1 2623 125 EPIGENOME-WIDE ASSOCIATION STUDIES OF THE FRACTIONAL EXHALED NITRIC OXIDE AND BRONCHODILATOR DRUG RESPONSE IN MODERATE-TO-SEVERE PEDIATRIC ASTHMA. ASTHMA IS THE MOST PREVALENT PEDIATRIC CHRONIC DISEASE. BRONCHODILATOR DRUG RESPONSE (BDR) AND FRACTIONAL EXHALED NITRIC OXIDE (FENO) ARE CLINICAL BIOMARKERS OF ASTHMA. ALTHOUGH DNA METHYLATION (DNAM) CONTRIBUTES TO ASTHMA PATHOGENESIS, THE INFLUENCE OF DNAM ON BDR AND FENO IS SCARCELY INVESTIGATED. THIS STUDY AIMS TO IDENTIFY DNAM MARKERS IN WHOLE BLOOD ASSOCIATED EITHER WITH BDR OR FENO IN PEDIATRIC ASTHMA. WE ANALYZED 121 SAMPLES FROM CHILDREN WITH MODERATE-TO-SEVERE ASTHMA. THE ASSOCIATION OF GENOME-WIDE DNAM WITH BDR AND FENO HAS BEEN ASSESSED USING REGRESSION MODELS, ADJUSTING FOR AGE, SEX, ANCESTRY, AND TISSUE HETEROGENEITY. CROSS-TISSUE VALIDATION WAS ASSESSED IN 50 NASAL SAMPLES. DIFFERENTIALLY METHYLATED REGIONS (DMRS) AND ENRICHMENT IN TRAITS AND BIOLOGICAL PATHWAYS WERE ASSESSED. A FALSE DISCOVERY RATE (FDR) < 0.1 AND A GENOME-WIDE SIGNIFICANCE THRESHOLD OF P < 9 X 10(-8) WERE USED TO CONTROL FOR FALSE-POSITIVE RESULTS. THE CPG CG12835256 (PLA2G12A) WAS GENOME-WIDE ASSOCIATED WITH FENO IN BLOOD SAMPLES (COEFFICIENT= -0.015, P = 2.53 X 10(-9)) AND NOMINALLY ASSOCIATED IN NASAL SAMPLES (COEFFICIENT = -0.015, P = 0.045). ADDITIONALLY, THREE CPGS WERE SUGGESTIVELY ASSOCIATED WITH BDR (FDR < 0.1). WE IDENTIFIED 12 AND FOUR DMRS ASSOCIATED WITH FENO AND BDR (FDR < 0.05), RESPECTIVELY. AN ENRICHMENT IN ALLERGIC AND INFLAMMATORY PROCESSES, SMOKING, AND AGING WAS OBSERVED. WE REPORTED NOVEL ASSOCIATIONS OF DNAM MARKERS ASSOCIATED WITH BDR AND FENO ENRICHED IN ASTHMA-RELATED PROCESSES. 2023 2 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 3 57 42 A GENOME-WIDE ASSOCIATION STUDY OF QUANTITATIVE COMPUTED TOMOGRAPHIC EMPHYSEMA IN KOREAN POPULATIONS. EMPHYSEMA IS AN IMPORTANT FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). GENETIC FACTORS LIKELY AFFECT EMPHYSEMA PATHOGENESIS, BUT THIS QUESTION HAS PREDOMINANTLY BEEN STUDIED IN THOSE OF EUROPEAN ANCESTRY. IN THIS STUDY, WE SOUGHT TO DETERMINE GENETIC COMPONENTS OF EMPHYSEMA SEVERITY AND CHARACTERIZE THE POTENTIAL FUNCTION OF THE ASSOCIATED LOCI IN KOREAN POPULATION. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) ON QUANTITATIVE EMPHYSEMA IN SUBJECTS WITH OR WITHOUT COPD FROM TWO KOREAN COPD COHORTS. WE INVESTIGATED THE FUNCTIONAL CONSEQUENCES OF THE LOCI USING EPIGENETIC ANNOTATION AND GENE EXPRESSION DATA. WE ALSO COMPARED OUR GWAS RESULTS WITH AN EPIGENOME-WIDE ASSOCIATION STUDY AND PREVIOUS DIFFERENTIAL GENE EXPRESSION ANALYSIS. IN TOTAL, 548 SUBJECTS (476 [86.9%] MALE) INCLUDING 514 COPD PATIENTS WERE EVALUATED. WE IDENTIFIED ONE GENOME-WIDE SIGNIFICANT SNP (P < 5.0 X 10(-8)), RS117084279, NEAR PIBF1. WE IDENTIFIED AN ADDITIONAL 57 SNPS (P < 5.0 X 10(-6)) ASSOCIATED WITH EMPHYSEMA IN ALL SUBJECTS, AND 106 SNPS (P < 5.0 X 10(-6)) IN COPD PATIENTS. OF THESE CANDIDATE SNPS, 2 (RS12459249, RS11667314) NEAR