1  2623 125 EPIGENOME-WIDE ASSOCIATION STUDIES OF THE FRACTIONAL EXHALED NITRIC OXIDE AND BRONCHODILATOR DRUG RESPONSE IN MODERATE-TO-SEVERE PEDIATRIC ASTHMA. ASTHMA IS THE MOST PREVALENT PEDIATRIC CHRONIC DISEASE. BRONCHODILATOR DRUG RESPONSE (BDR) AND FRACTIONAL EXHALED NITRIC OXIDE (FENO) ARE CLINICAL BIOMARKERS OF ASTHMA. ALTHOUGH DNA METHYLATION (DNAM) CONTRIBUTES TO ASTHMA PATHOGENESIS, THE INFLUENCE OF DNAM ON BDR AND FENO IS SCARCELY INVESTIGATED. THIS STUDY AIMS TO IDENTIFY DNAM MARKERS IN WHOLE BLOOD ASSOCIATED EITHER WITH BDR OR FENO IN PEDIATRIC ASTHMA. WE ANALYZED 121 SAMPLES FROM CHILDREN WITH MODERATE-TO-SEVERE ASTHMA. THE ASSOCIATION OF GENOME-WIDE DNAM WITH BDR AND FENO HAS BEEN ASSESSED USING REGRESSION MODELS, ADJUSTING FOR AGE, SEX, ANCESTRY, AND TISSUE HETEROGENEITY. CROSS-TISSUE VALIDATION WAS ASSESSED IN 50 NASAL SAMPLES. DIFFERENTIALLY METHYLATED REGIONS (DMRS) AND ENRICHMENT IN TRAITS AND BIOLOGICAL PATHWAYS WERE ASSESSED. A FALSE DISCOVERY RATE (FDR) < 0.1 AND A GENOME-WIDE SIGNIFICANCE THRESHOLD OF P < 9 X 10(-8) WERE USED TO CONTROL FOR FALSE-POSITIVE RESULTS. THE CPG CG12835256 (PLA2G12A) WAS GENOME-WIDE ASSOCIATED WITH FENO IN BLOOD SAMPLES (COEFFICIENT= -0.015, P = 2.53 X 10(-9)) AND NOMINALLY ASSOCIATED IN NASAL SAMPLES (COEFFICIENT = -0.015, P = 0.045). ADDITIONALLY, THREE CPGS WERE SUGGESTIVELY ASSOCIATED WITH BDR (FDR < 0.1). WE IDENTIFIED 12 AND FOUR DMRS ASSOCIATED WITH FENO AND BDR (FDR < 0.05), RESPECTIVELY. AN ENRICHMENT IN ALLERGIC AND INFLAMMATORY PROCESSES, SMOKING, AND AGING WAS OBSERVED. WE REPORTED NOVEL ASSOCIATIONS OF DNAM MARKERS ASSOCIATED WITH BDR AND FENO ENRICHED IN ASTHMA-RELATED PROCESSES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2  6368  30 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3  3709  33 INFLUENCE OF VITAMIN D AND COTININE ON T-REGULATORY CELLS AND ASTHMA SEVERITY IN CHILDREN. ASTHMA IS A COMMON CHRONIC RESPIRATORY DISEASES IN CHILDREN. UNDERSTANDING THE IMMUNE MECHANISMS OF EPIGENETIC FACTORS MAY CONTRIBUTE TO A BETTER CONTROL OF ASTHMA. THIS STUDY SEEKS TO DETERMINE THE EFFECTS OF SERUM VITAMIN D AND URINE COTININE ON ASTHMA SEVERITY AND ON T REGULATORY CELLS (TREGS) AND OTHER IMMUNE-RELATED FACTORS SUCH AS CD3, CD4, CD8, CD19, CD16/56, AND ANTI-CD3 HLA-DR3. THE STUDY INVOLVED 34 CHILDREN WITH ASTHMA. DISEASE SEVERITY WAS ASSESSED WITH THE ASTHMA CONTROL TEST, SPIROMETRY, AND THE FRACTIONAL EXHALED NITRIC OXIDE (FENO). THE CONTROL GROUP CONSISTED OF 18 HEALTHY CHILDREN. WE FOUND A SIGNIFICANTLY LOWER PROPORTION OF TREGS IN THE SERUM OF ASTHMATIC CHILDREN COMPARED WITH THE CONTROL GROUP (P < 0.002). THERE WERE NO SIGNIFICANT DIFFERENCES IN THE OTHER IMMUNOLOGICAL FACTORS INVESTIGATED. NOR WAS THERE ANY APPRECIABLE ASSOCIATION BETWEEN VITAMIN D OR COTININE AND THE COURSE OF ASTHMA, FENO, TREGS, AND THE OTHER IMMUNE FACTORS. HOWEVER, THE PERCENTAGE OF TREGS WAS POSITIVELY ASSOCIATED WITH THE LEVEL OF FENO (P < 0.02). IN CONCLUSION, THE STUDY SHOWS A ROLE OF T REGULATORY CELLS IN THE PATHOGENESIS OF ASTHMA IN CHILDREN, BUT FAILS TO SHOW ANY INFLUENCE OF SERUM VITAMIN D OR URINE COTININE ON DISEASE COURSE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4   642  30 BIOMARKERS OF PARTICULATE MATTER EXPOSURE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A SYSTEMATIC REVIEW. BACKGROUND: IN