1  3505 141 IDENTIFICATION OF SEX-SPECIFIC DNA METHYLATION CHANGES DRIVEN BY SPECIFIC CHEMICALS IN CORD BLOOD IN A FAROESE BIRTH COHORT. FAROE ISLANDERS CONSUME MARINE FOODS CONTAMINATED WITH METHYLMERCURY (MEHG), POLYCHLORINATED BIPHENYLS (PCBS), AND OTHER TOXICANTS ASSOCIATED WITH CHRONIC DISEASE RISKS. DIFFERENTIAL DNA METHYLATION AT SPECIFIC CPG SITES IN CORD BLOOD MAY SERVE AS A SURROGATE BIOMARKER OF HEALTH IMPACTS FROM CHEMICAL EXPOSURES. WE AIMED TO IDENTIFY KEY ENVIRONMENTAL CHEMICALS IN CORD BLOOD ASSOCIATED WITH DNA METHYLATION CHANGES IN A POPULATION WITH ELEVATED EXPOSURE TO CHEMICAL MIXTURES. WE STUDIED 72 PARTICIPANTS OF A FAROESE BIRTH COHORT RECRUITED BETWEEN 1986 AND 1987 AND FOLLOWED UNTIL ADULTHOOD. THE CORD BLOOD DNA METHYLOME WAS PROFILED USING INFINIUM HUMANMETHYLATION450 BEADCHIPS. WE DETERMINED THE ASSOCIATIONS OF CPG SITE CHANGES WITH CONCENTRATIONS OF MEHG, MAJOR PCBS, OTHER ORGANOCHLORINE COMPOUNDS [HEXACHLOROBENZENE (HCB), P,P'-DICHLORODIPHENYLDICHLOROETHYLENE (P,P'-DDE) AND P,P'-DICHLORODIPHENYLTRICHLOROETHANE], AND PERFLUOROALKYL SUBSTANCES. IN A COMBINED SEX ANALYSIS, AMONG THE 16 CHEMICALS STUDIED, PCB CONGENER 105 (CB-105) EXPOSURE WAS ASSOCIATED WITH THE MAJORITY OF DIFFERENTIALLY METHYLATED CPG SITES (214 OUT OF A TOTAL OF 250). IN FEMALE-ONLY ANALYSIS, ONLY 73 CB-105 ASSOCIATED CPG SITES WERE DETECTED, 44 OF WHICH WERE MAPPED TO GENES IN THE ELAV1-ASSOCIATED CANCER NETWORK. IN MALES-ONLY, METHYLATION CHANGES WERE SEEN FOR PERFLUOROOCTANE SULFONATE, HCB, AND P,P'-DDE IN 10,598, 1,238, AND 1,473 CPG SITES, RESPECTIVELY, 15% OF WHICH WERE ENRICHED IN CYTOBANDS OF THE X-CHROMOSOME ASSOCIATED WITH NEUROLOGICAL DISORDERS. IN THIS MULTIPLE-POLLUTANT AND GENOME-WIDE STUDY, WE IDENTIFIED KEY EPIGENETIC TOXICANTS. THE SIGNIFICANT ENRICHMENT OF SPECIFIC X-CHROMOSOME SITES IN MALES IMPLIES POTENTIAL SEX-SPECIFIC EPIGENOME RESPONSES TO PRENATAL CHEMICAL EXPOSURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2  1588  47 DNA METHYLATION PROFILING IMPLICATES EXPOSURE TO PCBS IN THE PATHOGENESIS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA. OBJECTIVES: TO CHARACTERIZE THE IMPACT OF PCB EXPOSURE ON DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES AND TO EVALUATE THE CORRESPONDING CHANGES IN RELATION TO POSSIBLE HEALTH EFFECTS, WITH A FOCUS ON B-CELL LYMPHOMA. METHODS: WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY ON 611 ADULTS FREE OF DIAGNOSED DISEASE, LIVING IN ITALY AND SWEDEN, IN WHOM WE ALSO MEASURED PLASMA CONCENTRATIONS OF 6 PCB CONGENERS, DDE AND HEXACHLOROBENZENE. RESULTS: WE IDENTIFIED 650 CPG SITES WHOSE METHYLATION CORRELATES STRONGLY (FDR < 0.01) WITH PLASMA