1 5070 122 PHYSICAL ACTIVITY, TELEVISION VIEWING TIME, AND DNA METHYLATION IN PERIPHERAL BLOOD. INTRODUCTION: PHYSICAL ACTIVITY MAY AFFECT HEALTH VIA DNA METHYLATION. THE EPIGENETIC INFLUENCES OF SEDENTARY BEHAVIORS SUCH AS TELEVISION VIEWING ARE UNKNOWN. WE PERFORMED A GENOMEWIDE STUDY OF DNA METHYLATION IN PERIPHERAL BLOOD IN RELATION TO PHYSICAL ACTIVITY AND TELEVISION VIEWING TIME. METHODS: DNA METHYLATION WAS MEASURED USING THE ILLUMINA INFINIUM HUMANMETHYLATION450K BEADCHIP ARRAY IN BLOOD SAMPLES COLLECTED AT BASELINE (N = 5513) AND FOLLOW-UP (N = 1249) FROM PARTICIPANTS IN THE MELBOURNE COLLABORATIVE COHORT STUDY. AT BASELINE, TIMES PER WEEK OF LEISURE-TIME PHYSICAL ACTIVITY WERE SELF-REPORTED. AT FOLLOW-UP, THE INTERNATIONAL PHYSICAL ACTIVITY QUESTIONNAIRE WAS USED TO ASSESS MET-HOURS PER WEEK OF TOTAL AND LEISURE-TIME PHYSICAL ACTIVITY AND HOURS PER DAY OF TELEVISION VIEWING TIME. LINEAR MIXED MODELS WERE USED TO ASSESS ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY AND TELEVISION VIEWING MEASURES AND DNA METHYLATION AT INDIVIDUAL CPG SITES, ADJUSTED FOR POTENTIAL CONFOUNDERS AND BATCH EFFECTS. RESULTS: AT FOLLOW-UP, TOTAL PHYSICAL ACTIVITY WAS ASSOCIATED WITH DNA METHYLATION AT CG10266336 (P = 6.0 X 10), ANNOTATED TO THE SAA2 GENE. WEAKER EVIDENCE OF ASSOCIATIONS (P < 1.0 X 10) WERE OBSERVED FOR AN ADDITIONAL 14 CPG SITES WITH TOTAL PHYSICAL ACTIVITY, FOR 7 CPG SITES WITH LEISURE-TIME PHYSICAL ACTIVITY, AND FOR 9 CPG SITES WITH TELEVISION VIEWING TIME. CHANGES IN LEISURE-TIME PHYSICAL ACTIVITY BETWEEN BASELINE AND FOLLOW-UP WERE ASSOCIATED WITH METHYLATION CHANGES (P < 0.05) AT FOUR OF THE SEVEN CPG SITES WITH WEAKER EVIDENCE OF CROSS-SECTIONAL ASSOCIATIONS WITH LEISURE-TIME PHYSICAL ACTIVITY. CONCLUSION: PHYSICAL ACTIVITY AND TELEVISION VIEWING MAY BE ASSOCIATED WITH BLOOD DNA METHYLATION, A POTENTIAL PATHWAY TO CHRONIC DISEASE DEVELOPMENT. FURTHER RESEARCH USING ACCELEROMETER DATA AND LARGER SAMPLE SIZES IS WARRANTED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 1529  40 DNA METHYLATION CHANGES IN WHOLE BLOOD AND CD16+ NEUTROPHILS IN RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IN WOMEN OF CHILDBEARING AGE. FOLATE, A WATER-SOLUBLE VITAMIN, IS A KEY SOURCE OF ONE-CARBON GROUPS FOR DNA METHYLATION, BUT STUDIES OF THE DNA METHYLATION RESPONSE TO SUPPLEMENTAL FOLIC ACID YIELD INCONSISTENT RESULTS. THESE STUDIES ARE COMMONLY CONDUCTED USING WHOLE BLOOD, WHICH CONTAINS A MIXED POPULATION OF WHITE BLOOD CELLS THAT HAVE BEEN SHOWN TO CONFOUND RESULTS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE IF CD16+ NEUTROPHILS MAY PROVIDE MORE SPECIFIC DATA THAN WHOLE BLOOD FOR IDENTIFYING DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION. THE STUDY WAS PERFORMED IN NORMAL WEIGHT (BMI 18.5 - 24.9 KG/M2) WOMEN (18 - 35 Y; N = 12), WITH BLOOD SAMPLES TAKEN BEFORE AND AFTER 8 WEEKS OF FOLIC ACID SUPPLEMENTATION AT 800 MUG/DAY. DNA METHYLATION PATTERNS FROM WHOLE BLOOD AND ISOLATED CD16+ NEUTROPHILS WERE MEASURED ACROSS >485,000 CPG SITES THROUGHOUT THE GENOME USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP. OVER THE COURSE OF THE 8-WEEK SUPPLEMENTATION, 6746 AND 7513 CPG SITES CHANGED (P < 0.05) IN WHOLE BLOOD AND CD16+ NEUTROPHILS, RESPECTIVELY. DNA METHYLATION DECREASED IN 68.4% (WHOLE BLOOD) AND 71.8% (CD16+ NEUTROPHILS) OF THESE SITES. THERE WERE ONLY 182 CPG SITES THAT CHANGED IN BOTH THE WHOLE BLOOD AND CD16+ NEUTROPHILS, 139 OF WHICH CHANGED IN THE SAME DIRECTION. THESE RESULTS SUGGEST THAT THE GENOME-WIDE DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IS DIFFERENT BETWEEN WHOLE BLOOD AND CD16+ NEUTROPHILS AND THAT A SINGLE WHITE BLOOD CELL TYPE MAY FUNCTION AS A MORE SPECIFIC EPIGENETIC REPORTER OF FOLATE STATUS THAN WHOLE BLOOD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3 6190  43 THE IMPACT OF METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ON ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES. BACKGROUND: METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ARE THE GENETIC VARIANTS THAT MAY AFFECT THE DNA METHYLATION PATTERNS OF CPG SITES. HOWEVER, THEIR ROLES IN INFLUENCING THE DISTURBANCES OF SMOKING-RELATED EPIGENETIC CHANGES HAVE NOT BEEN WELL ESTABLISHED. THIS STUDY WAS CONDUCTED TO ADDRESS WHETHER MQTLS EXIST IN THE VICINITY OF SMOKING-RELATED CPG SITES (+/- 50 KB) AND TO EXAMINE THEIR ASSOCIATIONS WITH