1 6491 191 TRAFFIC-DERIVED PARTICULATE MATTER EXPOSURE AND HISTONE H3 MODIFICATION: A REPEATED MEASURES STUDY. BACKGROUND: AIRBORNE PARTICULATE MATTER (PM) MAY INDUCE EPIGENETIC CHANGES THAT POTENTIALLY LEAD TO CHRONIC DISEASES. HISTONE MODIFICATIONS REGULATE GENE EXPRESSION BY INFLUENCING CHROMATIN STRUCTURE THAT CAN CHANGE GENE EXPRESSION STATUS. WE EVALUATED WHETHER TRAFFIC-DERIVED PM EXPOSURE IS ASSOCIATED WITH FOUR TYPES OF ENVIRONMENTALLY INDUCIBLE GLOBAL HISTONE H3 MODIFICATIONS. METHODS: THE BEIJING TRUCK DRIVER AIR POLLUTION STUDY INCLUDED 60 TRUCK DRIVERS AND 60 OFFICE WORKERS EXAMINED TWICE, 1-2 WEEKS APART, FOR AMBIENT PM(10) (BOTH DAY-OF AND 14-DAY AVERAGE EXPOSURES), PERSONAL PM(2.5), BLACK CARBON (BC), AND ELEMENTAL COMPONENTS (POTASSIUM, SULFUR, IRON, SILICON, ALUMINUM, ZINC, CALCIUM, AND TITANIUM). FOR BOTH PM(10) MEASURES, WE OBTAINED HOURLY AMBIENT PM(10) DATA FOR THE STUDY PERIOD FROM THE BEIJING MUNICIPAL ENVIRONMENTAL BUREAU'S 27 REPRESENTATIVELY DISTRIBUTED MONITORING STATIONS. WE THEN CALCULATED A 24H AVERAGE FOR EACH EXAMINATION DAY AND A MOVING AVERAGE OF AMBIENT PM(10) MEASURED IN THE 14 DAYS PRIOR TO EACH EXAMINATION. EXAMINATIONS MEASURED GLOBAL LEVELS OF H3 LYSINE 9 ACETYLATION (H3K9AC), H3 LYSINE 9 TRI-METHYLATION (H3K9ME3), H3 LYSINE 27 TRI-METHYLATION (H3K27ME3), AND H3 LYSINE 36 TRI-METHYLATION (H3K36ME3) IN BLOOD LEUKOCYTES COLLECTED AFTER WORK. WE USED ADJUSTED LINEAR MIXED-EFFECT MODELS TO EXAMINE PERCENT CHANGES IN HISTONE MODIFICATIONS PER EACH MUG/M(3) INCREASE IN PM EXPOSURE. RESULTS: IN ALL PARTICIPANTS EACH MUG/M(3) INCREASE IN 14-DAY AVERAGE AMBIENT PM(10) EXPOSURE WAS ASSOCIATED WITH LOWER H3K27ME3 (BETA=-1.1%, 95% CI: -1.6, -0.6) AND H3K36ME3 LEVELS (BETA=-0.8%, 95% CI: -1.4, -0.1). OCCUPATION-STRATIFIED ANALYSES SHOWED ASSOCIATIONS BETWEEN BC AND BOTH H3K9AC AND H3K36ME3 THAT WERE STRONGER IN OFFICE WORKERS (BETA=4.6%, 95% CI: 0.9, 8.4; AND BETA=4.1%, 95% CI: 1.3; 7.0 RESPECTIVELY) THAN IN TRUCK DRIVERS (BETA=0.1%, 95% CI: -1.3, 1.5; AND BETA=0.9%, 95% CI: -0.9, 2.7, RESPECTIVELY; BOTH P(INTERACTION) <0.05). SEX-STRATIFIED ANALYSES SHOWED ASSOCIATIONS BETWEEN EXAMINATION-DAY PM(10) AND H3K9AC, AND BETWEEN BC AND H3K9ME3, WERE STRONGER IN WOMEN (BETA=10.7%, 95% CI: 5.4, 16.2; AND BETA=7.5%, 95% CI: 1.2, 14.2, RESPECTIVELY) THAN IN MEN (BETA=1.4%, 95% CI: -0.9, 3.7; AND BETA=0.9%, 95% CI: -0.9, 2.7, RESPECTIVELY; BOTH P(INTERACTION) <0.05). WE OBSERVED NO ASSOCIATIONS BETWEEN PERSONAL PM(2.5) OR ELEMENTAL COMPONENTS AND HISTONE MODIFICATIONS. CONCLUSIONS: OUR RESULTS SUGGEST A POSSIBLE ROLE OF GLOBAL HISTONE H3 MODIFICATIONS IN EFFECTS OF TRAFFIC-DERIVED PM EXPOSURES, PARTICULARLY BC EXPOSURE. FUTURE STUDIES SHOULD ASSESS THE ROLES OF THESE MODIFICATIONS IN HUMAN DISEASES AND AS POTENTIAL MEDIATORS OF AIR POLLUTION-INDUCED DISEASE, IN PARTICULAR BC EXPOSURE.	2017	

2 5964  46 TEMPORAL VARIABILITY OF GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION IN BUCCAL CELLS OF HEALTHY ADULTS: ASSOCIATION WITH AIR POLLUTION. BACKGROUND: EPIGENETIC CHANGES, SUCH AS DNA METHYLATION, ARE OBSERVED IN RESPONSE TO ENVIRONMENTAL EXPOSURE AND IN THE DEVELOPMENT OF SEVERAL CHRONIC DISEASES. CONSEQUENTLY, DNA METHYLATION ALTERATIONS MIGHT SERVE AS INDICATORS OF EARLY EFFECTS. IN THIS CONTEXT, THE AIM OF THIS STUDY WAS TO ASSESS THE TEMPORAL VARIABILITY OF GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION LEVELS IN BUCCAL CELLS FROM HEALTHY ADULT VOLUNTEERS. METHODS: GLOBAL DNA METHYLATION (%5MDC) AND HYDROXYMETHYLATION (%5HMDC) LEVELS IN HUMAN BUCCAL CELLS, COLLECTED FROM 26 HEALTHY ADULTS AT DIFFERENT TIME POINTS, WERE QUANTIFIED BY UPLC-MS/MS. ASSOCIATIONS BETWEEN %5MDC AND %5HMDC, RESPECTIVELY, AND SHORT-TERM EXPOSURE (1-7DAYS) TO AIR POLLUTANTS PM(2.5) AND PM(10) WERE TESTED WITH MIXED-EFFECTS MODELS INCLUDING VARIOUS COVARIATES. RESULTS/DISCUSSION: DYNAMIC SHORT-TERM CHANGES IN DNA METHYLATION AND HYDROXYMETHYLATION LEVELS IN BUCCAL CELLS WERE OBSERVED, WHICH WERE INVERSELY ASSOCIATED WITH EXPOSURE TO PM(2.5) AND PM(10). AN IQR INCREASE IN PM(2.5) OVER A 7-DAY MOVING AVERAGE PERIOD WAS SIGNIFICANTLY ASSOCIATED WITH A DECREASE OF -1.47% (-1.74%, -1.20%) AND -0.043% (-0.054%, -0.032%) IN %5MDC AND %5HMDC, RESPECTIVELY. LIKEWISE, FOR PM(10), A