RECENT YEARS, AMBIENT PARTICULATE MATTER (PM) EXPOSURE HAS BEEN STRONGLY LINKED WITH HEALTH EFFECTS. ELEVATED LEVELS OF PM IN POLLUTED AIR HAVE BEEN CORRELATED WITH THE ONSET AND DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS SYSTEMATIC REVIEW WAS CONDUCTED TO EVALUATE BIOMARKERS THAT COULD REFLECT THE EFFECTS OF PM EXPOSURE IN PATIENTS WITH COPD. METHODS: WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES PUBLISHED ON BIOMARKERS ASSOCIATED WITH PM EXPOSURE IN PATIENTS WITH COPD BETWEEN JANUARY 01, 2012 AND JUNE 30, 2022 IN PUBMED/MEDLINE, EMBASE, AND COCHRANE DATABASES. STUDIES THAT INCLUDED DATA ON BIOMARKERS WITH COPD EXPOSED PM WERE ELIGIBLE FOR INCLUSION. BIOMARKERS WERE CLASSIFIED INTO 4 GROUPS ACCORDING TO THEIR MECHANISMS. RESULTS: OF THE 105 STUDIES IDENTIFIED, 22 WERE INCLUDED IN THIS STUDY. NEARLY 50 BIOMARKERS HAVE BEEN PROPOSED IN THE STUDIES INCLUDED IN THIS REVIEW, AND THE MOST STUDIED IN RELATION TO PM ARE SEVERAL INTERLEUKINS. VARIOUS MECHANISMS HAVE BEEN REPORTED BY WHICH PM INDUCES AND AGGRAVATES COPD. SIX STUDIES RELATED TO OXIDATIVE STRESS, ONE RELATED TO DIRECT EFFECT OF INNATE AND ADAPTIVE IMMUNE SYSTEMS, 16 ASSOCIATED WITH GENETIC REGULATION OF INFLAMMATION, AND TWO RELATED TO EPIGENETIC REGULATION OF PHYSIOLOGY AND SUSCEPTIBILITY WERE FOUND. BIOMARKERS RELATED TO THESE MECHANISMS WERE DETECTED IN SERUM, SPUTUM, URINE, EXHALED BREATH CONCENTRATION (EBC), AND SHOWED VARIOUS CORRELATIONS WITH PM IN COPD. CONCLUSIONS: VARIOUS BIOMARKERS HAVE SHOWN POTENTIAL IN PREDICTING THE EXTENT OF PM EXPOSURE IN COPD PATIENTS. FUTURE STUDIES ARE NEEDED TO ESTABLISH RECOMMENDATIONS FOR REGULATION TO REDUCE AIRBORNE PM, WHICH COULD BE USED TO DEVELOP STRATEGIES FOR PREVENTION AND MANAGEMENT OF ENVIRONMENTAL RESPIRATORY DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  6878  25 [REGIONAL EXPERIENCE OF A COMPREHENSIVE DYNAMIC ASSESSMENT OF THE ADOLESCENTS' HEALTH STATUS WITH POST-COVID-19 SYNDROME DURING AFTERCARE IN A SANATORIUM]. OBJECTIVE: TO DETERMINE THE CHARACTERISTICS OF SANATORIUM-RESORT THERAPY IMPACT ON CHILDREN WITH POST-COVID-19 SYNDROME OF VARIOUS SEVERITY, AS WELL AS TO REVEAL ASSOCIATION OF ITS SEVERITY WITH FAMILY HISTORY DATA AND GENETIC POLYMORPHISMS OF ALPHA-1-ANTITRYPSIN-SERPIN-1 COMPLEX. MATERIAL AND METHODS: THIS 2-WEEK RETROSPECTIVE COHORT STUDY INVOLVED 42 ADOLESCENTS AFTER NEW CORONAVIRUS INFECTION (COVID-19). THE FIRST GROUP INCLUDED 28 (67%) PATIENTS (MEAN AGE 13.1+/-0.8 YEARS) AFTER MILD COVID-19 (WITHOUT CONFIRMED CORONAVIRUS PNEUMONIA), THE SECOND GROUP - 14 (33%) PATIENTS (MEAN AGE 14.5+/-0.1.2 YEARS) AFTER MODERATE OR SEVERE DISEASE (WITH CONFIRMED CORONAVIRUS PNEUMONIA). A COMPLEX OF PROCEDURES, ACCORDING TO THE APPROVED STANDARD, WAS PRESCRIBED FOR ALL PATIENTS ADMITTED AFTER OUTPATIENT AND HOSPITAL TREATMENT TO THE PULMONOLOGY DEPARTMENT OF THE STATE CHILDREN'S SANATORIUM IN ORDER TO AFTERCARE. THE CERTAIN FOLLOW-UP PARAMETERS WERE EVALUATED: SYMPTOMS SEVERITY, LIFE QUALITY, RESPIRATORY FUNCTION AND RESPIRATORY GASES, AS WELL AS FAMILY MEDICAL HISTORY AND ALPHA-1-ANTITRYPSIN-SERPIN-1 COMPLEX. RESULTS: PATIENTS AFTER MODERATE AND SEVERE COVID-19 HAD INITIALLY LOWER AND LESS DYNAMIC GROWTH OF INTEGRAL LIFE QUALITY INDEX, MORE TORPID FOLLOW-UP RATES OF SPIROMETRY, PULSE OXIMETRY AND EXHALED GASES. ADDITIONALLY, THE