SMOKING EXPOSURE AND ALL-CAUSE MORTALITY IN OLDER ADULTS. RESULTS: WE OBTAINED DNA METHYLATION PROFILES IN WHOLE BLOOD SAMPLES BY ILLUMINA INFINIUM HUMAN METHYLATION 450 BEADCHIP ARRAY OF TWO INDEPENDENT SUBSAMPLES OF THE ESTHER STUDY (DISCOVERY SET, N = 581; VALIDATION SET, N = 368) AND THEIR CORRESPONDING GENOTYPING DATA USING THE ILLUMINA INFINIUM ONCOARRAY BEADCHIP. AFTER CORRECTION FOR MULTIPLE TESTING (FDR), WE SUCCESSFULLY IDENTIFIED THAT 70 OUT OF 151 PREVIOUSLY REPORTED SMOKING-RELATED CPG SITES WERE SIGNIFICANTLY ASSOCIATED WITH 192 SNPS WITHIN THE 50 KB SEARCH WINDOW OF EACH LOCUS. THE 192 MQTLS SIGNIFICANTLY INFLUENCED THE ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES, WITH PERCENTAGE CHANGES RANGING FROM 0.01 TO 18.96%, ESPECIALLY FOR THE WEAKLY/MODERATELY SMOKING-RELATED CPG SITES. HOWEVER, THESE IDENTIFIED MQTLS WERE NOT DIRECTLY ASSOCIATED WITH ACTIVE SMOKING EXPOSURE OR ALL-CAUSE MORTALITY. CONCLUSIONS: OUR FINDINGS CLEARLY DEMONSTRATED THAT IF NOT DEALT WITH PROPERLY, THE MQTLS MIGHT IMPAIR THE POWER OF EPIGENETIC-BASED MODELS OF SMOKING EXPOSURE TO A CERTAIN EXTENT. IN ADDITION, SUCH GENETIC VARIANTS COULD BE THE KEY FACTOR TO DISTINGUISH BETWEEN THE HERITABLE AND SMOKING-INDUCED IMPACT ON EPIGENOME DISPARITIES. THESE MQTLS ARE OF SPECIAL IMPORTANCE WHEN DNA METHYLATION MARKERS MEASURED BY ILLUMINA INFINIUM ASSAY ARE USED FOR ANY COMPARATIVE POPULATION STUDIES RELATED TO SMOKING-RELATED CANCERS AND CHRONIC DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4 2921  51 GENE-SPECIFIC DIFFERENTIAL DNA METHYLATION AND CHRONIC ARSENIC EXPOSURE IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF ADULTS IN BANGLADESH. BACKGROUND: INORGANIC ARSENIC IS ONE OF THE MOST COMMON NATURALLY OCCURRING CONTAMINANTS FOUND IN THE ENVIRONMENT. ARSENIC IS ASSOCIATED WITH A NUMBER OF HEALTH OUTCOMES, WITH EPIGENETIC MODIFICATION SUGGESTED AS A POTENTIAL MECHANISM OF TOXICITY. OBJECTIVE: AMONG A SAMPLE OF 400 ADULT PARTICIPANTS, WE EVALUATED THE ASSOCIATION BETWEEN ARSENIC EXPOSURE, AS MEASURED BY BLOOD AND URINARY TOTAL ARSENIC CONCENTRATIONS, AND EPIGENOME-WIDE WHITE BLOOD CELL DNA METHYLATION. METHODS: WE USED LINEAR REGRESSION MODELS TO EXAMINE THE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND METHYLATION AT EACH CPG SITE, ADJUSTED FOR SEX, AGE, AND BATCH. DIFFERENTIALLY METHYLATED LOCI WERE SUBSEQUENTLY EXAMINED IN RELATION TO CORRESPONDING GENE EXPRESSION FOR FUNCTIONAL EVIDENCE OF GENE REGULATION. RESULTS: IN ADJUSTED ANALYSES, WE OBSERVED FOUR DIFFERENTIALLY METHYLATED CPG SITES WITH URINARY TOTAL ARSENIC CONCENTRATION AND THREE DIFFERENTIALLY METHYLATED CPG SITES WITH BLOOD ARSENIC CONCENTRATION, BASED ON THE BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLD OF P < 1 X 10(-7). METHYLATION OF PLA2G2C (PROBE CG04605617) WAS THE MOST SIGNIFICANTLY ASSOCIATED LOCUS IN RELATION TO BOTH URINARY (P = 3.40 X 10(-11)) AND BLOOD ARSENIC CONCENTRATIONS (P = 1.48 X 10(-11)). THREE ADDITIONAL NOVEL METHYLATION LOCI-SQSTM1 (CG01225779), SLC4A4 (CG06121226), AND IGH (CG13651690)--WERE ALSO SIGNIFICANTLY ASSOCIATED WITH ARSENIC EXPOSURE. FURTHER, THERE WAS EVIDENCE OF METHYLATION-RELATED GENE REGULATION BASED ON GENE EXPRESSION FOR A SUBSET OF DIFFERENTIALLY METHYLATED LOCI. CONCLUSIONS: WE OBSERVED SIGNIFICANT ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENE-SPECIFIC DIFFERENTIAL WHITE BLOOD CELL DNA METHYLATION, SUGGESTING THAT EPIGENETIC MODIFICATIONS MAY BE AN IMPORTANT PATHWAY UNDERLYING ARSENIC TOXICITY. THE SPECIFIC DIFFERENTIALLY METHYLATED LOCI IDENTIFIED MAY INFORM POTENTIAL PATHWAYS FOR FUTURE INTERVENTIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 5092  33 PLACENTAL EPIGENETIC MARKS RELATED TO GESTATIONAL WEIGHT GAIN REVEAL POTENTIAL GENES ASSOCIATED WITH OFFSPRING OBESITY PARAMETERS. OBJECTIVE: OFFSPRING EXPOSED TO GESTATIONAL OBESITY HAVE AN INCREASED RISK FOR CHRONIC DISEASES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETICS MAY PLAY A MECHANISTIC ROLE IN METABOLIC PROGRAMMING. THIS STUDY AIMED TO IDENTIFY PLACENTAL DNA METHYLATION MARKS ASSOCIATED WITH GESTATIONAL WEIGHT GAIN (GWG) AND TO STUDY THEIR ASSOCIATION WITH OFFSPRING OBESITY PARAMETERS AT SCHOOL AGE. METHODS: A GLOBAL METHYLATION ARRAY WAS PERFORMED IN 24 PLACENTAS FROM MOTHERS WITH DIFFERENT DEGREES OF GWG (SCREENING SAMPLE). THE METHYLATION PERCENTAGE OF FOUR