DECREASE OF -1.42% (-1.70, -1.13) AND -0.040% (-0.051%, -0.028%) WAS OBSERVED. CONCLUSION: GLOBAL DNA METHYLATION AND HYDROXYMETHYLATATION VARIED OVER A TIME PERIOD OF THREE WEEKS. THE OBSERVED TEMPORAL VARIABILITY WAS ASSOCIATED WITH EXPOSURE TO AMBIENT PM(2.5) AND PM(10) LEVELS. THIS SHOULD BE TAKEN INTO ACCOUNT WHEN INTERPRETING EPIGENETIC ALTERATIONS IN BUCCAL CELLS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3 1849  38 EIGHT WEEKS OF PHYSICAL TRAINING DECREASES 2 YEARS OF DNA METHYLATION AGE OF SEDENTARY WOMEN. PURPOSE: THE ACCELERATION OF EPIGENETIC AGE IS A PREDICTOR OF MORTALITY AND CONTRIBUTES TO THE INCREASE IN CHRONIC DISEASES. ADHERENCE TO A HEALTHY LIFESTYLE IS A STRATEGY TO REDUCE EPIGENETIC AGE. THE PRESENT STUDY AIMED TO DETERMINE WHETHER EIGHT WEEKS OF COMBINED (AEROBIC AND STRENGTH) TRAINING (CT) CAN INFLUENCE THE EPIGENETIC AGE OF WOMEN BETWEEN 50 AND 70 YEARS OLD AND THE DIFFERENCES IN SITES AND METHYLATED REGIONS. METHODS: EIGHTEEN WOMEN (AAR(LOW): LOWER AGE ACCELERATION RESIDUAL, N = 10; AAR(HIGH): HIGHER AGE ACCELERATION RESIDUAL, N = 8) PARTICIPATED IN A COMBINED EXERCISE TRAINING PROGRAM (60 MINUTES, 3X A WEEK) FOR EIGHT WEEKS. DNA WAS EXTRACTED FROM WHOLE BLOOD USING THE SALTING OUT TECHNIQUE. DNA METHYLATION WAS PERFORMED USING THE ARRAY TECHNIQUE (ILLUMINA'S INFINIUM METHYLATION BEADCHIP 850K). WE USED THE DNA METHYLATION AGE CALCULATOR PLATFORM TO CALCULATE THE BIOLOGICAL EPIGENETIC AGE. TWO-WAY ANOVA FOLLOWED BY FISHER LSD POSTHOC WAS APPLIED, ADOPTING P < .05. RESULTS: AFTER EIGHT WEEKS OF CT, THERE WERE NO CHANGES TO THE EPIGENETIC AGE ACCELERATION FOR THE AAR(LOW) GROUP (PRE: -2.3 +/- 3.2 TO POST: -2.3 +/- 3.6). HOWEVER, THE AAR(HIGH) GROUP SIGNIFICANTLY DECREASED THE AGE ACCELERATION (PRE: 3.6 +/- 2.6 TO POST: 2.2 +/- 2.7) (GROUP EFFECT, P = .01; TIME EFFECT, P = .31; GROUP VS. TIME EFFECT, P = .005). CONCLUSION: CT FOR EIGHT WEEKS BENEFITS THE EPIGENETIC CLOCK OF WOMEN WITH THE MOST ACCELERATED AGE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 2921  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5 4024  40 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  501  51 ASSOCIATION OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY AND SEDENTARY TIME WITH EPIGENETIC MARKERS OF AGING. INTRODUCTION/PURPOSE: PHYSICAL ACTIVITY MAY INFLUENCE CHRONIC DISEASE RISK, IN PART, THROUGH EPIGENETIC MECHANISMS. PREVIOUS STUDIES HAVE DEMONSTRATED THAT AN ACUTE BOUT OF PHYSICAL ACTIVITY CAN INFLUENCE DNA METHYLATION STATUS. FEW STUDIES HAVE EXPLORED THE RELATIONSHIP BETWEEN HABITUAL, ACCELEROMETER-MEASURED PHYSICAL ACTIVITY OR SEDENTARY TIME WITH EPIGENETIC MARKERS OF AGING. METHODS: WE USED LINEAR REGRESSION TO EXAMINE CROSS-SECTIONAL ASSOCIATIONS OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY AND SEDENTARY TIME WITH EXTRINSIC AND INTRINSIC EPIGENETIC AGE ACCELERATION (EEAA AND IEAA) MODELS AND GRIMAGE MEASURED FROM BLOOD SAMPLES FROM FRAMINGHAM HEART STUDY PARTICIPANTS WITH ACCELEROMETRY AND DNA METHYLATION DATA ( N = 2435; MEAN AGE, 54.9 +/- 14.3; 46.0% MEN). RESIDUALS OF HANNUM-, HORVATH-, AND GRIMAGE-PREDICTED EPIGENETIC AGE WERE CALCULATED BY REGRESSING EPIGENETIC AGE ON CHRONOLOGICAL AGE. WE TOOK INTO ACCOUNT BLOOD CELL COMPOSITION FOR EEAA, IEAA, AND ADJGRIMAGE. MODERATE TO VIGOROUS PHYSICAL ACTIVITY WAS LOG-TRANSFORMED TO NORMALIZE ITS DISTRIBUTION. ADJUSTMENT MODELS ACCOUNTED FOR FAMILY STRUCTURE, AGE, SEX, SMOKING STATUS, COHORT-LABORATORY INDICATOR, AND ACCELEROMETER WEAR TIME. WE ADDITIONALLY EXPLORED ADJUSTMENT FOR BODY MASS INDEX (BMI). RESULTS: WALKING 1500 MORE STEPS PER DAY OR SPENDING 3 FEWER HOURS SEDENTARY WAS ASSOCIATED WITH >10 MONTHS LOWER GRIMAGE BIOLOGICAL AGE (OR ~1 MONTH LOWER ADJGRIMAGE, AFTER ADJUSTING FOR BLOOD CELLS, P < 0.05). EVERY 5 MIN.D -1 MORE MODERATE TO VIGOROUS PHYSICAL ACTIVITY WAS ASSOCIATED WITH 19-79 D OF LOWER GRIMAGE (4-23 D LOWER USING EEAA OR ADJGRIMAGE, P < 0.01). ADJUSTING FOR BMI ATTENUATED THESE RESULTS, BUT ALL STATISTICALLY SIGNIFICANT ASSOCIATIONS WITH ADJGRIMAGE REMAINED. CONCLUSIONS: GREATER HABITUAL PHYSICAL ACTIVITY AND LOWER SEDENTARY TIME WERE ASSOCIATED WITH LOWER EPIGENETIC AGE, WHICH WAS PARTIALLY EXPLAINED BY BMI. FURTHER RESEARCH SHOULD EXPLORE WHETHER CHANGES IN PHYSICAL ACTIVITY INFLUENCE METHYLATION STATUS AND WHETHER THOSE MODIFICATIONS INFLUENCE CHRONIC DISEASE RISK.