIOUS STUDY, AND WE PERFORMED WHOLE-GENOME GENOTYPING WITH PERIPHERAL BLOOD OF THE SAME SAMPLES TO EVALUATE THE UNDERLYING GENETIC EFFECT ON SKIN DNA METHYLATION. CAUSAL INFERENCE TEST (CIT) WAS USED TO ASSESS WHETHER DNAM REGULATE GENETIC VARIATION AND GAIN A BETTER UNDERSTANDING OF THE EPIGENETIC BASIS OF PSORIASIS SUSCEPTIBILITY. RESULTS: WE IDENTIFIED 129 SNP-CPG PAIRS ACHIEVING THE SIGNIFICANT ASSOCIATION THRESHOLD, WHICH CONSTITUTED 28 UNIQUE METHYLATION QUANTITATIVE TRAIT LOCI (METHQTL) AND 34 UNIQUE CPGS. THERE ARE 18 SNPS WERE ASSOCIATED WITH PSORIASIS AT A BONFERONI-CORRECTED P < 0.05, AND THESE 18 SNPS FORMED 93 SNP-CPG PAIRS WITH 17 UNIQUE CPG SITES. WE FOUND THAT 11 OF 93 SNP-CPG PAIRS, COMPOSED OF 5 UNIQUE SNPS AND 3 CPG SITES, PRESENTED A METHYLATION-MEDIATED RELATIONSHIP BETWEEN SNPS AND PSORIASIS. THE 3 CPG SITES WERE LOCATED ON THE BODY OF C1ORF106, THE TSS1500 PROMOTER REGION OF DMBX1 AND THE BODY OF SIK3. CONCLUSIONS: THIS STUDY REVEALED THAT DNAM OF SOME GENES CAN BE CONTROLLED BY GENETIC FACTORS AND ALSO MEDIATE RISK VARIATION FOR PSORIASIS IN CHINESE HAN POPULATION AND PROVIDED NOVEL MOLECULAR INSIGHTS INTO THE PATHOGENESIS OF PSORIASIS. 2016 8 4750 37 NOVEL REGIONAL AGE-ASSOCIATED DNA METHYLATION CHANGES WITHIN HUMAN COMMON DISEASE-ASSOCIATED LOCI. BACKGROUND: ADVANCING AGE PROGRESSIVELY IMPACTS ON RISK AND SEVERITY OF CHRONIC DISEASE. IT ALSO MODIFIES THE EPIGENOME, WITH CHANGES IN DNA METHYLATION, DUE TO BOTH RANDOM DRIFT AND VARIATION WITHIN SPECIFIC FUNCTIONAL LOCI. RESULTS: IN A DISCOVERY SET OF 2238 PERIPHERAL-BLOOD GENOME-WIDE DNA METHYLOMES AGED 19-82 YEARS, WE IDENTIFY 71 AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS WITHIN THE LINKAGE DISEQUILIBRIUM BLOCKS OF THE SINGLE NUCLEOTIDE POLYMORPHISMS FROM THE NIH GENOME-WIDE ASSOCIATION STUDY CATALOGUE. THIS INCLUDED 52 NOVEL REGIONS, 29 WITHIN LOCI NOT COVERED BY 450 K OR 27 K ILLUMINA ARRAY, AND WITH ENRICHMENT FOR DNASE-I HYPERSENSITIVITY SITES ACROSS THE FULL RANGE OF TISSUES. THESE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS ALSO SHOW MARKED ENRICHMENT FOR ENHANCERS AND POISED PROMOTERS ACROSS MULTIPLE CELL TYPES. IN A REPLICATION SET OF 2084 DNA METHYLOMES, 95.7 % OF THE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS SHOWED THE SAME DIRECTION OF AGEING EFFECT, WITH 80.3 % AND 53.5 % REPLICATED TO P < 0.05 AND P < 1.85 X 10(-8), RESPECTIVELY. CONCLUSION: BY ANALYSING THE FUNCTIONALLY ENRICHED DISEASE AND TRAIT-ASSOCIATED REGIONS OF THE HUMAN GENOME, WE IDENTIFY NOVEL EPIGENETIC AGEING CHANGES, WHICH COULD BE USEFUL BIOMARKERS OR PROVIDE MECHANISTIC INSIGHTS INTO AGE-RELATED COMMON DISEASES. 2016 9 5883 29 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 10 2048 39 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 11 6696 38 VARIATION IN GENOTYPE AND DNA METHYLATION PATTERNS BASED ON ALCOHOL USE AND CVD IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES). ALCOHOL CONSUMPTION CAN INCREASE THE RISK OF CHRONIC DISEASES, SUCH AS MYOCARDIAL INFARCTION, CORONARY ARTERY DISEASE, HYPERLIPIDEMIA, AND HYPERTENSION. WE AIMED TO ASSESS THE ASSOCIATION BETWEEN GENOTYPE, DNA METHYLATION PATTERNS, ALCOHOL CONSUMPTION, AND CHRONIC DISEASES IN KOREAN POPULATION. WE ANALYZED 8840 SUBJECTS FOR GENOTYPES AND 446 FOR DNA METHYLATION AMONG THE 9351 SUBJECTS FROM THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES). WE FURTHER DIVIDED BOTH GROUPS INTO TWO SUB-GROUPS ACCORDING TO THE PRESENCE/ABSENCE OF CHRONIC DISEASES. WE SELECTED GENES WHOSE METHYLATION VARIED SIGNIFICANTLY WITH ALCOHOL CONSUMPTION, AND VISUALIZED GENOTYPE AND