CYTOSINE-GUANINE (CPG) SITES AND THE RELATIVE EXPRESSION OF THE RESPECTIVE ANNOTATED GENES WERE STUDIED IN 90 ADDITIONAL PLACENTAS (VALIDATION SAMPLE). ASSOCIATIONS OF THESE EPIGENETIC MARKS WITH CLINICAL PARAMETERS IN THE OFFSPRING AT 6 YEARS OF AGE WERE EXAMINED. RESULTS: THE SCREENING ANALYSIS IDENTIFIED 104 CPG SITES (97 GENES) ASSOCIATED WITH GWG. THE VALIDATION ANALYSIS OF FOUR SELECTED CPG SITES (ANNOTATING FOR FRAT1, SNX5, AND KCNK3 GENES) SHOWED THAT THE UPREGULATION OF SNX5 METHYLATION, THE DOWNREGULATION OF FRAT1 METHYLATION, AND KCNK3 UNDEREXPRESSION ASSOCIATED WITH AN ADVERSE METABOLIC PHENOTYPE IN CHILDREN OF WOMEN WITH INCREASED GWG. CONCLUSIONS: THESE RESULTS SUGGEST THAT PLACENTAL REGULATION OF FRAT1, SNX5, AND KCNK3 RELATES TO OBESITY PARAMETERS IN OFFSPRING EXPOSED TO EXCESSIVE GWG AND THEREBY COULD CONDITION THE RISK FOR FUTURE METABOLIC DISORDERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6 2626  41 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7 3073  42 GENOME-WIDE DNA METHYLATION STATUS OF MONGOLIANS EXHIBITS SIGNS OF CELLULAR STRESS RESPONSE RELATED TO THEIR NOMADIC LIFESTYLE. BACKGROUND: EPIGENETICS IS CRUCIAL FOR CONNECTING ENVIRONMENTAL STRESSES WITH PHYSIOLOGICAL RESPONSES IN HUMANS. MONGOLIA, WHERE NOMADIC LIVESTOCK PASTORALISM HAS BEEN THE PRIMAL LIVELIHOOD, HAS A HIGHER PREVALENCE OF VARIOUS CHRONIC DISEASES THAN THE SURROUNDING EAST ASIAN REGIONS, WHICH ARE MORE SUITABLE FOR CROP FARMING. THE GENES RELATED TO DIETARY STRESS AND PATHOGENESIS OF RELATED DISORDERS MAY HAVE VARYING EPIGENETIC STATUSES AMONG THE HUMAN POPULATIONS WITH DIVERSE DIETARY CULTURES. HENCE, TO UNDERSTAND SUCH EPIGENETIC DIFFERENCES, WE CONDUCTED A COMPARATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION OF MONGOLIANS AND CROP-FARMING EAST ASIANS. METHODS: GENOME-WIDE DNA METHYLATION STATUS OF PERIPHERAL BLOOD CELLS (PBCS) FROM 23 MONGOLIAN ADULTS AND 24 THAI ADULTS WAS DETERMINED USING THE INFINIUM HUMAN METHYLATION 450K ARRAYS AND ANALYZED IN COMBINATION WITH PREVIOUSLY PUBLISHED 450K DATA OF 20 JAPANESE AND 8 CHINESE ADULTS. CPG SITES/REGIONS DIFFERENTIALLY METHYLATED BETWEEN MONGOLIANS AND CROP-FARMING EAST ASIANS WERE DETECTED USING A LINEAR MODEL ADJUSTED FOR SEX, AGE, ETHNICITY, AND IMMUNE CELL HETEROGENEITY ON RNBEADS SOFTWARE. RESULTS: OF THE QUALITY-CONTROLLED 389,454 AUTOSOMAL CPG SITES, 223 CPG SITES WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED AMONG MONGOLIANS AND THE FOUR CROP FARMING EAST ASIAN POPULATIONS (FALSE DISCOVERY RATE < 0.05). ANALYSES FOCUSED ON GENE PROMOTER REGIONS REVEALED THAT PM20D1 (PEPTIDASE M20 DOMAIN CONTAINING 1), WHICH IS INVOLVED IN MITOCHONDRIAL UNCOUPLING AND VARIOUS PROCESSES, INCLUDING CELLULAR PROTECTION FROM REACTIVE OXYGEN SPECIES (ROS) AND THERMOGENESIS, WAS THE TOP DIFFERENTIALLY METHYLATED GENE. MOREOVER, GENE ONTOLOGY ENRICHMENT ANALYSIS REVEALED THAT BIOLOGICAL PROCESSES RELATED TO ROS METABOLISM WERE OVERREPRESENTED AMONG THE TOP 1% DIFFERENTIALLY METHYLATED GENES. THE PROMOTER REGIONS OF THESE GENES WERE GENERALLY HYPERMETHYLATED IN MONGOLIANS, SUGGESTING THAT THE METABOLIC PATHWAY DETOXIFYING ROS MIGHT BE GLOBALLY SUPPRESSED IN MONGOLIANS, RESULTING IN THE HIGH SUSCEPTIBILITY OF THIS POPULATION TO VARIOUS CHRONIC DISEASES. CONCLUSIONS: THIS STUDY SHOWED A SIGNIFICANTLY DIVERSE DNA METHYLATION STATUS AMONG MONGOLIANS AND CROP-FARMING EAST ASIANS. FURTHER, WE FOUND AN ASSOCIATION BETWEEN THE DIFFERENTIALLY METHYLATED GENES AND VARIOUS METABOLIC AND NEURODEGENERATIVE DISEASES. KNOWLEDGE OF THE EPIGENETIC REGULATORS MIGHT HELP IN PROPER UNDERSTANDING, TREATMENT, AND CONTROL OF SUCH DISORDERS, AND PHYSIOLOGICAL ADAPTATION IN THE FUTURE.	2022	

8 3162  38 GREATER STRESS AND TRAUMA MEDIATE RACE-RELATED DIFFERENCES IN EPIGENETIC AGE BETWEEN BLACK AND WHITE YOUNG ADULTS IN A COMMUNITY SAMPLE. BLACK AMERICANS SUFFER LOWER LIFE EXPECTANCY AND SHOW SIGNS OF ACCELERATED AGING COMPARED TO OTHER AMERICANS. WHILE PREVIOUS STUDIES OBSERVE THESE DIFFERENCES IN CHILDREN AND POPULATIONS WITH CHRONIC ILLNESS, WHETHER THESE PATHOLOGIC PROCESSES EXIST OR HOW THESE PATHOLOGIC PROCESSES PROGRESS HAS YET TO BE EXPLORED PRIOR TO THE ONSET OF SIGNIFICANT CHRONIC ILLNESS, WITHIN A YOUNG ADULT POPULATION. THEREFORE, WE INVESTIGATED RACE-RELATED DIFFERENCES IN EPIGENETIC AGE IN A CROSS-SECTIONAL SAMPLE OF YOUNG PUTATIVELY HEALTHY ADULTS