CONCENTRATIONS OF AT LEAST ONE PCB CONGENER. STRONGER EFFECTS WERE OBSERVED IN MALES AND IN SWEDEN. THIS EPIGENETIC EXPOSURE PROFILE SHOWS EXTENSIVE AND HIGHLY STATISTICALLY SIGNIFICANT OVERLAPS WITH PUBLISHED PROFILES ASSOCIATED WITH THE RISK OF FUTURE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS WELL AS WITH CLINICAL CLL (38 AND 28 CPG SITES, RESPECTIVELY). FOR ALL THESE SITES, THE METHYLATION CHANGES WERE IN THE SAME DIRECTION FOR INCREASING EXPOSURE AND FOR HIGHER DISEASE RISK OR CLINICAL DISEASE STATUS, SUGGESTING AN ETIOLOGICAL LINK BETWEEN EXPOSURE AND CLL. MEDIATION ANALYSIS REINFORCED THE SUGGESTION OF A CAUSAL LINK BETWEEN EXPOSURE, CHANGES IN DNA METHYLATION AND DISEASE. DISEASE CONNECTIVITY ANALYSIS IDENTIFIED MULTIPLE ADDITIONAL DISEASES ASSOCIATED WITH DIFFERENTIALLY METHYLATED GENES, INCLUDING MELANOMA FOR WHICH AN ETIOLOGICAL LINK WITH PCB EXPOSURE IS ESTABLISHED, AS WELL AS DEVELOPMENTAL AND NEUROLOGICAL DISEASES FOR WHICH THERE IS CORRESPONDING EPIDEMIOLOGICAL EVIDENCE. DIFFERENTIALLY METHYLATED GENES INCLUDE MANY HOMEOBOX GENES, SUGGESTING THAT PCBS TARGET STEM CELLS. FURTHERMORE, NUMEROUS POLYCOMB PROTEIN TARGET GENES WERE HYPERMETHYLATED WITH INCREASING EXPOSURE, AN EFFECT KNOWN TO CONSTITUTE AN EARLY MARKER OF CARCINOGENESIS. CONCLUSIONS: THIS STUDY PROVIDES MECHANISTIC EVIDENCE IN SUPPORT OF A LINK BETWEEN EXPOSURE TO PCBS AND THE ETIOLOGY OF CLL AND UNDERLINES THE UTILITY OF OMIC PROFILING IN THE EVALUATION OF THE POTENTIAL TOXICITY OF ENVIRONMENTAL CHEMICALS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3   502  47 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  1956  34 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                       
5  3063  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  5463  36 RESIDENTIAL PM(2.5) EXPOSURE AND THE NASAL METHYLOME IN CHILDREN. RATIONALE: PM(2.5-)INDUCED ADVERSE EFFECTS ON RESPIRATORY HEALTH MAY BE DRIVEN BY EPIGENETIC MODIFICATIONS IN AIRWAY CELLS. THE POTENTIAL IMPACT OF EXPOSURE DURATION ON EPIGENETIC ALTERATIONS IN THE AIRWAYS IS NOT YET KNOWN. OBJECTIVES: WE AIMED TO STUDY ASSOCIATIONS OF FINE PARTICULATE MATTER PM(2.5) EXPOSURE WITH DNA METHYLATION IN NASAL CELLS. METHODS: WE CONDUCTED NASAL EPIGENOME-WIDE ASSOCIATION ANALYSES WITHIN 503 CHILDREN FROM PROJECT VIVA (MEAN AGE 12.9 Y), AND EXAMINED VARIOUS EXPOSURE DURATIONS (1-DAY, 1-WEEK, 1-MONTH, 3-MONTHS AND 1-YEAR) PRIOR TO NASAL SAMPLING. WE USED RESIDENTIAL ADDRESSES TO ESTIMATE AVERAGE DAILY PM(2.5) AT 1 KM RESOLUTION. WE COLLECTED NASAL SWABS FROM THE ANTERIOR NARES AND MEASURED DNA METHYLATION (DNAM) USING THE ILLUMINA METHYLATIONEPIC BEADCHIP. WE TESTED 719,075 