DNA METHYLATION PATTERNS SPECIFIC TO EACH GROUP. GENOME-WIDE ASSOCIATION STUDY (GWAS) REVEALED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) RS2074356 AND RS11066280 IN HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 4 (HECTD4) TO BE SIGNIFICANTLY ASSOCIATED WITH ALCOHOL CONSUMPTION IN BOTH THE PRESENCE. THE RS12229654 GENOTYPE ALSO DISPLAYED SIGNIFICANTLY DIFFERENT PATTERNS WITH ALCOHOL CONSUMPTION. FURTHERMORE, WE RETRIEVED DIFFERENTIALLY METHYLATED REGIONS (DMRS) FROM FOUR GROUPS BASED ON SEX AND CHRONIC DISEASES AND COMPARED THEM BY DRINKING STATUS. IN GENOTYPE ANALYSIS, CARDIOVASCULAR DISEASES (CVDS) SHOWED A HIGHER PROPORTION IN DRINKER THAN IN NON-DRINKER, BUT NOT IN DMR ANALYSIS. ADDITIONALLY, WE ANALYZED THE ENRICHED GENE ONTOLOGY TERMS AND KYOTO GENE AND GENOME ENCYCLOPEDIA (KEGG) PATHWAYS AND VISUALIZED THE NETWORK, HEATMAP, AND UPSET PLOT. WE SHOW THAT THE PATTERN OF DNA METHYLATION ASSOCIATED WITH CVD IS STRONGLY INFLUENCED BY ALCOHOLISM. OVERALL, THIS STUDY IDENTIFIED GENETIC AND EPIGENETIC VARIANTS INFLUENCED BY ALCOHOL CONSUMPTION AND CHRONIC DISEASES. 2022 12 2631 46 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 13 2921 42 GENE-SPECIFIC DIFFERENTIAL DNA METHYLATION AND CHRONIC ARSENIC EXPOSURE IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF ADULTS IN BANGLADESH. BACKGROUND: INORGANIC ARSENIC IS ONE OF THE MOST COMMON NATURALLY OCCURRING CONTAMINANTS FOUND IN THE ENVIRONMENT. ARSENIC IS ASSOCIATED WITH A NUMBER OF HEALTH OUTCOMES, WITH EPIGENETIC MODIFICATION SUGGESTED AS A POTENTIAL MECHANISM OF TOXICITY. OBJECTIVE: AMONG A SAMPLE OF 400 ADULT PARTICIPANTS, WE EVALUATED THE ASSOCIATION BETWEEN ARSENIC EXPOSURE, AS MEASURED BY BLOOD AND URINARY TOTAL ARSENIC CONCENTRATIONS, AND EPIGENOME-WIDE WHITE BLOOD CELL DNA METHYLATION. METHODS: WE USED LINEAR REGRESSION MODELS TO EXAMINE THE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND METHYLATION AT EACH CPG SITE, ADJUSTED FOR SEX, AGE, AND BATCH. DIFFERENTIALLY METHYLATED LOCI WERE SUBSEQUENTLY EXAMINED IN RELATION TO CORRESPONDING GENE EXPRESSION FOR FUNCTIONAL EVIDENCE OF GENE REGULATION. RESULTS: IN ADJUSTED ANALYSES, WE OBSERVED FOUR DIFFERENTIALLY METHYLATED CPG SITES WITH URINARY TOTAL ARSENIC CONCENTRATION AND THREE DIFFERENTIALLY METHYLATED CPG SITES WITH BLOOD ARSENIC CONCENTRATION, BASED ON THE BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLD OF P < 1 X 10(-7). METHYLATION OF PLA2G2C (PROBE CG04605617) WAS THE MOST SIGNIFICANTLY ASSOCIATED LOCUS IN RELATION TO BOTH URINARY (P = 3.40 X 10(-11)) AND BLOOD ARSENIC CONCENTRATIONS (P = 1.48 X 10(-11)). THREE ADDITIONAL NOVEL METHYLATION LOCI-SQSTM1 (CG01225779), SLC4A4 (CG06121226), AND IGH (CG13651690)--WERE ALSO SIGNIFICANTLY ASSOCIATED WITH ARSENIC EXPOSURE. FURTHER, THERE WAS EVIDENCE OF METHYLATION-RELATED GENE REGULATION BASED ON GENE EXPRESSION FOR A SUBSET OF DIFFERENTIALLY METHYLATED LOCI. CONCLUSIONS: WE OBSERVED SIGNIFICANT ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENE-SPECIFIC DIFFERENTIAL WHITE BLOOD CELL DNA METHYLATION, SUGGESTING THAT EPIGENETIC MODIFICATIONS MAY BE AN IMPORTANT PATHWAY UNDERLYING ARSENIC TOXICITY. THE SPECIFIC DIFFERENTIALLY METHYLATED LOCI IDENTIFIED MAY INFORM POTENTIAL PATHWAYS FOR FUTURE INTERVENTIONS. 2015 14 6080 39 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION. 2023 15 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 16 1552 48 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 17 3954 37 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 18 1909 35 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