HIGHER INCIDENCE DEGREE OF ADVERSE FAMILY MEDICAL HISTORY ASSOCIATED WITH RESPIRATORY ILLNESSES WAS ESTABLISHED IN THE GROUP AFTER NEW CORONAVIRUS INFECTION. MOREOVER, RELATIVELY MORE DEFICIENT ALPHA-1-ANTITRYPSIN AND MORE FREQUENT HETEROZYGOUS POLYMORPHISM TYPE OF SERPIN-1 WERE FOUND IN THE GROUP AFTER SEVERE NEW CORONAVIRUS INFECTION. CONCLUSION: THE REVEALED COMPLEX OF EPIGENETIC AND GENETIC FACTORS MAY INDICATE VARIOUS RISK AND DEVELOPMENT PHENOTYPES OF BOTH ACUTE AND CHRONIC RESPIRATORY DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                               
6  2628  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  4690  31 NEWBORN DNA-METHYLATION, CHILDHOOD LUNG FUNCTION, AND THE RISKS OF ASTHMA AND COPD ACROSS THE LIFE COURSE. RATIONALE: WE AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN CORD BLOOD DNA ASSOCIATED WITH CHILDHOOD LUNG FUNCTION, ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ACROSS THE LIFE COURSE. METHODS: WE META-ANALYSED EPIGENOME-WIDE DATA OF 1688 CHILDREN FROM FIVE COHORTS TO IDENTIFY CORD BLOOD DMRS AND THEIR ANNOTATED GENES, IN RELATION TO FORCED EXPIRATORY VOLUME IN 1 S (FEV(1)), FEV(1)/FORCED VITAL CAPACITY (FVC) RATIO AND FORCED EXPIRATORY FLOW AT 75% OF FVC AT AGES 7-13 YEARS. IDENTIFIED DMRS WERE EXPLORED FOR ASSOCIATIONS WITH CHILDHOOD ASTHMA, ADULT LUNG FUNCTION AND COPD, GENE EXPRESSION AND INVOLVEMENT IN BIOLOGICAL PROCESSES. RESULTS: WE IDENTIFIED 59 DMRS ASSOCIATED WITH CHILDHOOD LUNG FUNCTION, OF WHICH 18 WERE ASSOCIATED WITH CHILDHOOD ASTHMA AND NINE WITH COPD IN ADULTHOOD. GENES ANNOTATED TO THE TOP 10 IDENTIFIED DMRS WERE HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 AND TCL1A. DIFFERENTIAL GENE EXPRESSION IN BLOOD WAS OBSERVED FOR 32 DMRS IN CHILDHOOD AND 18 IN ADULTHOOD. GENES RELATED WITH 16 IDENTIFIED DMRS WERE ASSOCIATED WITH RESPIRATORY DEVELOPMENTAL OR PATHOGENIC PATHWAYS. INTERPRETATION: OUR FINDINGS SUGGEST THAT THE EPIGENETIC STATUS OF THE NEWBORN AFFECTS RESPIRATORY HEALTH AND DISEASE ACROSS THE LIFE COURSE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  4295  27 MICRORNA RESPONSE OF INHALATION EXPOSURE TO HEXANAL IN LUNG TISSUES FROM FISCHER 344 RATS. IN PREVIOUS STUDIES, WE HAVE INVESTIGATED THE RELATIONSHIPS BETWEEN ENVIRONMENTAL CHEMICALS AND HEALTH RISK BASED ON OMICS ANALYSIS AND IDENTIFIED SIGNIFICANT BIOMARKERS. OUR CURRENT FINDINGS INDICATE THAT HEXANAL MAY BE AN IMPORTANT TOXICANT OF THE PULMONARY SYSTEM IN EPIGENETIC INSIGHTS. MICRORNA (MIRNA) IS AN IMPORTANT INDICATOR OF BIOMEDICAL RISK ASSESSMENT AND TARGET IDENTIFICATION. HEXANAL IS HIGHLY DETECTABLE IN THE EXHALED BREATH OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND CHRONIC INFLAMMATORY LUNG DISEASE. IN THIS STUDY, WE AIMED TO IDENTIFY HEXANAL-CHARACTERIZED MIRNA-MRNA CORRELATIONS INVOLVED IN LUNG TOXICITY. MICROARRAY ANALYSIS IDENTIFIED 56 MIRNAS THAT COMMONLY CHANGED THEIR EXPRESSION MORE THAN 1.3-FOLD IN THREE DOSES (600, 1000, AND 1500 PPM) WITHIN HEXANAL-EXPOSED FISCHER 344 RATS BY INHALATION, AND 226 GENES WERE PREDICTED TO BE TARGET GENES OF MIRNAS THROUGH TARGETSCAN ANALYSIS. BY INTEGRATING ANALYSES OF MIRNA AND MRNA EXPRESSION PROFILES, WE IDENTIFIED ONE ANTI-CORRELATED TARGET GENE (CHGA; CHROMOGRANIN A; PARATHYROID SECRETORY PROTEIN 1). COMPARATIVE TOXICOGENOMICS DATABASE (CTD) ANALYSIS OF