1  5463 176 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2   308  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  3637  33 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4   382  49 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	
                                                                                                                                                                                                                                                                                                                                                        
5  3056  41 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	
                                                                                                                                                                                           
6  3063  58 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7   972  39 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8   502  49 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	

9    93  37 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10  5005  39 PERIPHERAL BLOOD DNA METHYLATION-BASED MACHINE LEARNING MODELS FOR PREDICTION OF KNEE OSTEOARTHRITIS PROGRESSION: BIOLOGIC SPECIMENS AND DATA FROM THE OSTEOARTHRITIS INITIATIVE AND JOHNSTON COUNTY OSTEOARTHRITIS PROJECT. OBJECTIVE: THE LACK OF ACCURATE BIOMARKERS TO PREDICT KNEE OSTEOARTHRITIS (OA) PROGRESSION IS A KEY UNMET NEED IN OA CLINICAL RESEARCH. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP BASELINE PERIPHERAL BLOOD EPIGENETIC BIOMARKER MODELS TO PREDICT KNEE OA PROGRESSION. METHODS: GENOME-WIDE BUFFY COAT DNA METHYLATION PATTERNS FROM 554 INDIVIDUALS FROM THE OSTEOARTHRITIS BIOMARKERS CONSORTIUM (OABC) WERE DETERMINED USING ILLUMINA INFINIUM METHYLATIONEPIC 850K ARRAYS. DATA WERE DIVIDED INTO MODEL DEVELOPMENT AND VALIDATION SETS, AND MACHINE LEARNING MODELS WERE TRAINED TO CLASSIFY FUTURE OA PROGRESSION BY KNEE PAIN, RADIOGRAPHIC IMAGING, KNEE PAIN PLUS RADIOGRAPHIC IMAGING, AND ANY PROGRESSION (PAIN, RADIOGRAPHIC, OR BOTH). PARSIMONIOUS MODELS USING THE TOP 13 CPG SITES MOST FREQUENTLY SELECTED DURING DEVELOPMENT WERE TESTED ON INDEPENDENT SAMPLES FROM PARTICIPANTS IN THE JOHNSTON COUNTY OSTEOARTHRITIS (JOCO OA) PROJECT (N = 128) AND A PREVIOUSLY PUBLISHED OSTEOARTHRITIS INITIATIVE (OAI) DATA SET (N = 55). RESULTS: FULL MODELS ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC-ONLY PROGRESSION (MEAN +/- SEM ACCURACY 87 +/- 0.8%, AREA UNDER THE CURVE [AUC] 0.94 +/- 0.004), PAIN-ONLY PROGRESSION (ACCURACY 89 +/- 0.9%, AUC 0.97 +/- 0.004), PAIN PLUS RADIOGRAPHIC PROGRESSION (ACCURACY 72 +/- 0.7%, AUC 0.79 +/- 0.006), AND ANY PROGRESSION (ACCURACY 78 +/- 0.4%, AUC 0.86 +/- 0.004). PAIN-ONLY AND RADIOGRAPHIC-ONLY PROGRESSORS WERE NOT DISTINGUISHABLE (MEAN +/- SEM ACCURACY 58 +/- 1%, AUC 0.62 +/- 0.001). PARSIMONIOUS MODELS SHOWED SIMILAR PERFORMANCE AND ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC PROGRESSORS IN THE OABC COHORT AND IN BOTH VALIDATION COHORTS (MEAN +/- SEM ACCURACY 80 +/- 0.3%, AUC 0.88 +/- 0.003 [USING JOCO OA PROJECT DATA], ACCURACY 80 +/- 0.8%, AUC 0.89 +/- 0.002 [USING PREVIOUS OAI DATA]). CONCLUSION: OUR DATA SUGGEST THAT PAIN AND STRUCTURAL PROGRESSION SHARE SIMILAR EARLY SYSTEMIC IMMUNE EPIGENOTYPES. FURTHER STUDIES SHOULD FOCUS ON EVALUATING THE PATHOPHYSIOLOGIC CONSEQUENCES OF DIFFERENTIAL DNA METHYLATION AND PERIPHERAL BLOOD CELL EPIGENOTYPES IN INDIVIDUALS WITH KNEE OA.	2023	
                                                                                                                                                                                                                                                                                 
11  3951  54 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	
                                                                                                                                                                                                                               
12   173  36 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  1586  37 DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC DIFFERENCES BETWEEN EARLY VERSUS LATE STAGES OF DIABETIC CHRONIC KIDNEY DISEASE. BACKGROUND: WE INVESTIGATED A CROSS-SECTIONAL EPIGENOME-WIDE ASSOCIATION STUDY OF PATIENTS WITH EARLY AND LATE DIABETES-ASSOCIATED CHRONIC KIDNEY DISEASE (CKD) TO IDENTIFY POSSIBLE EPIGENETIC DIFFERENCES BETWEEN THE TWO GROUPS AS WELL AS CHANGES IN METHYLATION ACROSS ALL STAGES OF DIABETIC CKD. WE ALSO EVALUATED THE POTENTIAL OF USING A PANEL OF IDENTIFIED 5'-C-PHOSPHATE-G-3' (CPG) SITES FROM THIS COHORT TO PREDICT THE PROGRESSION OF DIABETIC CKD. METHODS: THIS CROSS-SECTIONAL STUDY RECRUITED 119 ADULTS. DNA WAS EXTRACTED FROM BLOOD USING THE QIAGEN QIAAMPDNA MINI SPIN KIT. GENOME-WIDE METHYLATION ANALYSIS WAS PERFORMED USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIPS (HM850K). INTENSITY DATA FILES WERE PROCESSED AND ANALYSED USING THE MINFI AND MISSMETHYL PACKAGES FOR R. WE EXAMINED THE DEGREE OF METHYLATION OF CPG SITES IN EARLY VERSUS LATE DIABETIC CKD PATIENTS FOR CPG SITES WITH AN UNADJUSTED P-VALUE <0.01 AND AN ABSOLUTE CHANGE IN METHYLATION OF 5% (N = 239 CPG SITES). RESULTS: HIERARCHICAL CLUSTERING OF THE 239 CPG SITES LARGELY SEPARATED THE TWO GROUPS. A HEAT MAP FOR ALL 239 CPG SITES DEMONSTRATED DISTINCT METHYLATION PATTERNS IN THE EARLY VERSUS LATE GROUPS, WITH CPG SITES SHOWING EVIDENCE OF PROGRESSIVE CHANGE. BASED ON OUR DIFFERENTIALLY METHYLATED REGION (DMR) ANALYSIS OF THE 239 CPG SITES, WE HIGHLIGHTED TWO DMRS, NAMELY THE CYSTEINE-RICH SECRETORY PROTEIN 2 (CRISP2) AND PIWI-LIKE RNA-MEDIATED GENE SILENCING 1 (PIWIL1) GENES. THE BEST PREDICTABILITY FOR THE TWO GROUPS INVOLVED A RECEIVER OPERATING CHARACTERISTICS CURVE OF EIGHT CPG SITES