HIGH QUALITY AUTOSOMAL CPGS USING CPG-BY-CPG AND REGIONAL DNAM ANALYSES CONTROLLING FOR MULTIPLE COMPARISONS, AND ADJUSTED FOR MATERNAL EDUCATION, HOUSEHOLD SMOKERS, CHILD SEX, RACE/ETHNICITY, BMI Z-SCORE, AGE, SEASON AT SAMPLE COLLECTION AND CELL-TYPE HETEROGENEITY. WE FURTHER CORRECTED FOR BIAS AND GENOMIC INFLATION. WE TESTED FOR REPLICATION IN A COHORT FROM THE NETHERLANDS (PIAMA). RESULTS: IN ADJUSTED ANALYSES, WE FOUND 362 CPGS ASSOCIATED WITH 1-YEAR PM(2.5) (FDR < 0.05), 20 CPGS PASSING BONFERRONI CORRECTION (P < 7.0X10(-8)) AND 10 DIFFERENTIALLY METHYLATED REGIONS (DMRS). IN 445 PIAMA PARTICIPANTS (MEAN AGE 16.3 YEARS) 11 OF 203 AVAILABLE CPGS REPLICATED AT P < 0.05. WE OBSERVED DIFFERENTIAL DNAM AT/NEAR GENES IMPLICATED IN CELL CYCLE, IMMUNE AND INFLAMMATORY RESPONSES. THERE WERE NO CPGS OR REGIONS ASSOCIATED WITH PM(2.5) LEVELS AT 1-DAY, 1-WEEK, OR 1-MONTH PRIOR TO SAMPLE COLLECTION, ALTHOUGH 2 CPGS WERE ASSOCIATED WITH PAST 3-MONTH PM(2.5). CONCLUSION: WE OBSERVED WIDE-SPREAD DNAM VARIABILITY ASSOCIATED WITH AVERAGE PAST YEAR PM(2.5) EXPOSURE BUT WE DID NOT DETECT ASSOCIATIONS WITH SHORTER-TERM EXPOSURE. OUR RESULTS SUGGEST THAT NASAL DNAM MARKS REFLECT CHRONIC AIR POLLUTION EXPOSURE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7   713  39 CADMIUM EXPOSURE AND AGE-ASSOCIATED DNA METHYLATION CHANGES IN NON-SMOKING WOMEN FROM NORTHERN THAILAND. DNA METHYLATION CHANGES WITH AGE, AND MAY SERVE AS A BIOMARKER OF AGING. CADMIUM (CD) MODIFIES CELLULAR PROCESSES THAT PROMOTE AGING AND DISRUPTS METHYLATION GLOBALLY. WHETHER CD MODIFIES AGING PROCESSES BY INFLUENCING ESTABLISHMENT OF AGE-ASSOCIATED METHYLATION MARKS IS CURRENTLY UNKNOWN. IN THIS PILOT STUDY, WE CHARACTERIZED METHYLATION PROFILES IN > 450 000 CPG SITES IN 40 NON-SMOKING WOMEN (AGE 40-80) DIFFERENTIALLY EXPOSED TO ENVIRONMENTAL CD FROM THAILAND. BASED ON SPECIFIC GRAVITY ADJUSTED URINARY CD, WE CLASSIFIED THEM AS HIGH (HE) AND LOW (LE) EXPOSED AND AGE-MATCHED WITHIN 5 YEARS. URINARY CD WAS DEFINED AS BELOW 2 MICROG/L IN THE LE GROUP. WE PREDICTED EPIGENETIC AGE (DNAM-AGE) USING TWO PUBLISHED METHODS BY HORVATH AND HANNUM AND EXAMINED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGIC AGE (DELTAAGE). WE ASSESSED DIFFERENCES BY CD EXPOSURE USING LINEAR MIXED MODELS ADJUSTED FOR ESTIMATED WHITE BLOOD CELL PROPORTIONS, BMI, AND URINARY CREATININE. WE IDENTIFIED 213 AGE-ASSOCIATED CPG SITES IN OUR POPULATION (P < 10(-4)). COUNTERINTUITIVELY, THE MEAN DELTAAGE WAS SMALLER IN HE VS. LE (HANNUM: 3.6 VS. 7.6 YEARS, P = 0.0093; HORVATH: 2.4 VS. 4.5 YEARS, P = 0.1308). THE CD EXPOSED GROUP WAS ASSOCIATED WITH CHANGES IN METHYLATION (P < 0.05) AT 12, 8, AND 