THIS GENE SHOWED THAT CHGA IS INVOLVED WITH SEVERAL DISEASE CATEGORIES SUCH AS CANCER, RESPIRATORY TRACT DISEASE, NERVOUS SYSTEM DISEASE, AND CARDIOVASCULAR DISEASE. FURTHER RESEARCH IS NECESSARY TO ELUCIDATE THE MECHANISMS OF HEXANAL-RESPONSIVE TOXICOLOGIC PATHWAYS AT THE MOLECULAR LEVEL. THIS STUDY CONCLUDES THAT OUR INTEGRATED APPROACH TO MIRNA AND MRNA ENABLES US TO IDENTIFY MOLECULAR EVENTS IN DISEASE DEVELOPMENT INDUCED BY HEXANAL IN AN IN VIVO RAT MODEL. (C) 2015 WILEY PERIODICALS, INC. ENVIRON TOXICOL 31: 1909-1921, 2016.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9   383  41 AN EPIGENOME-WIDE STUDY OF DNA METHYLATION PROFILES AND LUNG FUNCTION AMONG AMERICAN INDIANS IN THE STRONG HEART STUDY. BACKGROUND: EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION (DNAM), ARE OFTEN RELATED TO ENVIRONMENTAL EXPOSURES, AND ARE INCREASINGLY RECOGNIZED AS KEY PROCESSES IN THE PATHOGENESIS OF CHRONIC LUNG DISEASE. AMERICAN INDIAN COMMUNITIES HAVE A HIGH BURDEN OF LUNG DISEASE COMPARED TO THE NATIONAL AVERAGE. THE OBJECTIVE OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION OF DNAM AND LUNG FUNCTION IN THE STRONG HEART STUDY (SHS). WE CONDUCTED A CROSS-SECTIONAL STUDY OF AMERICAN INDIAN ADULTS, 45-74 YEARS OF AGE WHO PARTICIPATED IN THE SHS. DNAM WAS MEASURED USING THE ILLUMINA INFINIUM HUMAN METHYLATIONEPIC PLATFORM AT BASELINE (1989-1991). LUNG FUNCTION WAS MEASURED VIA SPIROMETRY, INCLUDING FORCED EXPIRATORY VOLUME IN 1 S (FEV1) AND FORCED VITAL CAPACITY (FVC), AT VISIT 2 (1993-1995). AIRFLOW LIMITATION WAS DEFINED AS FEV1 < 70% PREDICTED AND FEV1/FVC < 0.7, RESTRICTION WAS DEFINED AS FEV1/FVC > 0.7 AND FVC < 80% PREDICTED, AND NORMAL SPIROMETRY WAS DEFINED AS FEV1/FVC > 0.7, FEV1 > 70% PREDICTED, FVC > 80% PREDICTED. WE USED ELASTIC-NET MODELS TO SELECT RELEVANT CPGS FOR LUNG FUNCTION AND SPIROMETRY-DEFINED LUNG DISEASE. WE ALSO CONDUCTED BIOINFORMATIC ANALYSES TO EVALUATE THE BIOLOGICAL PLAUSIBILITY OF THE FINDINGS. RESULTS: AMONG 1677 PARTICIPANTS, 21.2% HAD SPIROMETRY-DEFINED AIRFLOW LIMITATION AND 13.6% HAD SPIROMETRY-DEFINED RESTRICTIVE PATTERN LUNG FUNCTION. ELASTIC-NET MODELS SELECTED 1118 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AS PREDICTORS OF AIRFLOW LIMITATION AND 1385 FOR RESTRICTIVE PATTERN LUNG FUNCTION. A TOTAL OF 12 DMPS OVERLAPPED BETWEEN AIRFLOW LIMITATION AND RESTRICTIVE PATTERN. EGFR, MAPK1 AND PRPF8 GENES WERE THE MOST CONNECTED NODES IN THE PROTEIN-PROTEIN INTERACTION NETWORK. MANY OF THE DMPS TARGETED GENES WITH BIOLOGICAL ROLES RELATED TO LUNG FUNCTION SUCH AS PROTEIN KINASES. CONCLUSION: WE FOUND MULTIPLE DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CHRONIC LUNG DISEASE. THESE SIGNALS COULD CONTRIBUTE TO BETTER UNDERSTAND MOLECULAR MECHANISMS INVOLVED IN LUNG DISEASE, AS ASSESSED SYSTEMICALLY, AS WELL AS TO IDENTIFY PATTERNS THAT COULD BE USEFUL FOR DIAGNOSTIC PURPOSES. FURTHER EXPERIMENTAL AND LONGITUDINAL STUDIES ARE NEEDED TO ASSESS WHETHER DNA METHYLATION HAS A CAUSAL ROLE IN LUNG DISEASE.	2022	