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7 4818  31 OCCURRENCE OF ACCELERATED EPIGENETIC AGING AND METHYLATION DISRUPTIONS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE ANTIRETROVIRAL THERAPY. BACKGROUND: WHETHER ACCELERATED AGING DEVELOPS OVER THE COURSE OF CHRONIC HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION OR CAN BE OBSERVED BEFORE SIGNIFICANT IMMUNOSUPPRESSION ON IS UNKNOWN. WE STUDIED DNA METHYLATION IN BLOOD TO ESTIMATE CELLULAR AGING IN PERSONS LIVING WITH HIV (PLWH) BEFORE THE INITIATION OF ANTIRETROVIRAL THERAPY (ART). METHODS: A TOTAL OF 378 ART-NAIVE PLWH WHO HAD CD4 T-CELL COUNTS >500/MICROL AND WERE ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL THERAPY TRIAL (PULMONARY SUBSTUDY) WERE COMPARED WITH 34 HIV-NEGATIVE CONTROLS. DNA METHYLATION WAS PERFORMED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN PLWH COMPARED WITH CONTROLS WERE IDENTIFIED USING A ROBUST LINEAR MODEL. METHYLATION AGE WAS CALCULATED USING A PREVIOUSLY DESCRIBED EPIGENETIC CLOCK. RESULTS: THERE WERE A TOTAL OF 56 639 DMPS AND 6103 DMRS AT A FALSE DISCOVERY RATE OF <0.1. THE TOP 5 DMPS CORRESPONDED TO GENES NLRC5, VRK2, B2M, AND GPR6 AND WERE HIGHLY ENRICHED FOR CANCER-RELATED PATHWAYS. PLWH HAD SIGNIFICANTLY HIGHER METHYLATION AGE THAN HIV-NEGATIVE CONTROLS (P = .001), WITH BLACK RACE, LOW CD4 AND HIGH CD8 T-CELL COUNTS, AND DURATION OF HIV BEING RISK FACTORS FOR AGE ACCELERATION. CONCLUSIONS: PLWH BEFORE THE INITIATION OF ART AND WITH PRESERVED IMMUNE STATUS SHOW EVIDENCE OF ADVANCED METHYLATION AGING.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  382  41 AN EPIGENOME-WIDE STUDY OF BODY MASS INDEX AND DNA METHYLATION IN BLOOD USING PARTICIPANTS FROM THE SISTER STUDY COHORT. BACKGROUND/OBJECTIVES: THE RELATIONSHIP BETWEEN OBESITY AND CHRONIC DISEASE RISK IS WELL-ESTABLISHED; THE UNDERLYING BIOLOGICAL MECHANISMS DRIVING THIS RISK INCREASE MAY INCLUDE OBESITY-RELATED EPIGENETIC MODIFICATIONS. TO EXPLORE THIS HYPOTHESIS, WE CONDUCTED A GENOME-WIDE ANALYSIS OF DNA METHYLATION AND BODY MASS INDEX (BMI) USING DATA FROM A SUBSET OF WOMEN IN THE SISTER STUDY. SUBJECTS/METHODS: THE SISTER STUDY IS A COHORT OF 50 884 US WOMEN WHO HAD A SISTER WITH BREAST CANCER BUT WERE FREE OF BREAST CANCER THEMSELVES AT ENROLLMENT. STUDY PARTICIPANTS COMPLETED EXAMINATIONS WHICH INCLUDED MEASUREMENTS OF HEIGHT AND WEIGHT, AND PROVIDED BLOOD SAMPLES. BLOOD DNA METHYLATION DATA GENERATED WITH THE ILLUMINA INFINIUM HUMANMETHYLATION27 BEADCHIP ARRAY COVERING 27,589 CPG SITES WAS AVAILABLE FOR 871 WOMEN FROM A PRIOR STUDY OF BREAST CANCER AND DNA METHYLATION. TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH BMI, WE ANALYZED THIS METHYLATION DATA USING ROBUST LINEAR REGRESSION WITH ADJUSTMENT FOR AGE AND CASE STATUS. FOR THOSE CPGS PASSING THE FALSE DISCOVERY RATE SIGNIFICANCE LEVEL, WE EXAMINED THE ASSOCIATION IN A REPLICATION SET COMPRISED OF A NON-OVERLAPPING GROUP OF 187 WOMEN FROM THE SISTER STUDY WHO HAD DNA METHYLATION DATA GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. ANALYSIS OF THIS EXPANDED 450 K ARRAY IDENTIFIED ADDITIONAL BMI-ASSOCIATED SITES WHICH WERE INVESTIGATED WITH TARGETED PYROSEQUENCING. RESULTS: FOUR CPG SITES REACHED GENOME-WIDE SIGNIFICANCE (FALSE DISCOVERY RATE (FDR) Q<0.05) IN THE DISCOVERY SET AND ASSOCIATIONS FOR ALL FOUR WERE SIGNIFICANT AT STRICT BONFERRONI CORRECTION IN THE REPLICATION SET. AN ADDITIONAL 23 SITES PASSED FDR IN THE REPLICATION SET AND FIVE WERE REPLICATED BY PYROSEQUENCING IN THE DISCOVERY SET. SEVERAL OF THE GENES IDENTIFIED INCLUDING ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 AND CRHR2 HAVE BEEN LINKED TO OBESITY AND OBESITY-RELATED CHRONIC DISEASES. CONCLUSIONS: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT OBESITY-RELATED EPIGENETIC DIFFERENCES ARE DETECTABLE IN BLOOD AND MAY BE RELATED TO RISK OF CHRONIC DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9 3951  41 LOCUS-SPECIFIC DIFFERENTIAL DNA METHYLATION AND URINARY ARSENIC: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AMONG ADULTS WITH LOW-TO-MODERATE ARSENIC EXPOSURE. BACKGROUND: CHRONIC EXPOSURE TO ARSENIC (AS), A