20 AGE-ASSOCIATED SITES IDENTIFIED IN OUR POPULATION, HANNUM, AND HORVATH. FROM THE RESULTS OF THIS PILOT STUDY, ELEVATED CD EXPOSURE IS ASSOCIATED WITH METHYLATION CHANGES AT AGE-ASSOCIATED SITES AND SMALLER DIFFERENCES BETWEEN DNAM-AGE AND CHRONOLOGIC AGE, IN CONTRAST TO EXPECTED AGE-ACCELERATING EFFECTS. CD MAY MODIFY EPIGENETIC AGING, AND BIOMARKERS OF AGING WARRANT FURTHER INVESTIGATION WHEN EXAMINING CD AND ITS RELATIONSHIP WITH CHRONIC DISEASE AND MORTALITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  6460  31 TIME TO RELAPSE IN CHRONIC LYMPHOCYTIC LEUKEMIA AND DNA-METHYLATION-BASED BIOLOGICAL AGE. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MATURE B CELL NEOPLASM WITH A PREDILECTION FOR OLDER INDIVIDUALS. WHILE PREVIOUS STUDIES HAVE IDENTIFIED EPIGENETIC SIGNATURES ASSOCIATED WITH CLL, WHETHER AGE-RELATED DNA METHYLATION CHANGES MODULATE CLL RELAPSE REMAINS ELUSIVE. IN THIS STUDY, WE EXAMINED THE ASSOCIATION BETWEEN EPIGENETIC AGE ACCELERATION AND TIME TO CLL RELAPSE IN A PUBLICLY AVAILABLE DATASET. DNA METHYLATION PROFILING OF 35 CLL PATIENTS PRIOR TO INITIATING CHEMOIMMUNOTHERAPY WAS PERFORMED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP. FOUR EPIGENETIC AGE ACCELERATION METRICS (INTRINSIC EPIGENETIC AGE ACCELERATION [IEAA], EXTRINSIC EPIGENETIC AGE ACCELERATION [EEAA], PHENOAGE ACCELERATION [PHENOAA], AND GRIMAGE ACCELERATION [GRIMAA]) WERE ESTIMATED FROM BLOOD DNA METHYLATION LEVELS. LINEAR, QUANTILE, AND LOGISTIC REGRESSION AND RECEIVER OPERATING CHARACTERISTIC CURVE ANALYSES WERE CONDUCTED TO ASSESS THE ASSOCIATION BETWEEN EACH EPIGENETIC AGE METRIC AND TIME TO CLL RELAPSE. EEAA (P = 0.011) AND PHENOAA (P = 0.046) WERE NEGATIVELY AND GRIMAA (P = 0.040) WAS POSITIVELY ASSOCIATED WITH TIME TO CLL RELAPSE. SIMULTANEOUS ASSESSMENT OF EEAA AND GRIMAA IN MALE PATIENTS DISTINGUISHED PATIENTS WHO RELAPSED EARLY FROM PATIENTS WHO RELAPSED LATER (P = 0.039). NO ASSOCIATIONS WERE OBSERVED WITH IEAA. THESE FINDINGS SUGGEST EPIGENETIC AGE ACCELERATION PRIOR TO CHEMOIMMUNOTHERAPY INITIATION IS ASSOCIATED WITH TIME TO CLL RELAPSE. OUR RESULTS PROVIDE NOVEL INSIGHT INTO THE ASSOCIATION BETWEEN AGE-RELATED DNA METHYLATION CHANGES AND CLL RELAPSE AND MAY SERVE HAS BIOMARKERS FOR TREATMENT RELAPSE, AND POTENTIALLY, TREATMENT SELECTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9   490  31 ASSESSING THE IMPACT OF ARSENIC METABOLISM EFFICIENCY ON DNA METHYLATION USING MENDELIAN RANDOMIZATION. BACKGROUND: ARSENIC EXPOSURE AFFECTS >100 MILLION PEOPLE GLOBALLY AND INCREASES RISK FOR CHRONIC DISEASES. ONE POSSIBLE TOXICITY MECHANISM IS EPIGENETIC MODIFICATION. PREVIOUS EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG-SPECIFIC