ALONE AND ACHIEVED AN AREA UNDER THE CURVE OF 0.976. CONCLUSIONS: WE HAVE IDENTIFIED DISTINCT DNA METHYLATION PATTERNS BETWEEN EARLY AND LATE DIABETIC CKD PATIENTS AS WELL AS DEMONSTRATED NOVEL FINDINGS OF POTENTIAL PROGRESSIVE METHYLATION CHANGES ACROSS ALL STAGES (1-5) OF DIABETIC CKD AT SPECIFIC CPG SITES. WE HAVE ALSO IDENTIFIED ASSOCIATED GENES CRISP2 AND PIWIL1, WHICH MAY HAVE THE POTENTIAL TO ACT AS STAGE-SPECIFIC DIABETES-ASSOCIATED CKD MARKERS, AND SHOWED THAT THE USE OF A PANEL OF EIGHT IDENTIFIED CPG SITES ALONE HELPS TO INCREASE THE PREDICTABILITY FOR THE TWO GROUPS.	2021	
                                                                                                                                                                                                                                                                                                                      
14  3557  38 IMPACT OF BMI AND WAIST CIRCUMFERENCE ON EPIGENOME-WIDE DNA METHYLATION AND IDENTIFICATION OF EPIGENETIC BIOMARKERS IN BLOOD: AN EWAS IN MULTI-ETHNIC ASIAN INDIVIDUALS. BACKGROUND: THE PREVALENCE OF OBESITY AND ITS RELATED CHRONIC DISEASES HAVE BEEN INCREASING ESPECIALLY IN ASIAN COUNTRIES. OBESITY-RELATED GENETIC VARIANTS HAVE BEEN IDENTIFIED, BUT THESE EXPLAIN LITTLE OF THE VARIATION IN BMI. RECENT STUDIES REPORTED ASSOCIATIONS BETWEEN DNA METHYLATION AND OBESITY, MOSTLY IN NON-ASIAN POPULATIONS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ON GENERAL ADIPOSITY (BODY MASS INDEX, BMI) AND ABDOMINAL ADIPOSITY (WAIST CIRCUMFERENCE, WC) IN 409 MULTI-ETHNIC ASIAN INDIVIDUALS AND REPLICATED BMI AND WAIST-ASSOCIATED DNA METHYLATION CPGS IDENTIFIED IN OTHER POPULATIONS. THE CROSS-LAGGED PANEL MODEL AND MENDELIAN RANDOMIZATION WERE USED TO ASSESS THE TEMPORAL RELATIONSHIP BETWEEN METHYLATION AND BMI. THE TEMPORAL RELATIONSHIP BETWEEN THE IDENTIFIED CPGS AND INFLAMMATION AND METABOLIC MARKERS WAS ALSO EXAMINED. RESULTS: EWAS IDENTIFIED 116 DNA METHYLATION CPGS INDEPENDENTLY ASSOCIATED WITH BMI AND EIGHT INDEPENDENTLY ASSOCIATED WITH WC AT FALSE DISCOVERY RATE P(FDR) < 0.05 IN 409 ASIAN SAMPLES. WE REPLICATED 110 BMI-ASSOCIATED CPGS PREVIOUSLY REPORTED IN EUROPEANS AND IDENTIFIED SIX NOVEL BMI-ASSOCIATED CPGS AND TWO NOVEL WC-ASSOCIATED CPGS. WE OBSERVED HIGH CONSISTENCY IN ASSOCIATION DIRECTION OF EFFECT COMPARED TO STUDIES IN OTHER POPULATIONS. CAUSAL RELATIONSHIP ANALYSES INDICATED THAT BMI WAS MORE LIKELY TO BE THE CAUSE OF DNA METHYLATION ALTERATION, RATHER THAN THE CONSEQUENCE. THE CAUSAL ANALYSES USING BMI-ASSOCIATED METHYLATION RISK SCORE ALSO SUGGESTED THAT HIGHER LEVELS OF THE INFLAMMATION MARKER IL-6 WERE LIKELY THE CONSEQUENCE OF METHYLATION CHANGE. CONCLUSION: OUR STUDY PROVIDES EVIDENCE OF AN ASSOCIATION BETWEEN OBESITY AND DNA METHYLATION IN MULTI-ETHNIC ASIANS AND SUGGESTS THAT OBESITY CAN DRIVE METHYLATION CHANGE. THE RESULTS ALSO SUGGESTED POSSIBLE CAUSAL INFLUENCE THAT