AND ASSESSED WHETHER LIFETIME STRESS AND/OR TRAUMA MEDIATE THOSE DIFFERENCES. BIOLOGICAL AND PSYCHOLOGICAL DATA WERE COLLECTED FROM SELF-REPORTED HEALTHY ADULT VOLUNTEERS WITHIN THE LOCAL NEW HAVEN AREA (399 VOLUNTEERS, 19.8% BLACK, MEAN AGE: 29.28). STRESS AND TRAUMA DATA WAS COLLECTED USING THE CUMULATIVE ADVERSITY INVENTORY (CAI) INTERVIEW, WHICH ASSESSED SPECIFIC TYPES OF STRESSORS, INCLUDING MAJOR LIFE EVENTS, TRAUMATIC EVENTS, WORK, FINANCIAL, RELATIONSHIP AND CHRONIC STRESSORS CUMULATIVELY OVER TIME. GRIMAGE ACCELERATION (GAA), DETERMINED FROM WHOLE BLOOD COLLECTED FROM PARTICIPANTS, MEASURED EPIGENETIC AGE. IN ORDER TO UNDERSTAND THE IMPACT OF STRESS AND TRAUMA ON GAA, EXPLORATORY MEDIATION ANALYSES WERE THEN USED. WE FOUND CUMULATIVE STRESSORS ACROSS ALL TYPES OF EVENTS (MEAN DIFFERENCE OF 6.9 P = 2.14E-4) AND GAA (BETA = 2.29 YEARS [1.57-3.01, P = 9.70E-10] FOR RACE, PARTIAL ETA(2) = 0.091, MODEL ADJUSTED R(2) = 0.242) WERE SIGNIFICANTLY GREATER IN BLACK COMPARED TO WHITE PARTICIPANTS. CRITICALLY, CAI TOTAL SCORE (PROPORTION MEDIATED: 0.185 [0.073-0.34, P = 6E-4]) SIGNIFICANTLY MEDIATED THE RELATIONSHIP BETWEEN RACE AND GAA. FURTHER ANALYSIS ATTRIBUTED THIS DIFFERENCE TO MORE TRAUMATIC EVENTS, PARTICULARLY ASSAULTIVE TRAUMAS AND DEATH OF LOVED ONES. OUR RESULTS SUGGEST THAT, PRIOR TO DEVELOPMENT OF SIGNIFICANT CHRONIC DISEASE, BLACK INDIVIDUALS HAVE INCREASED EPIGENETIC AGE COMPARED TO WHITE PARTICIPANTS AND THAT INCREASED CUMULATIVE STRESS AND TRAUMATIC EVENTS MAY CONTRIBUTE SIGNIFICANTLY TO THIS EPIGENETIC AGING DIFFERENCE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 4689  38 NEW-ONSET POSTPARTUM PREECLAMPSIA: EPIGENETIC MECHANISM AND PREDICTION. OBJECTIVE: PLACENTAL CYTOSINE (CPG) METHYLATION WAS MEASURED TO PREDICT NEW-ONSET POSTPARTUM PREECLAMPSIA (NOPP) AND INTERROGATE ITS MOLECULAR PATHOGENESIS. METHODS: NOPP WAS DEFINED AS PATIENTS WITH A NEW DIAGNOSIS OF POSTPARTUM PREECLAMPSIA DEVELOPING >/=48 H TO </=6 WEEKS AFTER DELIVERY WITH NO PRIOR HYPERTENSIVE DISORDERS. PLACENTAL TISSUE WAS OBTAINED FROM 12 NOPP CASES AND 12 NORMOTENSIVE CONTROLS. GENOME-WIDE INDIVIDUAL CYTOSINE (CPG) METHYLATION LEVEL WAS MEASURED WITH THE INFINIUM METHYLATIONEPIC BEADCHIP ARRAY. SIGNIFICANT DIFFERENTIAL METHYLATION (NOPP VS. CONTROLS) FOR INDIVIDUAL CPG LOCI WAS DEFINED AS FALSE DISCOVERY RATE (FDR) P VALUE <.05. GENE FUNCTIONAL ENRICHMENT USING QIAGEN'S INGENUITY PATHWAY ANALYSIS (IPA) WAS PERFORMED TO HELP ELUCIDATE THE MOLECULAR PATHOGENESIS OF NOPP. A LOGISTIC REGRESSION MODEL FOR NOPP PREDICTION BASED ON THE METHYLATION LEVEL IN A COMBINATION OF CPG LOCI WAS GENERATED. THE AREA UNDER THE RECEIVER OPERATING CHARACTERISTIC CURVES (AUC [95% CI]) SENSITIVITY, AND SPECIFICITY FOR NOPP PREDICTION BASED ON THE CPG METHYLATION LEVEL WAS CALCULATED FOR EACH LOCUS. RESULTS: THERE WERE 537 (IN 540 SEPARATE GENES) SIGNIFICANTLY (FDR P<.05 WITH A >/= 2.0-FOLD METHYLATION DIFFERENCE) DIFFERENTIALLY METHYLATED CPG LOCI BETWEEN THE GROUPS. A TOTAL OF 143 INDIVIDUAL CPG MARKERS HAD EXCELLENT INDIVIDUAL PREDICTIVE ACCURACY FOR NOPP PREDICTION (AUC >/=0.80), OF WHICH 14 MARKERS HAD OUTSTANDING ACCURACY (AUC >/=0.90). A LOGISTIC REGRESSION MODEL BASED ON FIVE CPG MARKERS YIELDED AN AUC (95% CI)=0.99 (0.95-0.99) WITH SENSITIVITY 95% AND SPECIFICITY 93% FOR NOPP PREDICTION. IPA REVEALED DYSREGULATION OF CRITICAL PATHWAYS (E.G., ANGIOGENESIS, CHRONIC INFLAMMATION, AND EPITHELIAL-MESENCHYMAL TRANSITION) KNOWN TO BE LINKED TO CLASSIC PREECLAMPSIA, IN ADDITION TO OTHER PREVIOUSLY UNDESCRIBED GENES/PATHWAYS. CONCLUSIONS: THERE WAS SIGNIFICANT PLACENTAL EPIGENETIC DYSREGULATION IN NOPP. NOPP SHARED BOTH COMMON AND UNIQUE MOLECULAR PATHWAYS WITH CLASSIC PREECLAMPSIA. FINALLY, WE HAVE IDENTIFIED NOVEL POTENTIAL BIOMARKERS FOR THE EARLY POST-PARTUM PREDICTION OF NOPP.