DNA METHYLATION. TO PROVIDE ADDITIONAL EVIDENCE THAT OBSERVED ASSOCIATIONS REPRESENT CAUSAL RELATIONSHIPS, WE EXAMINE THE ASSOCIATION BETWEEN GENETIC DETERMINANTS OF ARSENIC METABOLISM EFFICIENCY (PERCENT DIMETHYLARSINIC ACID, DMA%, IN URINE) AND DNA METHYLATION AMONG INDIVIDUALS FROM THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (N = 379) AND BANGLADESH VITAMIN E AND SELENIUM TRIAL (N = 393). METHODS: WE USED MULTIVARIATE LINEAR MODELS TO ASSESS THE ASSOCIATION OF METHYLATION AT 221 ARSENIC-ASSOCIATED CPGS WITH DMA% AND MEASURES OF GENETICALLY PREDICTED DMA% DERIVED FROM THREE SNPS (RS9527, RS11191527, AND RS61735836). WE ALSO CONDUCTED TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES TO ESTIMATE THE ASSOCIATION BETWEEN ARSENIC METABOLISM EFFICIENCY AND CPG METHYLATION. RESULTS: AMONG THE ASSOCIATIONS BETWEEN DMA% AND METHYLATION AT EACH OF 221 CPGS, 64% WERE DIRECTIONALLY CONSISTENT WITH ASSOCIATIONS OBSERVED BETWEEN ARSENIC EXPOSURE AND THE 221 CPGS FROM A PRIOR EWAS. SIMILARLY, AMONG THE ASSOCIATIONS BETWEEN GENETICALLY PREDICTED DMA% AND EACH CPG, 62% WERE DIRECTIONALLY CONSISTENT WITH THE PRIOR EWAS RESULTS. TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES PRODUCED SIMILAR CONCLUSIONS. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT ARSENIC EXPOSURE EFFECTS DNA METHYLATION AT SPECIFIC CPGS IN WHOLE BLOOD. OUR NOVEL APPROACH FOR ASSESSING THE IMPACT OF ARSENIC EXPOSURE ON DNA METHYLATION REQUIRES LARGER SAMPLES IN ORDER TO DRAW MORE ROBUST CONCLUSIONS FOR SPECIFIC CPG SITES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10   308  32 ALCOHOL AND DNA METHYLATION: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AND NORMAL BREAST TISSUE. THE BIOLOGICAL MECHANISMS DRIVING ASSOCIATIONS BETWEEN ALCOHOL CONSUMPTION AND CHRONIC DISEASES MIGHT INCLUDE EPIGENETIC MODIFICATION OF DNA METHYLATION. WE EXPLORED THE HYPOTHESIS THAT ALCOHOL CONSUMPTION IS ASSOCIATED WITH METHYLATION IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF BLOOD AND NORMAL BREAST TISSUE DNA. INFINIUM HUMANMETHYLATION450 BEADCHIP (ILLUMINA INC., SAN DIEGO, CALIFORNIA) ARRAY DATA ON BLOOD DNA METHYLATION WAS EXAMINED IN A DISCOVERY SET OF 2,878 NON-HISPANIC WHITE WOMEN FROM THE SISTER STUDY (UNITED STATES, 2004-2015) WHO PROVIDED DETAILED QUESTIONNAIRE INFORMATION ON LIFETIME ALCOHOL USE. ROBUST LINEAR REGRESSION MODELING WAS USED TO IDENTIFY SIGNIFICANT ASSOCIATIONS (FALSE DISCOVERY RATE OF Q < 0.05) BETWEEN THE NUMBER OF ALCOHOLIC DRINKS PER WEEK AND DNA METHYLATION AT 5,458 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES. ASSOCIATIONS WERE REPLICATED (P < 0.05) FOR 677 CPGS