HUMAN TOXICANT AND CARCINOGEN, REMAINS A GLOBAL PUBLIC HEALTH PROBLEM. HEALTH RISKS PERSIST AFTER AS EXPOSURE HAS ENDED, SUGGESTING EPIGENETIC DYSREGULATION AS A MECHANISTIC LINK BETWEEN EXPOSURE AND HEALTH OUTCOMES. OBJECTIVES: WE INVESTIGATED THE ASSOCIATION BETWEEN TOTAL URINARY AS AND LOCUS-SPECIFIC DNA METHYLATION IN THE STRONG HEART STUDY, A COHORT OF AMERICAN INDIAN ADULTS WITH LOW-TO-MODERATE AS EXPOSURE [TOTAL URINARY AS, MEAN (+/-SD) MUG/G CREATININE: 11.7 (10.6)]. METHODS: DNA METHYLATION WAS MEASURED IN 2,325 PARTICIPANTS USING THE ILLUMINA METHYLATIONEPIC ARRAY. WE IMPLEMENTED LINEAR MODELS TO TEST DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND THE DMRCATE METHOD TO IDENTIFY REGIONS (DMRS) AND CONDUCTED GENE ONTOLOGY ENRICHMENT ANALYSIS. MODELS WERE ADJUSTED FOR ESTIMATED CELL TYPE PROPORTIONS, AGE, SEX, BODY MASS INDEX, SMOKING, EDUCATION, ESTIMATED GLOMERULAR FILTRATION RATE, AND STUDY CENTER. ARSENIC WAS MEASURED IN URINE AS THE SUM OF INORGANIC AND METHYLATED SPECIES. RESULTS: IN ADJUSTED MODELS, METHYLATION AT 20 CPGS WAS ASSOCIATED WITH URINARY AS AFTER FALSE DISCOVERY RATE (FDR) CORRECTION (FDR < 0.05). AFTER BONFERRONI CORRECTION, 5 CPGS REMAINED ASSOCIATED WITH TOTAL URINARY AS (PBONFERRONI < 0.05), LOCATED IN SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. WE IDENTIFIED ONE DMR ON CHROMOSOME 11 (CHR11:2,322,050-2,323,247), ANNOTATED TO C11ORF2; TSPAN32 GENES. DISCUSSION: THIS IS ONE OF THE FIRST EPIGENOME-WIDE ASSOCIATION STUDIES TO INVESTIGATE AS EXPOSURE AND LOCUS-SPECIFIC DNA METHYLATION USING THE ILLUMINA METHYLATIONEPIC ARRAY AND THE LARGEST EPIGENOME-WIDE STUDY OF AS EXPOSURE. THE TOP DMP WAS LOCATED IN SLC7A11A, A GENE INVOLVED IN CYSTINE/GLUTAMATE TRANSPORT AND THE BIOSYNTHESIS OF GLUTATHIONE, AN ANTIOXIDANT THAT MAY PROTECT AGAINST AS-INDUCED OXIDATIVE STRESS. ADDITIONAL DMPS WERE LOCATED IN GENES ASSOCIATED WITH TUMOR DEVELOPMENT AND GLUCOSE METABOLISM. FURTHER RESEARCH IS NEEDED, INCLUDING RESEARCH IN MORE DIVERSE POPULATIONS, TO INVESTIGATE WHETHER AS-RELATED DNA METHYLATION SIGNATURES ARE ASSOCIATED WITH GENE EXPRESSION OR MAY SERVE AS BIOMARKERS OF DISEASE DEVELOPMENT. HTTPS://DOI.ORG/10.1289/EHP6263.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10 3063  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11 3995  48 LONGITUDINAL STUDY OF DNA METHYLATION OF INFLAMMATORY GENES AND CANCER RISK. BACKGROUND: CHRONIC INFLAMMATION PLAYS A KEY ROLE IN CANCER ETIOLOGY. DNA METHYLATION MODIFICATION, ONE OF THE EPIGENETIC MECHANISMS REGULATING GENE EXPRESSION, IS CONSIDERED A HALLMARK OF CANCER. HUMAN AND ANIMAL MODELS HAVE IDENTIFIED NUMEROUS LINKS BETWEEN DNA METHYLATION AND INFLAMMATORY BIOMARKERS. OUR OBJECTIVE WAS TO PROSPECTIVELY AND LONGITUDINALLY EXAMINE ASSOCIATIONS BETWEEN METHYLATION OF FOUR INFLAMMATORY GENES AND CANCER RISK. METHODS: WE INCLUDED 795 NORMATIVE AGING STUDY PARTICIPANTS WITH BLOOD DRAWN ONE TO FOUR TIMES FROM 1999 TO 2012 (MEDIAN FOLLOW-UP, 10.6 YEARS). PROMOTER DNA METHYLATION OF IL6, ICAM-1, IFN, AND TLR2 IN BLOOD LEUKOCYTES WAS MEASURED USING PYROSEQUENCING AT MULTIPLE CPG SITES AND AVERAGED BY GENE FOR DATA ANALYSIS. WE USED COX REGRESSION MODELS TO EXAMINE PROSPECTIVE ASSOCIATIONS OF BASELINE AND TIME-DEPENDENT METHYLATION WITH CANCER RISK AND COMPARED MEAN METHYLATION DIFFERENCES OVER TIME BETWEEN CANCER CASES AND CANCER-FREE PARTICIPANTS. RESULTS: BASELINE IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.49; P = 0.04) AND PROSTATE CANCER INCIDENCE (HR, 1.69; P = 0.02). BASELINE ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.43; P = 0.02; HR, 0.70; P = 0.03, RESPECTIVELY). IN OUR TIME-DEPENDENT ANALYSES, IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.79; P = 0.007) AND PROSTATE CANCER (HR, 1.57; P = 0.03) INCIDENCE; AND ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, RESPECTIVELY). WE DETECTED SIGNIFICANT ICAM-1 HYPERMETHYLATION IN CANCER CASES (P = 0.0003) 10 TO 13 YEARS PREDIAGNOSIS. CONCLUSION: HYPERMETHYLATION OF IFN AND ICAM-1 MAY PLAY IMPORTANT ROLES IN EARLY CARCINOGENESIS, PARTICULARLY THAT OF PROSTATE CANCER. IMPACT: THESE METHYLATION CHANGES COULD INFORM THE DEVELOPMENT OF EARLY DETECTION BIOMARKERS AND POTENTIAL TREATMENTS OF INFLAMMATION-RELATED CARCINOGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12 1553  44 DNA METHYLATION LEVELS ASSOCIATED WITH RACE AND CHILDHOOD ASTHMA SEVERITY. OBJECTIVE: ASTHMA IS A COMMON CHRONIC CHILDHOOD DISEASE WORLDWIDE. SOCIOECONOMIC STATUS, GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS CONTRIBUTE TO ITS INCIDENCE AND SEVERITY. A DISPROPORTIONATE NUMBER OF CHILDREN WITH ASTHMA ARE ECONOMICALLY DISADVANTAGED AND LIVE IN SUBSTANDARD HOUSING WITH POTENTIAL INDOOR ENVIRONMENTAL EXPOSURES SUCH AS COCKROACHES, DUST MITES, RODENTS AND MOLDS. THESE EXPOSURES MAY MANIFEST THROUGH EPIGENETIC MECHANISMS THAT CAN LEAD TO CHANGES IN RELEVANT GENE EXPRESSION. WE EXAMINED THE ASSOCIATION OF GLOBAL DNA METHYLATION LEVELS WITH SOCIOECONOMIC STATUS, ASTHMA SEVERITY AND RACE/ETHNICITY. METHODS: WE MEASURED GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD OF CHILDREN WITH ASTHMA ENROLLED IN THE KANSAS CITY SAFE AND HEALTHY HOMES PROGRAM. INCLUSION CRITERIA INCLUDED RESIDING IN THE SAME HOME FOR A MINIMUM OF 4 DAYS PER WEEK AND TOTAL FAMILY INCOME OF LESS THAN 80% OF THE KANSAS CITY MEDIAN FAMILY INCOME. DNA METHYLATION LEVELS WERE QUANTIFIED BY AN IMMUNOASSAY THAT ASSESSED THE PERCENTAGE OF 5-METHYLCYTOSINE. RESULTS: OUR RESULTS INDICATE THAT OVERALL, AFRICAN AMERICAN CHILDREN HAD HIGHER LEVELS OF GLOBAL DNA METHYLATION THAN CHILDREN OF OTHER RACES/ETHNICITIES (P = 0.029). THIS DIFFERENCE WAS MORE PRONOUNCED WHEN SOCIOECONOMIC STATUS AND ASTHMA SEVERITY WERE COUPLED WITH RACE/ETHNICITY (P = 0.042) WHERE LOW-INCOME, AFRICAN AMERICAN CHILDREN WITH PERSISTENT ASTHMA HAD SIGNIFICANTLY ELEVATED METHYLATION LEVELS RELATIVE TO OTHER RACES/ETHNICITIES IN THE SAME CONTEXT (P = 0.006, HEDGES G = 1.14). CONCLUSION: OUR STUDY DEMONSTRATES A SIGNIFICANT INTERACTION EFFECT AMONG GLOBAL DNA METHYLATION LEVELS, ASTHMA SEVERITY, RACE/ETHNICITY, AND SOCIOECONOMIC STATUS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  659  38 BLOOD GLOBAL DNA METHYLATION IS DECREASED IN NON-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS. BACKGROUND: ALTERATIONS IN GLOBAL DNA METHYLATION HAVE BEEN ASSOCIATED WITH OXIDATIVE STRESS (OS). SINCE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY INCREASED OXIDATIVE STRESS WE AIMED TO EVALUATE THE LEVELS OF GLOBAL DNA METHYLATION IN THIS PATIENT GROUP. METHODS: WE ASSESSED METHYLCYTOSINE (MCYT) LEVELS IN DNA FROM BLOOD COLLECTED IN 43 COPD PATIENTS (29 WITH MILD AND 14 WITH MODERATE DISEASE) AND 43 AGE- AND SEX-MATCHED HEALTHY CONTROLS. RESULTS: DNA METHYLATION WAS SIGNIFICANTLY LOWER IN COPD PATIENTS VS. CONTROLS (4.20 +/- 0.18% MCYT VS. 4.29 +/- 0.18% MCYT, P = 0.02). FURTHERMORE, DNA METHYLATION IN COPD PATIENTS WITH MODERATE DISEASE WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH MILD DISEASE (4.14 +/- 0.15% MCYT VS. 4.23 +/- 0.19% MCYT, P < 0.05). UNIVARIATE LOGISTIC REGRESSION ANALYSIS SHOWED THAT LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH PRESENCE OF COPD (CRUDE OR = 0.06, 95% CI 0.00 TO 0.67, P = 0.023). THIS RELATIONSHIP REMAINED SIGNIFICANT AFTER ADJUSTING FOR SEVERAL CONFOUNDERS (OR 0.03, 95% CI 0.00 TO 0.67; P = 0.028). RECEIVER OPERATING CHARACTERISTICS (ROC) CURVE ANALYSIS DEMONSTRATED THE AREA UNDER THE CURVE OF MCYT WAS 0.646, WITH 46.6% SENSITIVITY AND 79.1% SPECIFICITY FOR PRESENCE OF COPD. CONCLUSIONS: THERE WERE NO SIGNIFICANT CORRELATIONS BETWEEN METHYLATION AND OS INDICES. THE PRESENCE AND SEVERITY OF COPD IS ASSOCIATED WITH PROGRESSIVELY LOWER DNA METHYLATION IN BLOOD. HOWEVER, THIS EPIGENETIC ALTERATION SEEMS INDEPENDENT OF OXIDATIVE STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14 3568  35 IMPACT OF INFLAMMATION ON EPIGENETIC DNA METHYLATION - A NOVEL RISK FACTOR FOR CARDIOVASCULAR DISEASE? OBJECTIVE: THE LIFESPAN OF DIALYSIS PATIENTS IS AS SHORT AS IN PATIENTS WITH METASTATIC CANCER DISEASE, MAINLY DUE TO CARDIOVASCULAR DISEASE (CVD). DNA METHYLATION IS AN IMPORTANT CELLULAR MECHANISM MODULATING GENE EXPRESSION ASSOCIATED WITH AGEING, INFLAMMATION AND ATHEROSCLEROTIC PROCESSES. DESIGN: DNA METHYLATION WAS ANALYSED IN PERIPHERAL BLOOD LEUCOCYTES FROM THREE DIFFERENT GROUPS OF CHRONIC KIDNEY DISEASE (CKD) POPULATIONS (37 CKD STAGES 3 AND 4 PATIENTS, 98 CKD STAGE 5 PATIENTS AND 20 PREVALENT HAEMODIALYSIS PATIENTS). THIRTY-SIX