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 1990  32 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11 1645  39 DOES THE EPIGENETIC CLOCK GRIMAGE PREDICT MORTALITY INDEPENDENT OF GENETIC INFLUENCES: AN 18 YEAR FOLLOW-UP STUDY IN OLDER FEMALE TWIN PAIRS. BACKGROUND: EPIGENETIC CLOCKS ARE BASED ON DNA METHYLATION (DNAM). IT HAS BEEN SUGGESTED THAT THESE CLOCKS ARE USEABLE MARKERS OF BIOLOGICAL AGING AND PREMATURE MORTALITY. BECAUSE GENETIC FACTORS EXPLAIN VARIATIONS IN BOTH EPIGENETIC AGING AND MORTALITY, THIS ASSOCIATION COULD ALSO BE EXPLAINED BY SHARED GENETIC FACTORS. WE INVESTIGATED THE INFLUENCE OF GENETIC AND LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, CHRONIC DISEASES, BODY MASS INDEX) AND EDUCATION ON THE ASSOCIATION OF ACCELERATED EPIGENETIC AGING WITH MORTALITY USING A LONGITUDINAL TWIN DESIGN. UTILIZING A PUBLICLY AVAILABLE ONLINE TOOL, WE CALCULATED THE EPIGENETIC AGE USING TWO EPIGENETIC CLOCKS, HORVATH DNAMAGE AND DNAM GRIMAGE, IN 413 FINNISH TWIN SISTERS, AGED 63-76 YEARS, AT THE BEGINNING OF THE 18-YEAR MORTALITY FOLLOW-UP. EPIGENETIC AGE ACCELERATION WAS CALCULATED AS THE RESIDUALS FROM A LINEAR REGRESSION MODEL OF EPIGENETIC AGE ESTIMATED ON CHRONOLOGICAL AGE (AA(HORVATH), AA(GRIMAGE), RESPECTIVELY). COX PROPORTIONAL HAZARD MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS. RESULTS: THE RESULTS OF THE INDIVIDUAL-BASED ANALYSES SHOWED AN INCREASED MORTALITY HAZARD RATIO (HR) OF 1.31 (CI(95): 1.13-1.53) PER ONE STANDARD DEVIATION (SD) INCREASE IN AA(GRIMAGE). THE RESULTS INDICATED NO SIGNIFICANT ASSOCIATIONS OF AA(HORVATH) WITH MORTALITY. PAIRWISE MORTALITY ANALYSES SHOWED AN HR OF 1.50 (CI(95): 1.02-2.20) PER 1 SD INCREASE IN AA(GRIMAGE). HOWEVER, AFTER ADJUSTING FOR SMOKING, THE HR ATTENUATED SUBSTANTIALLY AND WAS STATISTICALLY NON-SIGNIFICANT (1.29; CI(95): 0.84-1.99). SIMILARLY, IN MULTIVARIABLE ADJUSTED MODELS THE HR (1.42-1.49) WAS NON-SIGNIFICANT. IN AA(HORVATH), THE NON-SIGNIFICANT HRS WERE LOWER AMONG MONOZYGOTIC PAIRS IN COMPARISON TO DIZYGOTIC PAIRS, WHILE IN AA(GRIMAGE) THERE WERE NO SYSTEMATIC DIFFERENCES BY ZYGOSITY. FURTHER, THE PAIRWISE ANALYSIS IN QUARTILES SHOWED THAT THE INCREASED WITHIN PAIR DIFFERENCE IN AA(GRIMAGE) WAS ASSOCIATED WITH A HIGHER ALL-CAUSE MORTALITY RISK. CONCLUSIONS: IN CONCLUSION, THE FINDINGS SUGGEST THAT DNAM GRIMAGE IS A STRONG PREDICTOR OF MORTALITY INDEPENDENT OF GENETIC INFLUENCES. SMOKING, WHICH IS KNOWN TO ALTER DNAM LEVELS AND IS BUILT INTO THE DNAM GRIMAGE ALGORITHM, ATTENUATED THE ASSOCIATION BETWEEN EPIGENETIC AGING AND MORTALITY RISK.	2021	
                                                                                                                                                                                                     
12 2390  35 EPIGENETIC REPRESSION OF CCDC37 AND MAP1B LINKS CHRONIC OBSTRUCTIVE PULMONARY DISEASE TO LUNG CANCER. INTRODUCTION: LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) SHARE ENVIRONMENTAL RISK FACTORS. COPD ALSO INCREASES THE RISK OF LUNG CANCER; HOWEVER, THE MOLECULAR MECHANISMS ARE UNCLEAR. METHODS: AN EPIGENOME-WIDE ASSOCIATION STUDY OF LUNG TUMORS AND CANCER-FREE LUNG TISSUE (CFLT) PAIRS FROM NON-SMALL-CELL LUNG CANCER CASES WITH (N = 18) OR WITHOUT (N = 17) COPD WAS CONDUCTED USING THE HUMANMETHYLATION450 BEADCHIP (HM450K). COPD-ASSOCIATED METHYLATION OF TOP-RANKED GENES WAS CONFIRMED IN A LARGER SAMPLE SET, INDEPENDENTLY VALIDATED, AND THEIR POTENTIAL AS SPUTUM-BASED BIOMARKERS WAS INVESTIGATED. RESULTS: METHYLATION OF CCDC37 AND MAP1B WAS MORE PREVALENT IN LUNG TUMORS FROM COPD THAN NON-COPD CASES [54 OF 71 (76%) VERSUS 20 OF 46 (43%), P = 0.0013] AND [48 OF 71 (68%) VERSUS 17 OF 46 (37%), P = 0.0035], RESPECTIVELY, AFTER ADJUSTMENT FOR AGE, SEX, SMOKING STATUS, AND TUMOR HISTOLOGY. HM450K PROBES ACROSS CCDC37 AND MAP1B PROMOTERS SHOWED HIGHER METHYLATION IN TUMORS THAN CFLT WITH THE HIGHEST METHYLATION SEEN IN TUMORS FROM COPD CASES (P < 0.05). THESE RESULTS WERE INDEPENDENTLY VALIDATED USING THE CANCER GENOME ATLAS DATA. CCDC37 METHYLATION WAS MORE PREVALENT IN SPUTUM FROM COPD THAN NON-COPD SMOKERS (P < 0.005) FROM TWO COHORTS. CCDC37 AND MAP1B EXPRESSION WAS DRAMATICALLY REPRESSED IN TUMORS AND CFLT FROM COPD THAN NON-COPD CASES, P LESS THAN 0.02. CONCLUSIONS: THE REDUCED EXPRESSION OF CCDC37 AND MAP1B ASSOCIATED WITH COPD LIKELY PREDISPOSES THESE GENES TO METHYLATION THAT IN TURN, MAY CONTRIBUTE TO LUNG CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13 1849  42 EIGHT WEEKS OF PHYSICAL TRAINING DECREASES 2 YEARS OF DNA METHYLATION AGE OF SEDENTARY WOMEN. PURPOSE: THE ACCELERATION OF EPIGENETIC AGE IS A PREDICTOR OF MORTALITY AND CONTRIBUTES TO THE INCREASE IN CHRONIC DISEASES. ADHERENCE TO A HEALTHY LIFESTYLE IS A STRATEGY TO REDUCE EPIGENETIC AGE. THE PRESENT STUDY AIMED TO DETERMINE WHETHER EIGHT WEEKS OF COMBINED (AEROBIC AND STRENGTH) TRAINING (CT) CAN INFLUENCE