10  2147  39 EPIGENETIC MARKER OF TELOMERIC AGE IS ASSOCIATED WITH EXACERBATIONS AND HOSPITALIZATIONS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AN AGE-RELATED CONDITION THAT HAS BEEN ASSOCIATED WITH EARLY TELOMERE ATTRITION; THE CLINICAL IMPLICATIONS OF TELOMERE SHORTENING IN COPD ARE NOT WELL KNOWN. IN THIS STUDY WE AIMED TO DETERMINE THE RELATIONSHIP OF THE EPIGENETIC REGULATION OF TELOMERIC LENGTH IN PERIPHERAL BLOOD WITH THE RISK OF EXACERBATIONS AND HOSPITALIZATION IN PATIENTS WITH COPD. METHODS: BLOOD DNA METHYLATION PROFILES WERE OBTAINED FROM 292 PATIENTS WITH COPD ENROLLED IN THE PLACEBO ARM OF THE MACROLIDE AZITHROMYCIN TO PREVENT RAPID WORSENING OF SYMPTOMS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (MACRO) STUDY AND WHO WERE FOLLOWED FOR 1-YEAR. WE CALCULATED TELOMERE LENGTH BASED ON DNA METHYLATION MARKERS (DNAMTL) AND RELATED THIS BIOMARKER TO THE RISK OF EXACERBATION AND HOSPITALIZATION AND HEALTH STATUS (ST. GEORGE RESPIRATORY QUESTIONNAIRE [SGRQ]) SCORE OVER TIME USING A COX PROPORTIONAL HAZARDS MODEL. WE ALSO USED LINEAR MODELS TO INVESTIGATE THE ASSOCIATIONS OF DNAMTL WITH THE RATES OF EXACERBATION AND HOSPITALIZATION (ADJUSTED FOR CHRONOLOGICAL AGE, LUNG FUNCTION, RACE, SEX, SMOKING, BODY MASS INDEX AND CELL COMPOSITION). RESULTS: PARTICIPANTS WITH SHORT DNAMTL DEMONSTRATED INCREASED RISK OF EXACERBATION (P = 0.02) AND HOSPITALIZATION (P = 0.03) COMPARED TO THOSE WITH LONGER DNAMTL. DNAMTL AGE ACCELERATION WAS ASSOCIATED WITH HIGHER RATES OF EXACERBATION (P = 1.35 X 10(-04)) AND HOSPITALIZATION (P = 5.21 X 10(-03)) AND POOR HEALTH STATUS (LOWER SGRQ SCORES) INDEPENDENT OF CHRONOLOGICAL AGE (P = 0.03). CONCLUSION: TELOMERIC AGE BASED ON BLOOD DNA METHYLATION IS ASSOCIATED WITH COPD EXACERBATION AND HOSPITALIZATION AND THUS A PROMISING BIOMARKER FOR POOR OUTCOMES IN COPD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  6314  28 THE RELATIONSHIP BETWEEN THE EPIGENETIC AGING BIOMARKER "GRIMAGE" AND LUNG FUNCTION IN BOTH THE AIRWAY AND BLOOD OF PEOPLE LIVING WITH HIV: AN OBSERVATIONAL COHORT STUDY. BACKGROUND: AGE-RELATED COMORBIDITIES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE COMMON IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (PLWH). WE INVESTIGATED THE RELATIONSHIP BETWEEN COPD AND THE EPIGENETIC AGE OF THE AIRWAY EPITHELIUM AND PERIPHERAL BLOOD OF PLWH. METHODS: AIRWAY EPITHELIAL BRUSHINGS FROM 34 PLWH ENROLLED IN THE ST. PAUL'S HOSPITAL HIV BRONCHOSCOPY COHORT AND PERIPHERAL BLOOD FROM 378 PLWH ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL TREATMENT (START) STUDY WERE PROFILED FOR DNA METHYLATION. THE DNA METHYLATION BIOMARKER OF AGE AND HEALTHSPAN, GRIMAGE, WAS CALCULATED IN BOTH TISSUE COMPARTMENTS. WE TESTED THE ASSOCIATION OF GRIMAGE WITH COPD IN THE AIRWAY EPITHELIUM AND AIRFLOW OBSTRUCTION AS DEFINED BY AN FEV(1)/FVC<0.70, AND FEV(1) DECLINE OVER 6 YEARS IN BLOOD. FINDINGS: THE AIRWAY EPITHELIUM OF PLWH WITH COPD WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS COMPARED TO PLWH WITHOUT COPD (BETA=3.18, 95%CI=1.06-5.31, P=0.005). IN BLOOD, FEV(1)/FVC<LLN WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS (BETA=1.74, 95%CI=0.37-3.24, P=0.019). FEV(1) DECLINE WAS INVERSELY CORRELATED WITH GRIMAGE RESIDUALS IN BLOOD (R=-0.13, P=0.012). PLWH WHO HAD NORMAL LUNG FUNCTION BUT WHO SUBSEQUENTLY DEVELOPED AN FEV(1)/FVC<0.70 OVER THE COURSE OF 6 YEARS HAD HIGHER GRIMAGE RESIDUALS AT BASELINE (BETA=2.33, 95%CI=0.23-4.44, P=0.031). INTERPRETATION: GRIMAGE MAY REFLECT LUNG AND SYSTEMIC EPIGENETIC CHANGES THAT OCCUR WITH ADVANCED AIRFLOW OBSTRUCTION AND MAY HELP TO IDENTIFY PLWH WITH A HIGHER RISK OF DEVELOPING COPD. FUNDING: CANADIAN INSTITUTES OF HEALTH RESEARCH AND THE BRITISH COLUMBIA LUNG ASSOCIATION. THE START SUBSTUDY WAS FUNDED BY NIH GRANTS: UM1-AI068641, UM1-AI120197, AND RO1HL096453.