CYP2A6 WERE EXPRESSION QUANTITATIVE TRAIT LOCI IN LUNG TISSUE AND A SNP (RS11214944) NEAR NNMT WAS AN EXPRESSION QUANTITATIVE TRAIT LOCUS IN WHOLE BLOOD. OF NOTE, RS11214944 WAS IN LINKAGE DISEQUILIBRIUM WITH VARIANTS IN ENHANCER HISTONE MARKS IN LUNG TISSUE. SEVERAL GENES NEAR ADDITIONAL SNPS WERE IDENTIFIED IN OUR PREVIOUS EWAS STUDY WITH NOMINAL LEVEL OF SIGNIFICANCE. WE IDENTIFIED A NOVEL SNP ASSOCIATED WITH QUANTITATIVE EMPHYSEMA ON CT. INCLUDING THE NOVEL SNP, SEVERAL CANDIDATE SNPS IN OUR STUDY MAY PROVIDE CLUES TO THE GENETIC ETIOLOGY OF EMPHYSEMA IN ASIAN POPULATIONS. FURTHER RESEARCH AND VALIDATION OF THE LOCI WILL HELP DETERMINE THE GENETIC FACTORS FOR THE DEVELOPMENT OF EMPHYSEMA. 2021 4 2921 42 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 4818 35 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 6 1590 36 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS. 2016 7 5883 31 SYSTEMIC AND AIRWAY EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH HEALTH STATUS IN COPD. EPIGENETIC MODIFICATIONS ARE COMMON IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD); HOWEVER, THEIR CLINICAL RELEVANCE IS LARGELY UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH SYMPTOMS AND HEALTH STATUS IN COPD. WE PROFILED THE BLOOD (N = 57) AND AIRWAYS (N = 62) OF COPD PATIENTS FOR DNA METHYLATION (N = 55 PAIRED). THE PATIENTS' HEALTH STATUS WAS ASSESSED USING THE ST. GEORGE'S RESPIRATORY QUESTIONNAIRE (SGRQ). WE CONDUCTED DIFFERENTIAL METHYLATION ANALYSES AND IDENTIFIED PATHWAYS CHARACTERIZED BY EPIGENETIC DISRUPTIONS ASSOCIATED WITH SGRQ SCORES AND ITS INDIVIDUAL DOMAINS. 29,211 AND 5044 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE ASSOCIATED WITH TOTAL SGRQ SCORES IN BLOOD AND AIRWAY SAMPLES, RESPECTIVELY. THE ACTIVITY, IMPACT, AND SYMPTOM DOMAINS WERE ASSOCIATED WITH 9161, 25,689 AND 17,293 DMPS IN BLOOD, RESPECTIVELY; AND 4674, 3730 AND 5063 DMPS IN AIRWAYS, RESPECTIVELY. THERE WAS A SUBSTANTIAL OVERLAP OF DMPS BETWEEN AIRWAY AND BLOOD. DMPS WERE ENRICHED FOR PATHWAYS RELATED TO COMMON CO-MORBIDITIES OF COPD (E.G., AGEING, CANCER AND NEUROLOGICAL) IN BOTH TISSUES. HEALTH STATUS IN COPD IS ASSOCIATED WITH AIRWAY AND SYSTEMIC EPIGENETIC CHANGES ESPECIALLY IN PATHWAYS RELATED TO CO-MORBIDITIES OF COPD. THERE ARE MORE BLOOD DMPS THAN IN THE AIRWAYS SUGGESTING THAT BLOOD EPIGENOME IS A PROMISING SOURCE TO DISCOVER BIOMARKERS FOR CLINICAL OUTCOMES IN COPD. 2023 8 1529 35 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 9 1849 31 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 10 4750 36 NOVEL REGIONAL AGE-ASSOCIATED DNA METHYLATION CHANGES WITHIN HUMAN COMMON DISEASE-ASSOCIATED LOCI. BACKGROUND: ADVANCING AGE PROGRESSIVELY IMPACTS ON RISK AND SEVERITY OF CHRONIC DISEASE. IT ALSO MODIFIES THE EPIGENOME, WITH CHANGES IN DNA METHYLATION, DUE TO BOTH RANDOM DRIFT AND VARIATION WITHIN SPECIFIC FUNCTIONAL LOCI. RESULTS: IN A DISCOVERY SET OF 2238 PERIPHERAL-BLOOD GENOME-WIDE DNA