THE EPIGENETIC AGE OF WOMEN BETWEEN 50 AND 70 YEARS OLD AND THE DIFFERENCES IN SITES AND METHYLATED REGIONS. METHODS: EIGHTEEN WOMEN (AAR(LOW): LOWER AGE ACCELERATION RESIDUAL, N = 10; AAR(HIGH): HIGHER AGE ACCELERATION RESIDUAL, N = 8) PARTICIPATED IN A COMBINED EXERCISE TRAINING PROGRAM (60 MINUTES, 3X A WEEK) FOR EIGHT WEEKS. DNA WAS EXTRACTED FROM WHOLE BLOOD USING THE SALTING OUT TECHNIQUE. DNA METHYLATION WAS PERFORMED USING THE ARRAY TECHNIQUE (ILLUMINA'S INFINIUM METHYLATION BEADCHIP 850K). WE USED THE DNA METHYLATION AGE CALCULATOR PLATFORM TO CALCULATE THE BIOLOGICAL EPIGENETIC AGE. TWO-WAY ANOVA FOLLOWED BY FISHER LSD POSTHOC WAS APPLIED, ADOPTING P < .05. RESULTS: AFTER EIGHT WEEKS OF CT, THERE WERE NO CHANGES TO THE EPIGENETIC AGE ACCELERATION FOR THE AAR(LOW) GROUP (PRE: -2.3 +/- 3.2 TO POST: -2.3 +/- 3.6). HOWEVER, THE AAR(HIGH) GROUP SIGNIFICANTLY DECREASED THE AGE ACCELERATION (PRE: 3.6 +/- 2.6 TO POST: 2.2 +/- 2.7) (GROUP EFFECT, P = .01; TIME EFFECT, P = .31; GROUP VS. TIME EFFECT, P = .005). CONCLUSION: CT FOR EIGHT WEEKS BENEFITS THE EPIGENETIC CLOCK OF WOMEN WITH THE MOST ACCELERATED AGE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  508  39 ASSOCIATION OF LOW-DOSE EXPOSURE TO PERSISTENT ORGANIC POLLUTANTS WITH E-CADHERIN PROMOTER METHYLATION IN HEALTHY KOREANS. BACKGROUND: PERSISTENT ORGANIC POLLUTANTS (POPS), DESPITE THEIR CONSIDERABLY LOW LEVELS IN HUMANS, ARE AN INCREASING CONCERN FOR THE GENERAL POPULATIONS GIVEN THEIR VARIOUS ADVERSE HEALTH PROBLEMS, INCLUDING METABOLIC AND CARCINOGENIC EFFECTS. DNA METHYLATION DEREGULATION IS THOUGHT TO BE A KEY MECHANISM IN THE DEVELOPMENT OF HUMAN CHRONIC DISEASES INCLUDING CANCER. METHODS: IN AN ATTEMPT TO IDENTIFY BIOMARKERS MONITORING LOW-DOSE EXPOSURE AND HAZARD, WE EXPLORED WHETHER ORGANOCHLORINE PESTICIDES (OCPS) AND POLYCHLORINATED BIPHENYLS (PCBS) MAY INFLUENCE THE METHYLATION OF TUMOUR SUPPRESSOR GENE E-CADHERIN (CDH1) USING PERIPHERAL BLOOD CELLS FROM 364 HEALTHY KOREAN SUBJECTS. RESULTS: CDH1 METHYLATION WAS OBSERVED IN 78.3% OF STUDY SUBJECTS. SERUM CONCENTRATIONS OF OCPS OR PCBS COMPOUNDS WERE HIGHER IN CDH1 METHYLATION-POSITIVE SUBJECTS THAN IN METHYLATION-NEGATIVE ONES. AFTER ADJUSTING FOR VARIOUS COVARIATES, THE ODDS RATIO OF CDH1 METHYLATION OF THE SUMMARY MEASURE OF PCBS WERE 1.0, 2.5 (95% CONFIDENCE INTERVAL: 1.2-5.3), 3.6 (1.6-8.1), 3.6 (1.4-8.6), AND 2.5 (1.1-5.7) ACROSS QUINTILES OF PCBS (P(TREND) = 0.01). THE VALUES OF OCPS WERE 1.0, 0.9, 1.2, 2.4 (1.0-5.9), AND 1.7 (P(TREND) = 0.05). CONCLUSIONS: IN THIS EXPLORATORY STUDY WITH A SMALL SAMPLE, CDH1 METHYLATION MIGHT BE SERVED AS THE EPIGENETIC BIOMARKER ASSOCIATED WITH POPS EXPOSURE AND ADVERSE HEALTH EFFECT.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 4818  34 OCCURRENCE OF ACCELERATED EPIGENETIC AGING AND METHYLATION DISRUPTIONS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE ANTIRETROVIRAL THERAPY. BACKGROUND: WHETHER ACCELERATED AGING DEVELOPS OVER THE COURSE OF CHRONIC HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION OR CAN BE OBSERVED BEFORE SIGNIFICANT IMMUNOSUPPRESSION ON IS UNKNOWN. WE STUDIED DNA METHYLATION IN BLOOD TO ESTIMATE CELLULAR AGING IN PERSONS LIVING WITH HIV (PLWH) BEFORE THE INITIATION OF ANTIRETROVIRAL THERAPY (ART). METHODS: A TOTAL OF 378 ART-NAIVE PLWH WHO HAD CD4 T-CELL COUNTS >500/MICROL AND WERE ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL THERAPY TRIAL (PULMONARY SUBSTUDY) WERE COMPARED WITH 34 HIV-NEGATIVE CONTROLS. DNA METHYLATION WAS PERFORMED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN PLWH COMPARED WITH CONTROLS WERE IDENTIFIED USING A ROBUST LINEAR MODEL. METHYLATION AGE WAS CALCULATED USING A PREVIOUSLY DESCRIBED EPIGENETIC CLOCK. RESULTS: THERE WERE A TOTAL OF 56 639 DMPS AND 6103 DMRS AT A FALSE DISCOVERY RATE OF <0.1. THE TOP 5 DMPS CORRESPONDED TO GENES NLRC5, VRK2, B2M, AND GPR6 AND WERE HIGHLY ENRICHED FOR CANCER-RELATED PATHWAYS. PLWH HAD SIGNIFICANTLY HIGHER METHYLATION AGE THAN HIV-NEGATIVE CONTROLS (P = .001), WITH BLACK RACE, LOW CD4 AND HIGH CD8 T-CELL COUNTS, AND DURATION OF HIV BEING RISK FACTORS FOR AGE ACCELERATION. CONCLUSIONS: PLWH BEFORE THE INITIATION OF ART AND WITH PRESERVED IMMUNE STATUS SHOW EVIDENCE OF ADVANCED METHYLATION AGING.