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  1550  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13   178  29 ACCELERATED EPIGENETIC AGING AS A RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND DECREASED LUNG FUNCTION IN TWO PROSPECTIVE COHORT STUDIES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A FREQUENT DIAGNOSIS IN OLDER INDIVIDUALS AND CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY. GIVEN THE LINK BETWEEN LUNG DISEASE AND AGING, WE NEED TO UNDERSTAND HOW MOLECULAR INDICATORS OF AGING RELATE TO LUNG FUNCTION AND DISEASE. USING DATA FROM THE POPULATION-BASED KORA (COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG) SURVEYS, WE ASSOCIATED BASELINE EPIGENETIC (DNA METHYLATION) AGE ACCELERATION WITH INCIDENT COPD AND LUNG FUNCTION. MODELS WERE ADJUSTED FOR AGE, SEX, SMOKING, HEIGHT, WEIGHT, AND BASELINE LUNG DISEASE AS APPROPRIATE. ASSOCIATIONS WERE REPLICATED IN THE NORMATIVE AGING STUDY. OF 770 KORA PARTICIPANTS, 131 DEVELOPED INCIDENT COPD OVER 7 YEARS. BASELINE ACCELERATED EPIGENETIC AGING WAS SIGNIFICANTLY ASSOCIATED WITH INCIDENT COPD. THE CHANGE IN AGE ACCELERATION (FOLLOW-UP - BASELINE) WAS MORE STRONGLY ASSOCIATED WITH COPD THAN BASELINE AGING ALONE. THE ASSOCIATION BETWEEN THE CHANGE IN AGE ACCELERATION BETWEEN BASELINE AND FOLLOW-UP AND INCIDENT COPD REPLICATED IN THE NORMATIVE AGING STUDY. ASSOCIATIONS WITH SPIROMETRIC LUNG FUNCTION PARAMETERS WERE WEAKER THAN THOSE WITH COPD, BUT A META-ANALYSIS OF BOTH COHORTS PROVIDE SUGGESTIVE EVIDENCE OF ASSOCIATIONS. ACCELERATED EPIGENETIC AGING, BOTH BASELINE MEASURES AND CHANGES OVER TIME, MAY BE A RISK FACTOR FOR COPD AND REDUCED LUNG FUNCTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  2018  32 EPIGENETIC CHANGE (GATA-4 GENE METHYLATION) IS ASSOCIATED WITH HEALTH STATUS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. GENE METHYLATION IS AN EPIGENETIC CHANGE THAT INVOLVES A HERITABLE MODIFICATION OF CHROMATIN STRUCTURE THAT ALTERS GENE EXPRESSION WITHOUT A CHANGE IN DNA SEQUENCE. IT HAS PREVIOUSLY BEEN SHOWN THAT METHYLATION OF THE GATA-4 GENE PROMOTER REGION IN SPUTUM DNA IS ASSOCIATED WITH LOW LUNG FUNCTION AND INCREASED ODDS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AMONG SMOKERS. GIVEN THESE FINDINGS, WE HYPOTHESIZED THAT GATA-4 GENE METHYLATION IN SPUTUM DNA WOULD BE ASSOCIATED WITH LOW HEALTH STATUS, AS MEASURED BY THE ST. GEORGE'S RESPIRATORY QUESTIONNAIRE (SGRQ), IN SUBJECTS WITH COPD. SELF-REPORTED SGRQ, SPIROMETRY, AND INDUCED SPUTUM SAMPLES WERE OBTAINED FROM 168 COPD SUBJECTS FROM THE LOVELACE SMOKERS COHORT. GATA-4 GENE METHYLATION WAS EVALUATED IN SPUTUM DNA USING NESTED METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) ASSAYS. USING GENERAL LINEAR MODEL WITH POISSON REGRESSION, WE FOUND THAT GATA-4 GENE METHYLATION WAS SIGNIFICANTLY ASSOCIATED WITH OVERALL LOWER SGRQ HEALTH STATUS (PARAMETER ESTIMATE = .296, P < .001). THIS FINDING REMAINED SIGNIFICANT EVEN AFTER CONTROLLING FOR AGE, LUNG FUNCTION, AND OTHER COVARIATES. IN AN ADDITIONAL ANALYSIS USING LOGISTIC REGRESSION AND COMPARING EXTREME TERTILES OF OVERALL SGRQ SCORE, WE CONFIRMED THAT