HEALTHY SUBJECTS SERVED AS CONTROLS. CLINICAL CHARACTERISTICS (DIABETES MELLITUS, NUTRITIONAL STATUS AND PRESENCE OF CLINICAL CVD), INFLAMMATION AND OXIDATIVE STRESS BIOMARKERS, HOMOCYSTEINE AND GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES (DEFINED AS HPAII/MSPI RATIO BY THE LUMINOMETRIC METHYLATION ASSAY METHOD) WERE EVALUATED. CKD STAGE 5 PATIENTS (N=98) STARTING DIALYSIS TREATMENT WERE FOLLOWED FOR A PERIOD OF 36 +/- 2 MONTHS. RESULTS: INFLAMED PATIENTS HAD LOWER RATIOS OF HPAII/MSPI, INDICATING GLOBAL DNA HYPERMETHYLATION. ANALYSIS BY THE COX REGRESSION MODEL DEMONSTRATED THAT DNA HYPERMETHYLATION (HPAII/MSPI RATIO <MEDIAN) WAS SIGNIFICANTLY ASSOCIATED WITH BOTH ALL-CAUSE (RR 5.0; 95% CI: 1.7-14.8; P<0.01) AND CARDIOVASCULAR (RR 13.9; 95% CI: 1.8-109.3; P<0.05) MORTALITY, EVEN FOLLOWING THE ADJUSTMENT FOR AGE, CVD, DIABETES MELLITUS AND INFLAMMATION. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT GLOBAL DNA HYPERMETHYLATION IS ASSOCIATED WITH INFLAMMATION AND INCREASED MORTALITY IN CKD.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 1847  40 EFFECTS OF VARIOUS ENVIRONMENTS ON EPIGENETIC SETTINGS AND CHROMOSOMAL DAMAGE. AIR POLLUTION IS A DOMINANT ENVIRONMENTAL EXPOSURE FACTOR WITH SIGNIFICANT HEALTH CONSEQUENCES. UNEXPECTEDLY, RESEARCH IN A HEAVILY POLLUTED REGION OF THE CZECH REPUBLIC, WITH TRADITIONAL HEAVY INDUSTRY, REVEALED REPEATEDLY THE LOWEST FREQUENCY OF MICRONUCLEI IN THE SEASON WITH THE HIGHEST CONCENTRATIONS OF AIR POLLUTANTS INCLUDING CARCINOGENIC BENZO[A]PYRENE (B[A]P). MOLECULAR FINDINGS HAVE BEEN COLLECTED FOR MORE THAN 10 YEARS FROM VARIOUS LOCATIONS OF THE CZECH REPUBLIC, WITH DIFFERING QUALITY OF AMBIENT AIR. PRELIMINARY CONCLUSIONS HAVE SUGGESTED ADAPTATION OF THE POPULATION FROM THE POLLUTED LOCALITY (OSTRAVA, MORAVIAN-SILESIAN REGION (MSR)) TO CHRONIC AIR POLLUTION EXPOSURE. IN THIS STUDY WE UTILIZE THE PREVIOUS FINDINGS AND, FOR THE FIRST TIME, INVESTIGATE MICRONUCLEI (MN) FREQUENCY BY TYPE: (I) CENTROMERE POSITIVE (CEN+) MN, REPRESENTING CHROMOSOMAL LOSSES, AND (II) CENTROMERE NEGATIVE (CEN-) MN REPRESENTING CHROMOSOMAL BREAKS. AS PREVIOUS RESULTS INDICATED DIFFERENCES BETWEEN POPULATIONS IN THE EXPRESSION OF XRCC5, A GENE INVOLVED IN THE NON-HOMOLOGOUS END-JOINING (NHEJ) REPAIR PATHWAY, POSSIBLE VARIATIONS IN EPIGENETIC SETTINGS IN THIS GENE WERE ALSO INVESTIGATED. THIS NEW RESEARCH WAS CONDUCTED IN TWO SEASONS IN THE GROUPS FROM TWO LOCALITIES WITH DIFFERENT AIR QUALITY LEVELS (OSTRAVA (OS) AND PRAGUE (PG)). THE OBTAINED NEW RESULTS SHOW SIGNIFICANTLY LOWER FREQUENCIES OF CHROMOSOMAL BREAKS IN THE OS SUBJECTS, RELATED TO THE HIGHEST AIR POLLUTION LEVELS (P < 0.001). IN CONTRAST, CHROMOSOMAL LOSSES WERE COMPARABLE BETWEEN BOTH GROUPS. IN ADDITION, SIGNIFICANTLY LOWER DNA METHYLATION WAS FOUND IN 14.3% OF THE ANALYZED CPG LOCI OF XRCC5 IN THE POPULATION FROM OS. IN CONCLUSION, THE EPIGENETIC ADAPTATION (HYPOMETHYLATION) IN XRCC5 INVOLVED IN THE NHEJ REPAIR PATHWAY IN THE POPULATION FROM THE POLLUTED REGION, WAS SUGGESTED AS A REASON FOR THE REDUCED LEVEL OF CHROMOSOMAL BREAKS. FURTHER RESEARCH IS NEEDED TO EXPLORE THE ADDITIONAL MECHANISMS, INCLUDING GENETIC ADAPTATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 2716  31 EXERCISE-MODULATED EPIGENETIC MARKERS AND INFLAMMATORY RESPONSE IN COPD INDIVIDUALS: A PILOT STUDY. THE STUDY INVESTIGATED THE EFFECTS OF EXERCISE ON EPIGENETIC SIGNALS AND SYSTEMIC CYTOKINE LEVELS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDIVIDUALS. TEN PARTICIPANTS OF A PULMONARY REHABILITATION PROGRAM WERE SUBMITTED TO 24 SESSIONS OF A SUPERVISIONED EXERCISE PROTOCOL THRICE-WEEKLY (90MIN/SESSION). BLOOD SAMPLES WERE COLLECTED AT BASELINE, AFTER THE 1ST SESSION, BEFORE AND AFTER THE 24TH SESSION. A DNA HYPOMETHYLATION STATUS WAS OBSERVED AFTER THE 1ST SESSION WHEN COMPARED AT BASELINE, WHILE GLOBAL HISTONE H4 ACETYLATION STATUS WAS UNALTERED IN ANY TIME-POINTS EVALUATED. NO SIGNIFICANT CHANGES WERE OBSERVED ON CYTOKINE LEVELS AFTER THE 1ST SESSION. A SIGNIFICANT ENHANCEMENT ON INTERLEUKIN 6 (IL-6) AND A DECREASE ON TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) LEVELS WERE FOUND AFTER THE 24TH SESSION WHEN COMPARED TO THE PRE 24TH SESSION. MOREOVER, 23 SESSIONS OF EXERCISE WERE ABLE TO DIMINISH