IN AN INDEPENDENT SET OF 187 BLOOD DNA SAMPLES FROM THE SISTER STUDY AND FOR 628 CPGS IN AN INDEPENDENT SET OF 171 NORMAL BREAST DNA SAMPLES; 1,207 CPGS WERE REPLICATED IN EITHER BLOOD OR NORMAL BREAST, WITH 98 CPGS REPLICATED IN BOTH TISSUES. INDIVIDUAL GENE EFFECTS WERE NOTABLE FOR PHOSPHOGLYCERATE DEHYDROGENASE (PGHDH), PEPTIDYL-PROLYL CIS-TRANS ISOMERASE (PPIF), SOLUTE CARRIER 15 (SLC15), SOLUTE CARRIER FAMILY 43 MEMBER 1 (SLC43A1), AND SOLUTE CARRIER FAMILY 7 MEMBER 11 (SLC7A11). WE ALSO FOUND THAT HIGH ALCOHOL CONSUMPTION WAS ASSOCIATED WITH SIGNIFICANTLY LOWER GLOBAL METHYLATION AS MEASURED BY THE AVERAGE OF CPGS ON THE ENTIRE ARRAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  1953  32 EPIGENETIC AGE ACCELERATION AND CHRONIC HEALTH CONDITIONS AMONG ADULT SURVIVORS OF CHILDHOOD CANCER. BACKGROUND: MOUNTING EVIDENCE SUPPORTS THE OCCURRENCE OF ACCELERATING AGING AMONG LONG-TERM SURVIVORS OF CHILDHOOD CANCER. WE AIMED TO INVESTIGATE EPIGENETIC AGE ACCELERATION (EAA) IN SURVIVORS AND EVALUATE ASSOCIATIONS BETWEEN EAA, TREATMENT EXPOSURES, HEALTH BEHAVIORS, AND CHRONIC HEALTH CONDITIONS (CHCS). METHODS: GENOME-WIDE METHYLATION DATA WERE GENERATED WITH INFINIUM EPIC BEADCHIP ON BLOOD-DERIVED DNA FROM 2139 SURVIVORS AND 282 FREQUENCY MATCHED CONTROLS FROM THE ST JUDE LIFETIME COHORT STUDY. EAAS WERE ESTIMATED AS RESIDUALS FROM A LINEAR REGRESSION OF EPIGENETIC AGE (LEVINE'S CLOCK) AGAINST CHRONOLOGICAL AGE. ADJUSTED LEAST SQUARE MEAN (ALSM) OF EAA WAS CALCULATED AND COMPARED BETWEEN SURVIVORS AND CONTROLS, ACROSS TREATMENT EXPOSURES AND HEALTH BEHAVIORS. ASSOCIATIONS OF EAA WITH 20 CLINICALLY ASSESSED CHCS WERE EVALUATED WITH MULTIVARIABLE PIECEWISE-EXPONENTIAL MODELS. ALL STATISTICAL TESTS FOR P VALUES BELOW WERE 2-SIDED. RESULTS: EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS THAN CONTROLS (ALSM = 0.63, 95% CONFIDENCE INTERVAL [CI] = 0.26 TO 1.01 VS -3.61, 95% CI = -4.43 TO 2.80). IN A MULTIVARIABLE MODEL AMONG SURVIVORS, STATISTICALLY SIGNIFICANTLY HIGHER EAA (P < .05) WAS OBSERVED IN THOSE EXPOSED TO CHEST RADIOTHERAPY, ABDOMEN OR PELVIC RADIOTHERAPY, ALKYLATING AGENTS, GLUCOCORTICOIDS, OR EPIPODOPHYLLOTOXINS. COMPARED WITH SURVIVORS WITH FAVORABLE HEALTH BEHAVIORS (ALSM = 0.26, 95% CI=-0.36 TO 0.87), EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER AMONG SURVIVORS WITH INTERMEDIATE (ALSM = 1.07, 95% CI = 0.59 TO 1.54) OR UNFAVORABLE HEALTH BEHAVIORS (ALSM = 1.45, 95% CI = 0.60 TO 2.30). IN TIME-TO-EVENT ANALYSES, STATISTICALLY SIGNIFICANT ASSOCIATIONS WERE IDENTIFIED BETWEEN EAA TERTILES AND INCIDENCE OF 7 CHCS: HYPERTENSION (3RD VS 1ST TERTILE, RELATIVE RATE [RR] = 1.83, 95% CI = 1.17 TO 