GATA-4 GENE METHYLATION WAS ASSOCIATED WITH A 3-FOLD INCREASE IN RISK OF POOR HEALTH STATUS (OR 2.95 AND P = .028). THE UNEXPLORED LINKS BETWEEN EPIGENETIC CHANGES AND PSYCHOSOCIAL FACTORS SUCH AS HEALTH STATUS ARE CRITICAL GAPS IN THE LITERATURE. THIS STUDY IS THE FIRST TO SUGGEST THAT AIRWAY GATA-4 GENE METHYLATION STATUS MAY INDEPENDENTLY PREDICT HEALTH STATUS IN INDIVIDUALS WITH COPD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  1552  46 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	
                                                                                                                                                                                                                                                                                                                                                                        
16  3063  43 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17   304  37 AIRWAY AGING AND METHYLATION DISRUPTIONS IN HIV-ASSOCIATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. RATIONALE: AGE-RELATED DISEASES LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OCCUR AT HIGHER RATES IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (PLWH) THAN IN UNINFECTED POPULATIONS. OBJECTIVES: TO IDENTIFY WHETHER ACCELERATED AGING CAN BE OBSERVED IN THE AIRWAYS OF PLWH WITH COPD, MANIFEST BY A UNIQUE DNA METHYLATION SIGNATURE. METHODS: BRONCHIAL EPITHELIAL BRUSHINGS FROM PLWH WITH AND WITHOUT COPD AND HIV-UNINFECTED ADULTS WITH AND WITHOUT COPD (N = 76) WERE PROFILED FOR DNA METHYLATION AND GENE EXPRESSION. WE EVALUATED GLOBAL ALU AND LINE-1 METHYLATION AND CALCULATED THE EPIGENETIC AGE USING THE HORVATH CLOCK AND THE METHYLATION TELOMERE LENGTH ESTIMATOR. TO IDENTIFY GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND GENE EXPRESSION ASSOCIATED WITH HIV AND COPD, ROBUST LINEAR MODELS WERE USED FOLLOWED BY AN EXPRESSION QUANTITATIVE TRAIT METHYLATION (EQTM) ANALYSIS. MEASUREMENTS AND MAIN RESULTS: EPIGENETIC AGE ACCELERATION AND SHORTER METHYLATION ESTIMATES OF TELOMERE LENGTH WERE FOUND IN PLWH WITH COPD COMPARED WITH PLWH WITHOUT COPD AND UNINFECTED PATIENTS WITH AND WITHOUT COPD. GLOBAL HYPOMETHYLATION WAS IDENTIFIED IN PLWH. WE IDENTIFIED 7,970 CYTOSINE BASES LOCATED NEXT TO A GUANINE BASE (CPG SITES), 293 GENES, AND 9 EXPRESSION QUANTITATIVE TRAIT METHYLATION-GENE PAIRS ASSOCIATED WITH THE INTERACTION BETWEEN HIV AND COPD. ACTIN BINDING LIM PROTEIN FAMILY MEMBER 3 (ABLIM3) WAS ONE OF THE NOVEL CANDIDATE GENES FOR HIV-ASSOCIATED COPD HIGHLIGHTED BY OUR ANALYSIS. CONCLUSIONS: METHYLATION AGE ACCELERATION IS OBSERVED IN THE AIRWAY EPITHELIUM OF PLWH WITH COPD, A PROCESS THAT MAY BE RESPONSIBLE FOR THE HEIGHTENED RISK OF COPD IN THIS POPULATION. THEIR DISTINCT METHYLATION PROFILE, DIFFERING FROM THAT OBSERVED IN PATIENTS WITH COPD ALONE, SUGGESTS A UNIQUE PATHOGENESIS TO HIV-ASSOCIATED COPD. THE ASSOCIATIONS WARRANT FURTHER INVESTIGATION TO ESTABLISH CAUSALITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                   