METHYLOMES AGED 19-82 YEARS, WE IDENTIFY 71 AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS WITHIN THE LINKAGE DISEQUILIBRIUM BLOCKS OF THE SINGLE NUCLEOTIDE POLYMORPHISMS FROM THE NIH GENOME-WIDE ASSOCIATION STUDY CATALOGUE. THIS INCLUDED 52 NOVEL REGIONS, 29 WITHIN LOCI NOT COVERED BY 450 K OR 27 K ILLUMINA ARRAY, AND WITH ENRICHMENT FOR DNASE-I HYPERSENSITIVITY SITES ACROSS THE FULL RANGE OF TISSUES. THESE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS ALSO SHOW MARKED ENRICHMENT FOR ENHANCERS AND POISED PROMOTERS ACROSS MULTIPLE CELL TYPES. IN A REPLICATION SET OF 2084 DNA METHYLOMES, 95.7 % OF THE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS SHOWED THE SAME DIRECTION OF AGEING EFFECT, WITH 80.3 % AND 53.5 % REPLICATED TO P < 0.05 AND P < 1.85 X 10(-8), RESPECTIVELY. CONCLUSION: BY ANALYSING THE FUNCTIONALLY ENRICHED DISEASE AND TRAIT-ASSOCIATED REGIONS OF THE HUMAN GENOME, WE IDENTIFY NOVEL EPIGENETIC AGEING CHANGES, WHICH COULD BE USEFUL BIOMARKERS OR PROVIDE MECHANISTIC INSIGHTS INTO AGE-RELATED COMMON DISEASES. 2016 11 4024 36 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT. 2021 12 2645 35 EPIGENOMIC INDICATORS OF AGE IN AFRICAN AMERICANS. AGE IS A WELL-ESTABLISHED RISK FACTOR FOR CHRONIC DISEASES. HOWEVER, THE CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH AGING PROCESSES THAT ARE RELATED TO CHRONIC DISEASE INITIATION AND PROGRESSION ARE NOT WELL-UNDERSTOOD. THUS, THERE IS AN INCREASED NEED TO IDENTIFY NEW MARKERS OF CELLULAR AND MOLECULAR CHANGES THAT OCCUR DURING AGING PROCESSES. IN THIS STUDY, WE USE GENOME-WIDE DNA METHYLATION FROM 26,428 CPG SITES IN 13,877 GENES TO INVESTIGATE THE RELATIONSHIP BETWEEN AGE AND EPIGENETIC VARIATION IN THE PERIPHERAL BLOOD CELLS OF 972 AFRICAN AMERICAN ADULTS FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY (GENOA) STUDY (MEAN AGE=66.3 YEARS, RANGE=39-95). AGE WAS SIGNIFICANTLY ASSOCIATED WITH 7,601 (28.8%) CPG SITES AFTER BONFERRONI CORRECTION FOR ALPHA=0.05 (P<1.89X10(-6)). DUE TO THE EXTRAORDINARILY STRONG ASSOCIATIONS BETWEEN AGE AND MANY OF THE CPG SITES (>7,000 SITES WITH P-VALUES RANGING FROM 10(-6) TO 10(-43)), WE INVESTIGATED HOW WELL THE DNA METHYLATION MARKERS PREDICT AGE. WE FOUND THAT 2,095 (7.9%) CPG SITES WERE SIGNIFICANT PREDICTORS OF AGE AFTER BONFERRONI CORRECTION. THE TOP FIVE PRINCIPAL COMPONENTS OF THE 2,095 AGE-ASSOCIATED CPG SITES ACCOUNTED FOR 69.3% OF THE VARIABILITY IN THESE CPG SITES, AND THEY EXPLAINED 26.8% OF THE VARIATION IN AGE. THE ASSOCIATIONS BETWEEN METHYLATION MARKERS AND ADULT AGE ARE SO UBIQUITOUS AND STRONG THAT WE HYPOTHESIZE THAT DNA METHYLATION PATTERNS MAY BE AN IMPORTANT MEASURE OF CELLULAR AGING PROCESSES. GIVEN THE HIGHLY CORRELATED NATURE OF THE AGE-ASSOCIATED EPIGENOME (AS EVIDENCED BY THE PRINCIPAL COMPONENTS ANALYSIS), WHOLE PATHWAYS MAY BE REGULATED AS A CONSEQUENCE OF AGING. 