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 1355  25 DEVELOPMENT AND VALIDATION OF A SIMPLE GENERAL POPULATION LUNG CANCER RISK MODEL INCLUDING AHRR-METHYLATION. INTRODUCTION: SCREENING REDUCES LUNG CANCER MORTALITY OF HIGH-RISK POPULATIONS. CURRENTLY PROPOSED SCREENING ELIGIBILITY CRITERIA ONLY IDENTIFY HALF OF THOSE INDIVIDUALS, WHO LATER DEVELOP LUNG CANCER. THIS STUDY AIMED TO DEVELOP AND VALIDATE A SENSITIVE AND SIMPLE MODEL FOR PREDICTING 10-YEAR LUNG CANCER RISK. METHODS: USING THE 1991-94 EXAMINATION OF THE COPENHAGEN CITY HEART STUDY IN DENMARK, 6,820 FORMER OR CURRENT SMOKERS FROM THE GENERAL POPULATION WERE FOLLOWED FOR LUNG CANCER WITHIN 10 YEARS AFTER EXAMINATION. LOGISTIC REGRESSION OF BASELINE VARIABLES (AGE, SEX, EDUCATION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, FAMILY HISTORY OF LUNG CANCER, SMOKING STATUS AND CUMULATIVE SMOKING, SECONDHAND SMOKING, OCCUPATIONAL EXPOSURES TO DUST AND FUME, BODY MASS INDEX, LUNG FUNCTION, PLASMA C-REACTIVE PROTEIN, AND AHRR(CG05575921) METHYLATION) IDENTIFIED THE BEST PREDICTIVE MODEL. THE MODEL WAS VALIDATED AMONG 3,740 FORMER OR CURRENT SMOKERS FROM THE 2001-03 EXAMINATION, ALSO FOLLOWED FOR 10 YEARS. A SIMPLE RISK CHART WAS DEVELOPED WITH POISSON REGRESSION. RESULTS: AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION IDENTIFIED 65 OF 88 INDIVIDUALS WHO DEVELOPED LUNG CANCER IN THE VALIDATION COHORT. THE HIGHEST RISK GROUP, CONSISTING OF LESS EDUCATED MEN AGED >65 WITH CURRENT SMOKING STATUS AND CUMULATIVE SMOKING >20 PACK-YEARS, HAD ABSOLUTE 10-YEAR RISKS VARYING FROM 4% TO 16% BY AHRR(CG05575921) METHYLATION. CONCLUSION: A SIMPLE RISK CHART INCLUDING AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION, IDENTIFIES INDIVIDUALS WITH 10-YEAR LUNG CANCER RISK FROM BELOW 1% TO 16%. INCLUDING AHRR(CG05575921) METHYLATION IN THE ELIGIBILITY CRITERIA FOR SCREENING IDENTIFIES SMOKERS WHO WOULD BENEFIT THE MOST FROM SCREENING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17 1138  29 COMPUTATIONAL METHODS FOR DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING KERNEL DISTANCE AND SCAN STATISTICS. MOTIVATION: RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE SEQUENCE OF DNA. ABNORMAL DNA METHYLATION IS ASSOCIATED WITH MANY HUMAN DISEASES. RESULTS: WE PROPOSE TWO DIFFERENT APPROACHES TO TEST FOR DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH COMPLEX TRAITS, WHILE ACCOUNTING FOR CORRELATIONS AMONG CPG SITES IN THE DMRS. THE FIRST APPROACH IS A NONPARAMETRIC METHOD USING A KERNEL DISTANCE STATISTIC AND THE SECOND ONE IS A LIKELIHOOD-BASED METHOD USING A BINOMIAL SPATIAL SCAN STATISTIC. THE KERNEL DISTANCE METHOD USES THE KERNEL FUNCTION, WHILE THE BINOMIAL SCAN STATISTIC APPROACH USES A MIXED-EFFECTS MODEL TO INCORPORATE CORRELATIONS AMONG CPG SITES. EXTENSIVE SIMULATIONS SHOW THAT BOTH APPROACHES HAVE EXCELLENT CONTROL OF TYPE I ERROR, AND BOTH HAVE REASONABLE STATISTICAL POWER. THE BINOMIAL SCAN STATISTIC APPROACH APPEARS TO HAVE HIGHER POWER, WHILE THE KERNEL DISTANCE METHOD IS COMPUTATIONALLY FASTER. THE PROPOSED METHODS ARE DEMONSTRATED USING DATA FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18 1846  28 EFFECTS OF TWO TYPES OF ENERGY RESTRICTION ON METHYLATION LEVELS OF ADIPONECTIN RECEPTOR 1 AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT IN A MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA BREAST CANCER MOUSE MODEL. THE ROLE OF ADIPONECTIN AND LEPTIN SIGNALLING PATHWAYS HAS BEEN SUGGESTED TO PLAY IMPORTANT ROLES IN THE PROTECTIVE EFFECTS OF ENERGY RESTRICTION (ER) ON MAMMARY TUMOUR (MT) DEVELOPMENT. TO STUDY THE EFFECTS OF ER ON THE METHYLATION LEVELS IN ADIPONECTIN RECEPTOR 1 (ADIPOR1) AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT (LEPROT) GENES USING THE PYROSEQUENCING METHOD IN MAMMARY FAT PAD TISSUE, MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA (MMTV-TGF-ALPHA) FEMALE MICE WERE RANDOMLY ASSIGNED TO AD LIBITUM (AL), CHRONIC ER (CER, 15 % ER) OR INTERMITTENT ER (3 WEEKS AL AND 1 WEEK 60 % ER IN CYCLIC PERIODS) GROUPS AT 10 WEEKS OF AGE UNTIL 82 WEEKS OF AGE. THE METHYLATION LEVELS OF ADIPOR1 IN THE CER GROUP WERE HIGHER THAN THOSE IN THE AL GROUP AT WEEK 49/50 (P < 0.05), WHILE THE LEVELS OF METHYLATION FOR ADIPOR1 AND LEPROT GENES WERE SIMILAR AMONG THE OTHER GROUPS. ALSO, THE METHYLATION LEVELS AT CPG2 AND CPG3 REGIONS OF THE PROMOTER REGION OF THE ADIPOR1 GENE IN THE CER GROUP WERE THREE TIMES HIGHER (P < 0.05), WHILE CPG1 ISLAND OF LEPROT