OBESITY-RELATED METHYLATION CHANGES MIGHT HAVE ON INFLAMMATION AND LIPOPROTEIN LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  2624  40 EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) OF BMI, BMI CHANGE AND WAIST CIRCUMFERENCE IN AFRICAN AMERICAN ADULTS IDENTIFIES MULTIPLE REPLICATED LOCI. OBESITY IS AN IMPORTANT COMPONENT OF THE PATHOPHYSIOLOGY OF CHRONIC DISEASES. IDENTIFYING EPIGENETIC MODIFICATIONS ASSOCIATED WITH ELEVATED ADIPOSITY, INCLUDING DNA METHYLATION VARIATION, MAY POINT TO GENOMIC PATHWAYS THAT ARE DYSREGULATED IN NUMEROUS CONDITIONS. THE ILLUMINA 450K BEAD CHIP ARRAY WAS USED TO ASSAY DNA METHYLATION IN LEUKOCYTE DNA OBTAINED FROM 2097 AFRICAN AMERICAN ADULTS IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY. MIXED-EFFECTS REGRESSION MODELS WERE USED TO TEST THE ASSOCIATION OF METHYLATION BETA VALUE WITH CONCURRENT BODY MASS INDEX (BMI) AND WAIST CIRCUMFERENCE (WC), AND BMI CHANGE, ADJUSTING FOR BATCH EFFECTS AND POTENTIAL CONFOUNDERS. REPLICATION USING WHOLE-BLOOD DNA FROM 2377 WHITE ADULTS IN THE FRAMINGHAM HEART STUDY AND CD4+ T CELL DNA FROM 991 WHITES IN THE GENETICS OF LIPID LOWERING DRUGS AND DIET NETWORK STUDY WAS FOLLOWED BY TESTING USING ADIPOSE TISSUE DNA FROM 648 WOMEN IN THE MULTIPLE TISSUE HUMAN EXPRESSION RESOURCE COHORT. SEVENTY-SIX BMI-RELATED PROBES, 164 WC-RELATED PROBES AND 8 BMI CHANGE-RELATED PROBES PASSED THE THRESHOLD FOR SIGNIFICANCE IN ARIC (P < 1 X 10(-7); BONFERRONI), INCLUDING PROBES IN THE RECENTLY REPORTED HIF3A, CPT1A AND ABCG1 REGIONS. REPLICATION USING BLOOD DNA WAS ACHIEVED FOR 37 BMI PROBES AND 1 ADDITIONAL WC PROBE. SIXTEEN OF THESE ALSO REPLICATED IN ADIPOSE TISSUE, INCLUDING 15 NOVEL METHYLATION FINDINGS NEAR GENES INVOLVED IN LIPID METABOLISM, IMMUNE RESPONSE/CYTOKINE SIGNALING AND OTHER DIVERSE PATHWAYS, INCLUDING LGALS3BP, KDM2B, PBX1 AND BBS2, AMONG OTHERS. ADIPOSITY TRAITS ARE ASSOCIATED WITH DNA METHYLATION AT NUMEROUS CPG SITES THAT REPLICATE ACROSS STUDIES DESPITE VARIATION IN TISSUE TYPE, ETHNICITY AND ANALYTIC APPROACHES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  2643  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17   713  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18  6460  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  4730  44 NOVEL AGE-ASSOCIATED DNA METHYLATION CHANGES AND EPIGENETIC AGE ACCELERATION IN MIDDLE-AGED AFRICAN AMERICANS AND WHITES. BACKGROUND: AFRICAN AMERICANS (AAS) EXPERIENCE PREMATURE CHRONIC HEALTH OUTCOMES AND LONGEVITY DISPARITIES CONSISTENT WITH AN ACCELERATED AGING PHENOTYPE. DNA METHYLATION (DNAM) LEVELS AT SPECIFIC CPG POSITIONS ARE HALLMARKS OF AGING EVIDENCED BY THE PRESENCE OF AGE-ASSOCIATED DIFFERENTIALLY METHYLATED CPG POSITIONS (ADMPS) THAT ARE THE BASIS FOR THE EPIGENETIC CLOCK FOR MEASURING BIOLOGICAL AGE ACCELERATION. SINCE DNAM HAS NOT BEEN WIDELY STUDIED AMONG NON-EUROPEAN POPULATIONS, WE EXAMINED THE ASSOCIATION BETWEEN DNAM AND