2.83), MYOCARDIAL INFARCTION (RR = 2.91, 95% CI = 1.27 TO 7.21), OBESITY (RR = 1.39, 95% CI = 1.17 TO 1.66), OBSTRUCTIVE PULMONARY DEFICIT (RR = 1.86, 95% CI = 0.95 TO 3.77), PERIPHERAL MOTOR NEUROPATHY (RR = 2.89, 95% CI = 1.24 TO 6.97), PERIPHERAL SENSORY NEUROPATHY (RR = 2.04, 95% CI = 0.99 TO 4.26), AND PULMONARY DIFFUSION DEFICITS (RR = 2.75, 95% CI = 0.95 TO 7.63). CONCLUSIONS: EAA IS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS OF CHILDHOOD CANCER THAN IN NONCANCER CONTROLS AND IS ASSOCIATED WITH SPECIFIC TREATMENT EXPOSURES, UNFAVORABLE HEALTH BEHAVIORS, AND PRESENCE OF SPECIFIC CHCS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12   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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  2632  40 EPIGENOME-WIDE DNA METHYLATION AND PESTICIDE USE IN THE AGRICULTURAL LUNG HEALTH STUDY. BACKGROUND: PESTICIDE EXPOSURE IS ASSOCIATED WITH MANY LONG-TERM HEALTH OUTCOMES; THE POTENTIAL UNDERLYING MECHANISMS ARE NOT WELL ESTABLISHED FOR MOST ASSOCIATIONS. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, MAY CONTRIBUTE. INDIVIDUAL PESTICIDES MAY BE ASSOCIATED WITH SPECIFIC DNA METHYLATION PATTERNS BUT NO EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) HAS EVALUATED METHYLATION IN RELATION TO INDIVIDUAL PESTICIDES. OBJECTIVES: WE CONDUCTED AN EWAS OF DNA METHYLATION IN RELATION TO SEVERAL PESTICIDE ACTIVE INGREDIENTS. METHODS: THE AGRICULTURAL LUNG HEALTH STUDY IS A CASE-CONTROL STUDY OF ASTHMA, NESTED WITHIN THE AGRICULTURAL HEALTH STUDY. WE ANALYZED BLOOD DNA METHYLATION MEASURED USING ILLUMINA'S EPIC ARRAY IN 1,170 MALE FARMERS OF EUROPEAN ANCESTRY. FOR PESTICIDES STILL ON THE MARKET AT BLOOD COLLECTION (2009-2013), WE EVALUATED NINE ACTIVE INGREDIENTS FOR WHICH AT LEAST 30 PARTICIPANTS REPORTED PAST AND CURRENT (WITHIN THE LAST 12 MONTHS) USE, AS WELL AS SEVEN BANNED ORGANOCHLORINES WITH AT LEAST 30 PARTICIPANTS REPORTING PAST USE. WE USED ROBUST LINEAR REGRESSION TO COMPARE METHYLATION AT INDIVIDUAL C-PHOSPHATE-G SITES (CPGS) AMONG USERS OF A SPECIFIC PESTICIDE TO NEVER USERS. RESULTS: USING FAMILY-WISE ERROR RATE (P < 9 X 10-8) OR FALSE-DISCOVERY RATE (FDR < 0.05), WE IDENTIFIED 162 DIFFERENTIALLY METHYLATED CPGS ACROSS 8 OF 9 CURRENTLY MARKETED ACTIVE INGREDIENTS (ACETOCHLOR, ATRAZINE, DICAMBA, GLYPHOSATE, MALATHION, METOLACHLOR, MESOTRIONE, AND PICLORAM) AND ONE BANNED ORGANOCHLORINE (HEPTACHLOR). DIFFERENTIALLY METHYLATED CPGS WERE UNIQUE TO EACH ACTIVE INGREDIENT, AND A DOSE-RESPONSE RELATIONSHIP WITH LIFETIME DAYS OF USE WAS OBSERVED FOR MOST. SIGNIFICANT CPGS WERE ENRICHED FOR TRANSCRIPTION MOTIFS AND 28% OF CPGS WERE ASSOCIATED WITH WHOLE