18  5882  32 SYSTEMATIC REVIEW OF LUNG FUNCTION AND COPD WITH PERIPHERAL BLOOD DNA METHYLATION IN POPULATION BASED STUDIES. BACKGROUND: EPIGENETIC VARIATIONS IN PERIPHERAL BLOOD HAVE POTENTIAL AS BIOMARKERS FOR DISEASE. THIS SYSTEMATIC REVIEW ASSESSES THE ASSOCIATION OF LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WITH DNA METHYLATION PROFILES IN PERIPHERAL BLOOD FROM POPULATION-BASED STUDIES. METHODS: ONLINE DATABASES MEDLINE, EMBASE, AND WEB OF SCIENCE WERE SEARCHED. GOOGLE SCHOLAR WAS SEARCHED TO IDENTIFY GREY LITERATURE. AFTER REMOVING DUPLICATE ARTICLES, 1155 ARTICLES WERE INDEPENDENTLY SCREENED BY TWO INVESTIGATORS. PEER REVIEWED REPORTS ON POPULATION-BASED STUDIES THAT EXAMINED PERIPHERAL BLOOD DNA METHYLATION IN PARTICIPANTS WITH MEASURED LUNG FUNCTION (FEV1, FEV1/FVC RATIO) OR KNOWN COPD STATUS WERE SELECTED FOR FULL-TEXT REVIEW. SIX ARTICLES WERE SUITABLE FOR INCLUSION. INFORMATION REGARDING STUDY CHARACTERISTICS, DESIGNS, METHODOLOGIES AND CONCLUSIONS WAS EXTRACTED. A NARRATIVE SYNTHESIS WAS PERFORMED BASED ON PUBLISHED RESULTS. RESULTS: THREE OF THE SIX ARTICLES ASSESSED THE ASSOCIATION OF COPD WITH DNA METHYLATION, AND TWO OF THESE ALSO INCLUDED ASSOCIATIONS WITH LUNG FUNCTION. OVERALL, FIVE REPORTS EXAMINED THE ASSOCIATION OF LUNG FUNCTION WITH DNA METHYLATION PROFILES. FIVE OF THE SIX ARTICLES REPORTED 'SIGNIFICANT' RESULTS. HOWEVER, NO CONSISTENT CPG SITES WERE IDENTIFIED ACROSS STUDIES FOR COPD STATUS OR LUNG FUNCTION VALUES. CONCLUSIONS: DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD FROM INDIVIDUALS WITH REDUCED LUNG FUNCTION OR COPD MAY BE DIFFERENT TO THOSE IN PEOPLE WITH NORMAL LUNG FUNCTION. HOWEVER, THIS SYSTEMATIC REVIEW DID NOT FIND ANY CONSISTENT ASSOCIATIONS OF LUNG FUNCTION OR COPD WITH DIFFERENTIALLY METHYLATED CPG SITES. LARGE STUDIES WITH A LONGITUDINAL DESIGN TO ADDRESS REVERSE CAUSALITY MAY PROVE A MORE FRUITFUL AREA OF RESEARCH. TRIAL REGISTRATION: PROSPERO 2016: CRD42016037352 .	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  3631  31 INCORPORATING BIOMARKERS IN COPD MANAGEMENT: THE RESEARCH KEEPS GOING. GLOBALLY, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) REMAINS A MAJOR CAUSE OF MORBIDITY AND MORTALITY, HAVING A SIGNIFICANT SOCIOECONOMIC EFFECT. SEVERAL MOLECULAR MECHANISMS HAVE BEEN RELATED TO COPD INCLUDING CHRONIC INFLAMMATION, TELOMERE SHORTENING, AND EPIGENETIC MODIFICATIONS. NOWADAYS, THERE IS AN INCREASING NEED FOR NOVEL THERAPEUTIC APPROACHES FOR THE MANAGEMENT OF COPD. THESE TREATMENT STRATEGIES SHOULD BE BASED ON FINDING THE SOURCE OF ACUTE EXACERBATION OF COPD EPISODES AND ESTIMATING THE PATIENT'S OWN RISK. THE USE OF BIOMARKERS AND THE MEASUREMENT OF THEIR LEVELS IN CONJUNCTION WITH COPD EXACERBATION RISK AND DISEASE PROGNOSIS IS CONSIDERED AN ENCOURAGING APPROACH. MANY TYPES OF COPD BIOMARKERS HAVE BEEN IDENTIFIED WHICH INCLUDE BLOOD PROTEIN BIOMARKERS, CELLULAR BIOMARKERS, AND PROTEASE ENZYMES. THEY HAVE BEEN ISOLATED FROM DIFFERENT SOURCES INCLUDING PERIPHERAL BLOOD, SPUTUM, BRONCHOALVEOLAR FLUID, EXHALED AIR, AND GENETIC MATERIAL. HOWEVER, THERE IS STILL NOT AN EXCLUSIVE BIOMARKER THAT IS USED FOR THE EVALUATION OF COPD BUT RATHER A COMBINATION OF THEM, AND THIS IS ATTRIBUTED TO DISEASE COMPLEXITY. IN THIS REVIEW, WE SUMMARIZE THE CLINICAL SIGNIFICANCE OF COPD-RELATED BIOMARKERS, THEIR ASSOCIATION WITH DISEASE OUTCOMES, AND COPD PATIENTS' MANAGEMENT. FINALLY, WE DEPICT THE VARIOUS SAMPLES THAT ARE USED FOR IDENTIFYING AND MEASURING THESE BIOMARKERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20   972  40 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022