SIGNIFICANTLY THE BASAL LEVELS OF IL-6 AND INTERLEUKIN 8 (IL-8). THESE DATA SUGGEST A POTENTIAL ROLE OF EPIGENETIC MACHINERY IN MEDIATING THE ANTI-INFLAMMATORY EFFECTS OF EXERCISE IN COPD PATIENTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 5722  38 SISTER CHROMATID EXCHANGE AND PROLIFERATIVE RATE INDEX IN THE LONGITUDINAL RISK ASSESSMENT OF OCCUPATIONAL EXPOSURE TO PESTICIDES. AT PRESENT, THERE ARE MORE THAN 1,000 CHEMICALS CLASSIFIED AS PESTICIDES AND MANY REPORTS HAVE SHOWN THAT SOME OF THEM HAVE GENOTOXIC PROPERTIES. IN THE PRESENT LONGITUDINAL STUDY, POSSIBLE GENETIC DAMAGE ON A POPULATION OF WORKERS OCCUPATIONALLY EXPOSED TO A MIXTURE OF PESTICIDES BY USING SISTER CHROMATID EXCHANGE (SCE) ANALYSIS HAS BEEN EVALUATED. AS AN ADDITIONAL CYTOGENETIC PARAMETER, THE PROPORTION OF LYMPHOCYTES THAT UNDERGO ONE, TWO OR THREE CELL DIVISIONS AS WELL AS PROLIFERATIVE RATE INDEX HAVE BEEN DETERMINED. THIS STUDY WAS PERFORMED ON THE EXPOSED GROUP OF WORKERS EMPLOYED IN PESTICIDE PRODUCTION, SIMULTANEOUSLY EXPOSED TO A COMPLEX MIXTURE OF PESTICIDES (ATRAZINE, ALACHLOR, CYANAZINE, 2,4-DICHLOROPHENOXYACETIC ACID, AND MALATHION). THE BLOOD SAMPLES OF THE EXPOSED SUBJECTS WERE COLLECTED IN THREE DIFFERENT PERIODS: BEFORE THE BEGINNING OF THE NEW PESTICIDE PRODUCTION PERIOD, AFTER 8 MONTHS OF EVERYDAY WORK IN THE PESTICIDE PRODUCTION, AND 8 MONTHS AFTER THE REMOVAL OF SUBJECTS OUT OF THE PRODUCTION. IN ALL THREE SAMPLINGS, THE MEAN VALUE OF SCE AND NUMBER OF CELLS WITH HIGH SISTER CHROMATID EXCHANGE FREQUENCY (HFC) IN THE EXPOSED GROUP WAS SIGNIFICANTLY HIGHER IN THE COMPARISON WITH THE CONTROL GROUP. THERE WERE NO DIFFERENCES IN THE PROLIFERATIVE RATE INDEX (PRI) BETWEEN THE CONTROL AND EXPOSED GROUP, REGARDLESS OF THE SAMPLING PERIOD. IN BOTH GROUPS EXAMINED, THE MAJORITY OF LYMPHOCYTES WERE FOUND IN THE SECOND CELL DIVISION, FOLLOWING CULTIVATION. THESE RESULTS SUGGEST THAT THE INCREASE IN THE NUMBER OF SCE FOUND IN THE EXPOSED SUBJECTS IS NOT THE RESULT OF EITHER CYTOTOXIC OR EPIGENETIC ACTION OF PESTICIDE MIXTURE, BUT CHRONIC OCCUPATIONAL EXPOSURE TO MIXTURE OF PESTICIDES.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 1512  45 DNA METHYLATION AND PROTEIN MARKERS OF CHRONIC INFLAMMATION AND THEIR ASSOCIATIONS WITH BRAIN AND COGNITIVE AGING. BACKGROUND AND OBJECTIVES: TO INVESTIGATE CHRONIC INFLAMMATION IN RELATION TO COGNITIVE AGING BY COMPARISON OF AN EPIGENETIC AND SERUM BIOMARKER OF C-REACTIVE PROTEIN AND THEIR ASSOCIATIONS WITH NEUROIMAGING AND COGNITIVE OUTCOMES. METHODS: AT BASELINE, PARTICIPANTS (N = 521) WERE COGNITIVELY NORMAL, AROUND 73 YEARS OF AGE (MEAN 72.4, SD 0.716), AND HAD INFLAMMATION, VASCULAR RISK (CARDIOVASCULAR DISEASE HISTORY, HYPERTENSION, DIABETES, SMOKING, ALCOHOL CONSUMPTION, BODY MASS INDEX), AND NEUROIMAGING (STRUCTURAL AND DIFFUSION MRI) DATA AVAILABLE. BASELINE INFLAMMATORY STATUS WAS QUANTIFIED BY A TRADITIONAL MEASURE OF PERIPHERAL INFLAMMATION-SERUM C-REACTIVE PROTEIN (CRP)-AND AN EPIGENETIC MEASURE (DNA METHYLATION [DNAM] SIGNATURE OF CRP). LINEAR MODELS WERE USED TO EXAMINE THE INFLAMMATION-BRAIN HEALTH ASSOCIATIONS; MEDIATION ANALYSES WERE PERFORMED TO INTERROGATE THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION, BRAIN STRUCTURE, AND COGNITIVE FUNCTIONING. RESULTS: WE DEMONSTRATE THAT DNAM CRP SHOWS SIGNIFICANTLY (ON AVERAGE 6.4-FOLD) STRONGER ASSOCIATIONS WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP. DNAM CRP IS ASSOCIATED WITH TOTAL BRAIN VOLUME (BETA = -0.197, 95% CONFIDENCE INTERVAL [CI] -0.28 TO -0.12, P (FDR) = 8.42 X 10(-6)), GRAY MATTER VOLUME (BETA = -0.200, 95% CI -0.28 TO -0.12, P (FDR) = 1.66 X 10(-5)), AND WHITE MATTER VOLUME (BETA = -0.150, 95% CI -0.23 TO -0.07, P (FDR) = 0.001) AND REGIONAL BRAIN ATROPHY. WE ALSO FIND THAT DNAM CRP HAS AN INVERSE ASSOCIATION WITH GLOBAL AND DOMAIN-SPECIFIC (SPEED, VISUOSPATIAL, AND MEMORY) COGNITIVE FUNCTIONING AND THAT BRAIN STRUCTURE PARTIALLY MEDIATES THIS CRP-COGNITIVE ASSOCIATION (UP TO 29.7%), DEPENDENT ON LIFESTYLE AND HEALTH FACTORS. DISCUSSION: THESE RESULTS SUPPORT THE HYPOTHESIS THAT CHRONIC INFLAMMATION MAY CONTRIBUTE TO NEURODEGENERATIVE BRAIN CHANGES THAT UNDERLIE DIFFERENCES IN COGNITIVE ABILITY IN LATER LIFE AND HIGHLIGHT THE POTENTIAL OF DNAM PROXIES FOR