CHRONOLOGICAL AGE IN AAS AND WHITES, AND THE ASSOCIATION BETWEEN RACE, POVERTY, SEX, AND EPIGENETIC AGE ACCELERATION. RESULTS: WE MEASURED GENOME-WIDE DNA METHYLATION (866,836 CPGS) USING THE ILLUMINA METHYLATIONEPIC BEADCHIP IN BLOOD DNA EXTRACTED FROM 487 MIDDLE-AGED AA (N = 244) AND WHITE (N = 243), MEN (N = 248), AND WOMEN (N = 239). THE MEAN (SD) AGE WAS 48.4 (8.8) IN AA AND 49.0 (8.7) IN WHITES (P = 0.48). WE IDENTIFIED 4930 SIGNIFICANTLY ASSOCIATED ADMPS IN AAS AND 469 IN WHITES. OF THESE, 75.6% AND 53.1% WERE NOVEL, LARGELY DRIVEN BY THE INCREASED NUMBER OF MEASURED CPGS IN THE EPIC ARRAY, IN AA AND WHITES, RESPECTIVELY. AAS HAD MORE AGE-ASSOCIATED DNAM CHANGES THAN WHITES IN GENES IMPLICATED IN AGE-RELATED DISEASES AND CELLULAR PATHWAYS INVOLVED IN GROWTH AND DEVELOPMENT. WE ASSESSED THREE EPIGENETIC AGE ACCELERATION MEASURES (UNIVERSAL, INTRINSIC, AND EXTRINSIC). AAS HAD A SIGNIFICANTLY SLOWER EXTRINSIC AGING COMPARED TO WHITES. FURTHERMORE, COMPARED TO AA WOMEN, BOTH AA AND WHITE MEN HAD FASTER AGING IN THE UNIVERSAL AGE ACCELERATION MEASURE (+ 2.04 AND + 1.24 YEARS, RESPECTIVELY, P < 0.05). CONCLUSIONS: AAS HAVE MORE WIDE-SPREAD METHYLATION CHANGES THAN WHITES. RACE AND SEX INTERACT TO UNDERLIE BIOLOGICAL AGE ACCELERATION SUGGESTING ALTERED DNA METHYLATION PATTERNS MAY BE IMPORTANT IN AGE-ASSOCIATED HEALTH DISPARITIES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  5746  30 SMOKING-RELATED DNA METHYLATION IS ASSOCIATED WITH DNA METHYLATION PHENOTYPIC AGE ACCELERATION: THE VETERANS AFFAIRS NORMATIVE AGING STUDY. DNA METHYLATION MAY PLAY A CRITICAL ROLE IN AGING AND AGE-RELATED DISEASES. DNA METHYLATION PHENOTYPIC AGE (DNAMPHENOAGE) IS A NEW AGING BIOMARKER AND PREDICTOR OF CHRONIC DISEASE RISK. WHILE SMOKING IS A STRONG RISK FACTOR FOR CHRONIC DISEASES AND INFLUENCES METHYLATION, ITS INFLUENCE ON DNAMPHENOAGE IS UNKNOWN. WE INVESTIGATED ASSOCIATIONS OF SELF-REPORTED AND EPIGENETIC SMOKING INDICATORS WITH DNAMPHENOAGE ACCELERATION IN A LONGITUDINAL AGING STUDY IN EASTERN MASSACHUSETTS. DNA METHYLATION WAS MEASURED IN WHOLE BLOOD SAMPLES FROM MULTIPLE VISITS FOR 692 MALE PARTICIPANTS IN THE VETERANS AFFAIRS NORMATIVE AGING STUDY DURING 1999-2013. ACCELERATION WAS DEFINED USING RESIDUALS FROM LINEAR REGRESSION OF THE DNAMPHENOAGE ON THE CHRONOLOGICAL AGE. CUMULATIVE SMOKING (PACK-YEARS) WAS SIGNIFICANTLY ASSOCIATED WITH DNAMPHENOAGE ACCELERATION, WHEREAS SELF-REPORTED SMOKING STATUS WAS NOT. WE OBSERVED SIGNIFICANT VALIDATED ASSOCIATIONS BETWEEN SMOKING-RELATED LOCI AND DNAMPHENOAGE ACCELERATION FOR 52 CPG SITES, WHERE 18 WERE HYPOMETHYLATED AND 34 WERE HYPERMETHYLATED, MAPPED TO 16 GENES. THE AHRR GENE HAD THE MOST LOCI (N = 8) AMONG THE 16 GENES. WE GENERATED A SMOKING AGING INDEX BASED ON THESE 52 LOCI, WHICH SHOWED POSITIVE SIGNIFICANT ASSOCIATIONS WITH DNAMPHENOAGE ACCELERATION. THESE EPIGENETIC BIOMARKERS MAY HELP TO PREDICT AGE-RELATED RISKS DRIVEN BY SMOKING.	2019