BLOOD CIS-GENE EXPRESSION, SUPPORTING FUNCTIONAL EFFECTS OF FINDINGS. WE CORROBORATED A PREVIOUSLY REPORTED ASSOCIATION BETWEEN DICHLORODIPHENYLTRICHLOROETHANE (BANNED IN THE UNITED STATES IN 1972) AND EPIGENETIC AGE ACCELERATION. DISCUSSION: WE IDENTIFIED DIFFERENTIAL METHYLATION FOR SEVERAL ACTIVE INGREDIENTS IN MALE FARMERS OF EUROPEAN ANCESTRY. THESE MAY SERVE AS BIOMARKERS OF CHRONIC EXPOSURE AND COULD INFORM MECHANISMS OF LONG-TERM HEALTH OUTCOMES FROM PESTICIDE EXPOSURE. HTTPS://DOI.ORG/10.1289/EHP8928.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  3056  36 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  4249  30 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16   403  39 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022	

17  3951  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  5100  29 POLYCHLORINATED BIPHENYLS (PCBS) ALTER DNA METHYLATION AND GENOMIC INTEGRITY OF SHEEP FETAL CELLS IN A SIMPLIFIED IN VITRO MODEL OF PREGNANCY EXPOSURE. POLYCHLORINATED BIPHENYLS (PCBS) ARE PERSISTENT ORGANIC POLLUTANTS UBIQUITOUSLY DETECTABLE IN THE ENVIRONMENT AND IN THE FOOD CHAIN. PRENATAL EXPOSURE TO PCBS NEGATIVELY AFFECTS FETAL DEVELOPMENT AND PRODUCES LONG-TERM DETRIMENTAL EFFECTS ON CHILD HEALTH. THE PRESENT STUDY SOUGHT TO EVALUATE THE CYTOTOXIC AND GENOTOXIC EFFECTS OF CHRONIC PCB EXPOSURE ON FETAL CELLS DURING PREGNANCY. TO THIS AIM, SHEEP EMBRYONIC FIBROBLASTS (SEF) AND AMNIOCYTES (SA) WERE CULTURED IN VITRO IN THE PRESENCE OF LOW DOSES OF PCBS FOR A PERIOD OF 120DAYS, COMPARABLE TO THE FULL TERM OF OVINE PREGNANCY. CELLULAR PROLIFERATION RATES, GLOBAL DNA METHYLATION, CHROMOSOME INTEGRITY, AND MARKERS OF DNA DAMAGE WERE EVALUATED AT DIFFERENT TIME POINTS. MOREOVER, SEF TREATED WITH PCBS FOR 60DAYS WERE LEFT UNTREATED FOR ONE FURTHER MONTH AND THEN EXAMINED IN ORDER TO EVALUATE THE REVERSIBILITY OF PCB-INDUCED EPIGENETIC DEFECTS. PCB-TREATED SEF WERE MORE SENSITIVE THAN SA TREATED WITH PCBS, IN TERMS OF LOW CELL PROLIFERATION, AND INCREASED DNA DAMAGE AND GLOBAL DNA METHYLATION, WHICH WERE STILL DETECTABLE AFTER INTERRUPTION OF PCB TREATMENT. THESE DATA INDICATE THAT CHRONIC EXPOSURE OF FETAL CELLS TO PCBS CAUSES PERMANENT GENOMIC AND EPIGENETIC INSTABILITY, WHICH MAY INFLUENCE BOTH PRENATAL AND POST-NATAL GROWTH UP TO ADULTHOOD. OUR IN VITRO MODEL OFFER A SIMPLE AND CONTROLLED MEANS OF STUDYING THE EFFECTS OF DIFFERENT CONTAMINANTS ON FETAL CELLS - ONE THAT COULD SET THE STAGE FOR TARGETED IN VIVO STUDIES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19   974  34 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  2643  37 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013