INDEXING CHRONIC INFLAMMATORY STATUS. CLASSIFICATION OF EVIDENCE: THIS STUDY PROVIDES CLASS II EVIDENCE THAT A DNAM SIGNATURE OF CRP LEVELS IS MORE STRONGLY ASSOCIATED WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 1573  42 DNA METHYLATION PATTERNS IN NEWBORNS EXPOSED TO TOBACCO IN UTERO. BACKGROUND: MATERNAL SMOKING DURING PREGNANCY IS A MAJOR RISK FACTOR FOR ADVERSE HEALTH OUTCOMES. THE MAIN OBJECTIVE OF THE STUDY WAS TO ASSESS THE IMPACT OF IN UTERO TOBACCO EXPOSURE ON DNA METHYLATION IN CHILDREN BORN AT TERM WITH APPROPRIATE WEIGHT AT BIRTH. METHODS: TWENTY MOTHER-NEWBORN DYADS, AFTER UNCOMPLICATED PREGNANCIES, IN THE ABSENCE OF PERINATAL ILLNESS WERE INCLUDED. ALL MOTHERS WERE HEALTHY WITH NO CARDIOVASCULAR RISK FACTORS, EXCEPT FOR THE ASSOCIATED RISKS AMONG THOSE MOTHERS WHO SMOKED. UMBILICAL CORD BLOOD AND MATERNAL PERIPHERAL VENOUS BLOOD WERE COLLECTED AND AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING A 450 K EPIGENOME-WIDE SCAN (ILLUMINA INFINIUM HUMANMETHYLATION 450BEADCHIP) WITH ADJUSTMENT TO NORMALIZE THE DNA METHYLATION FOR DATA CELL VARIABILITY IN WHOLE BLOOD. RESULTS: THE MATERNAL PLASMATIC COTININE LEVELS RANGED FROM 10.70-115.40 NG/ML IN THE EXPOSED GROUP TO 0-0.59 NG/ML IN THE NON-EXPOSED GROUP. AFTER ADJUSTING FOR MULTIPLE COMPARISONS IN 427102 PROBES, STATISTICALLY SIGNIFICANT DIFFERENCES FOR 31 CPG SITES, ASSOCIATED TO 25 GENES WERE OBSERVED. THERE WAS A GREATER THAN EXPECTED PROPORTION OF STATISTICALLY-SIGNIFICANT LOCI LOCATED IN CPG ISLANDS (FISHER'S EXACT TEST, P = 0.029) AND OF THOSE CPG ISLANDS, 90.3% EXHIBIT HIGHER METHYLATION LEVELS IN THE EXPOSED GROUP. THE MOST STRIKING AND SIGNIFICANT CPG SITE, CG05727225, IS LOCATED IN THE CHROMOSOME 11P15.4, WITHIN THE ADRENOMEDULLIN GENE. CONCLUSIONS: IN UTERO TOBACCO EXPOSURE, EVEN IN THE ABSENCE OF FETAL GROWTH RESTRICTION, MAY ALTER THE EPIGENOME, CONTRIBUTING TO GLOBAL DNA HYPOMETHYLATION. THEREFORE, DNA STATUS CAN BE USED AS A BIOMARKER OF PRENATAL INSULTS. CONSIDERING THE POSSIBILITY TO REVERSE EPIGENETIC MODIFICATIONS, A WINDOW OF OPPORTUNITY EXISTS TO CHANGE THE PROGRAMMED CHRONIC DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20  832  46 CHARACTERIZING OPRM1 DNA METHYLATION IN PRESCRIPTION OPIOID USERS WITH CHRONIC MUSCULOSKELETAL PAIN. INTRODUCTION: MANY PATIENTS WITH CHRONIC PAIN USE PRESCRIPTION OPIOIDS. EPIGENETIC MODIFICATION OF THE MU-OPIOID RECEPTOR 1 (OPRM1) GENE, WHICH CODES FOR THE TARGET PROTEIN OF OPIOIDS, MAY INFLUENCE VULNERABILITY TO OPIOID ABUSE AND RESPONSE TO OPIOID PHARMACOTHERAPY, POTENTIALLY AFFECTING PAIN OUTCOMES. OBJECTIVE: OUR OBJECTIVE WAS TO INVESTIGATE ASSOCIATIONS OF CLINICAL AND SOCIODEMOGRAPHIC FACTORS WITH OPRM1 DNA METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN ON LONG-TERM PRESCRIPTION OPIOIDS. METHODS: SOCIODEMOGRAPHIC VARIABLES, SURVEY DATA (RAPID ESTIMATE OF ADULT HEALTH LITERACY IN MEDICINE-SHORT FORM, FUNCTIONAL COMORBIDITY INDEX [FCI], PROMIS 43V2.1 PROFILE, OPIOID RISK TOOL, AND PROMIS PRESCRIPTION PAIN MEDICATION MISUSE), AND SALIVA SAMPLES WERE COLLECTED. THE GENOMIC DNA EXTRACTED FROM SALIVA SAMPLES WERE BISULFITE CONVERTED, AMPLIFIED BY POLYMERASE CHAIN REACTION, AND PROCESSED FOR OPRM1-TARGETED DNA METHYLATION ANALYSIS ON A PYROSEQUENCING INSTRUMENT (QIAGEN INC, VALENCIA, CA). GENERAL LINEAR MODELS WERE USED TO EXAMINE THE RELATIONSHIPS BETWEEN THE PREDICTORS AND OPRM1 DNA METHYLATION. RESULTS: DATA FROM 112 PATIENTS WERE ANALYZED. THE BEST-FITTED MULTIVARIABLE MODEL INDICATED, COMPARED WITH THEIR COUNTERPARTS, PATIENTS WITH > EIGHTH GRADE READING LEVEL, DEGENERATIVE DISK DISEASE, SUBSTANCE ABUSE COMORBIDITY, AND OPIOID USE < 1 YEAR (COMPARED WITH >5 YEARS), HAD AVERAGE METHYLATION LEVELS THAT WERE 7.7% (95% CONFIDENCE INTERVAL [CI] 0.95%, 14.4%), 11.7% (95% CI 2.7%, 21.1%), 21.7% (95% CI 10.7%, 32.5%), AND 16.1% (95% CI 3.3%, 28.8%) HIGHER THAN THE REFERENCE GROUPS, RESPECTIVELY. METHYLATION LEVELS WERE 2.2% (95% CI 0.64%, 3.7%) LOWER FOR EVERY 1 UNIT INCREASE IN FCI AND GREATER BY 0.45% (95% CI 0.08%, 0.82%) FOR EVERY FATIGUE T SCORE UNIT INCREASE. CONCLUSIONS: OPRM1 METHYLATION LEVELS VARIED BY SEVERAL PATIENT FACTORS. FURTHER STUDIES ARE WARRANTED TO REPLICATE THESE FINDINGS AND DETERMINE POTENTIAL CLINICAL UTILITY.	2022