METHYLATION WAS SIGNIFICANTLY LOWER COMPARED WITH THE OTHER GROUPS (P < 0.05). ADIPONECTIN AND LEPTIN GENE EXPRESSION LEVELS WERE CONSISTENT WITH THE METHYLATION LEVELS. WE ALSO OBSERVED A CHANGE WITH AGEING IN METHYLATION LEVELS OF THESE GENES. THESE RESULTS INDICATE THAT DIFFERENT TYPES OF ER MODIFY METHYLATION LEVELS OF ADIPOR1 AND LEPROT IN DIFFERENT WAYS AND CER HAD A MORE SIGNIFICANT EFFECT ON METHYLATION LEVELS OF BOTH GENES. EPIGENETIC REGULATION OF THESE GENES MAY PLAY IMPORTANT ROLES IN THE PREVENTIVE EFFECTS OF ER AGAINST MT DEVELOPMENT AND AGEING PROCESSES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  475  38 ARSENIC EXPOSURE AND HUMAN BLOOD DNA METHYLATION AND HYDROXYMETHYLATION PROFILES IN TWO DIVERSE POPULATIONS FROM BANGLADESH AND SPAIN. BACKGROUND: ASSOCIATIONS OF ARSENIC (AS) WITH THE SUM OF 5-MC AND 5-HMC LEVELS HAVE BEEN REPORTED; HOWEVER, AS EXPOSURE-RELATED DIFFERENCES OF THE SEPARATED 5-MC AND 5-HMC MARKERS HAVE RARELY BEEN STUDIED. METHODS: IN THIS STUDY, WE EVALUATED THE ASSOCIATION OF ARSENIC EXPOSURE BIOMARKERS AND 5-MC AND 5-HMC IN 30 HEALTHY MEN (43-55 YEARS) FROM THE ARAGON WORKERS HEALTH STUDY (AWHS) (SPAIN) AND 31 HEALTHY MEN (31-50 YEARS) FROM THE FOLIC ACID AND CREATININE TRIAL (FACT) (BANGLADESH). WE CONDUCTED 5-MC AND 5-HMC PROFILING USING INFINIUM METHYLATIONEPIC ARRAYS, ON PAIRED STANDARD AND MODIFIED (OX-BS IN AWHS AND TAB IN FACT) BISULFITE CONVERTED BLOOD DNA SAMPLES. RESULTS: THE MEDIAN FOR THE SUM OF URINE INORGANIC AND METHYLATED AS SPECIES (SIGMAAS) (MUG/L) WAS 12.5 FOR AWHS AND 89.6 FOR FACT. THE MEDIAN OF BLOOD AS (MUG/L) WAS 8.8 FOR AWHS AND 10.2 FOR FACT. AT A STATISTICAL SIGNIFICANCE P-VALUE CUT-OFF OF 0.01, THE DIFFERENTIALLY METHYLATED (DMP) AND HYDROXYMETHYLATED (DHP) POSITIONS WERE MOSTLY LOCATED IN DIFFERENT GENOMIC SITES. SEVERAL DMPS AND DHPS WERE CONSISTENTLY FOUND IN AWHS AND FACT BOTH FOR URINE SIGMAAS AND BLOOD MODELS, BEING OF SPECIAL INTEREST THOSE ATTRIBUTED TO THE DIP2C GENE. THREE DMPS (ANNOTATED TO CLEC12A) FOR AWHS AND ONE DHP (ANNOTATED TO NPLOC4) FOR FACT REMAINED STATISTICALLY SIGNIFICANT AFTER FALSE DISCOVERY RATE (FDR) CORRECTION. PATHWAYS RELATED TO CHRONIC DISEASES INCLUDING CARDIOVASCULAR, CANCER AND NEUROLOGICAL WERE ENRICHED. CONCLUSIONS: WHILE WE IDENTIFIED COMMON 5-HMC AND 5-MC SIGNATURES IN TWO POPULATIONS EXPOSED TO VARYING LEVELS OF INORGANIC AS, DIFFERENCES IN AS-RELATED EPIGENETIC SITES ACROSS THE STUDY POPULATIONS MAY ADDITIONALLY REFLECT LOW AND HIGH AS-SPECIFIC ASSOCIATIONS. THIS WORK CONTRIBUTES A DEEPER UNDERSTANDING OF POTENTIAL EPIGENETIC DYSREGULATIONS OF AS. HOWEVER, FURTHER RESEARCH IS NEEDED TO CONFIRM BIOLOGICAL CONSEQUENCES ASSOCIATED WITH DIP2C EPIGENETIC REGULATION AND TO INVESTIGATE THE ROLE OF 5-HMC AND 5-MC SEPARATELY IN AS-INDUCED HEALTH DISORDERS AT DIFFERENT EXPOSURE LEVELS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20 1541  26 DNA METHYLATION IN GENES OF LONGEVITY-REGULATING PATHWAYS: ASSOCIATION WITH OBESITY AND METABOLIC COMPLICATIONS. AGING IS THE MAIN RISK FACTOR FOR MOST CHRONIC DISEASES. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION (DNAM) PLAYS A PIVOTAL ROLE IN THE REGULATION OF PHYSIOLOGICAL RESPONSES THAT CAN VARY ALONG LIFESPAN. THE AIM OF THIS RESEARCH WAS TO ANALYZE THE ASSOCIATION BETWEEN LEUKOCYTE DNAM IN GENES INVOLVED IN LONGEVITY AND THE OCCURRENCE OF OBESITY AND RELATED METABOLIC ALTERATIONS IN AN ADULT POPULATION. SUBJECTS FROM THE MENA COHORT (N=474) WERE CATEGORIZED ACCORDING TO AGE (<45 VS 45>) AND THE PRESENCE OF METABOLIC ALTERATIONS: INCREASED WAIST CIRCUMFERENCE, HYPERCHOLESTEROLEMIA, INSULIN RESISTANCE, AND METABOLIC SYNDROME. THE METHYLATION LEVELS OF 58 CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE STRONGLY CORRELATED (FDR-ADJUSTED< 0.0001) WITH BMI. FIFTEEN OF THEM WERE DIFFERENTIALLY METHYLATED (P<0.05) BETWEEN YOUNGER AND OLDER SUBJECTS THAT EXHIBITED AT LEAST ONE METABOLIC ALTERATION. SIX OF THESE CPG SITES, LOCATED AT MTOR (CG08862778), ULK1 (CG07199894), ADCY6 (CG11658986), IGF1R (CG01284192), CREB5 (CG11301281), AND RELA (CG08128650), WERE COMMON TO THE METABOLIC TRAITS, AND CREB5, RELA, AND ULK1 WERE STATISTICALLY ASSOCIATED WITH AGE. IN SUMMARY, LEUKOCYTE DNAM LEVELS OF SEVERAL CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME TRAITS, SUGGESTING A ROLE OF DNAM IN AGING-RELATED METABOLIC ALTERATIONS.	2019