2014 13 475 43 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 14 2110 44 EPIGENETIC FINDINGS IN PERIODONTITIS IN UK TWINS: A CROSS-SECTIONAL STUDY. BACKGROUND: GENETIC AND ENVIRONMENTAL RISK FACTORS CONTRIBUTE TO PERIODONTAL DISEASE, BUT THE UNDERLYING SUSCEPTIBILITY PATHWAYS ARE NOT FULLY UNDERSTOOD. EPIGENETIC MECHANISMS ARE MALLEABLE REGULATORS OF GENE FUNCTION THAT CAN CHANGE IN RESPONSE TO GENETIC AND ENVIRONMENTAL STIMULI, THEREBY PROVIDING A POTENTIAL MECHANISM FOR MEDIATING RISK EFFECTS IN PERIODONTITIS. THE AIM OF THIS STUDY IS TO IDENTIFY EPIGENETIC CHANGES ACROSS TISSUES THAT ARE ASSOCIATED WITH PERIODONTAL DISEASE. METHODS: SELF-REPORTED GINGIVAL BLEEDING AND HISTORY OF GUM DISEASE, OR TOOTH MOBILITY, WERE USED AS INDICATORS OF PERIODONTAL DISEASE. DNA METHYLATION PROFILES WERE GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP IN WHOLE BLOOD, BUCCAL, AND ADIPOSE TISSUE SAMPLES FROM PREDOMINANTLY OLDER FEMALE TWINS (MEAN AGE 58) FROM THE TWINSUK COHORT. EPIGENOME-WIDE ASSOCIATION SCANS (EWAS) OF GINGIVAL BLEEDING AND TOOTH MOBILITY WERE CONDUCTED IN WHOLE BLOOD IN 528 AND 492 TWINS, RESPECTIVELY. SUBSEQUENTLY, TARGETED CANDIDATE GENE ANALYSIS AT 28 GENOMIC REGIONS WAS CARRIED OUT TESTING FOR PHENOTYPE-METHYLATION ASSOCIATIONS IN 41 (TOOTH MOBILITY) AND 43 (GINGIVAL BLEEDING) BUCCAL, AND 501 (TOOTH MOBILITY) AND 556 (GINGIVAL BLEEDING) ADIPOSE DNA SAMPLES. RESULTS: EPIGENOME-WIDE ANALYSES IN BLOOD IDENTIFIED ONE CPG-SITE (CG21245277 IN ZNF804A) ASSOCIATED WITH GINGIVAL BLEEDING (FDR = 0.03, NOMINAL P VALUE = 7.17E-8) AND 58 SITES ASSOCIATED WITH TOOTH MOBILITY (FDR < 0.05) WITH THE TOP SIGNALS IN IQCE AND XKR6. EPIGENETIC VARIATION AT 28 CANDIDATE REGIONS (247 CPG-SITES) FOR CHRONIC PERIODONTITIS SHOWED AN ENRICHMENT FOR ASSOCIATION WITH PERIODONTAL TRAITS, AND SIGNALS IN EIGHT GENES (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, AND CXCL1) WERE SIGNIFICANT IN BOTH TRAITS. THE METHYLATION-PHENOTYPE ASSOCIATION SIGNALS VALIDATED IN BUCCAL SAMPLES, AND A SUBSET (25%) ALSO VALIDATED IN ADIPOSE TISSUE. CONCLUSIONS: EPIGENOME-WIDE ANALYSES IN ADULT FEMALE TWINS IDENTIFIED SPECIFIC DNA METHYLATION CHANGES LINKED TO SELF-REPORTED PERIODONTAL DISEASE. FUTURE WORK WILL EXPLORE THE ENVIRONMENTAL BASIS AND FUNCTIONAL IMPACT OF THESE RESULTS TO INFER POTENTIAL FOR STRATEGIC PERSONALIZED TREATMENTS AND PREVENTION OF CHRONIC PERIODONTITIS. 2019 15 382 46 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 16 4689 39 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 /= 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 17 504 33 ASSOCIATION OF CIGARETTE SMOKING AND CRP LEVELS WITH DNA METHYLATION IN ALPHA-1 ANTITRYPSIN DEFICIENCY. ALPHA-1 ANTITRYPSIN (AAT) DEFICIENCY AND TOBACCO SMOKING ARE CONFIRMED RISK FACTORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. WE HYPOTHESIZED THAT VARIABLE DNA METHYLATION WOULD BE ASSOCIATED WITH SMOKING AND INFLAMMATION, AS REFLECTED BY THE LEVEL OF C-REACTIVE PROTEIN (CRP) IN AAT-DEFICIENT SUBJECTS. METHYLATION LEVELS OF 1,411 AUTOSOMAL CPG SITES FROM THE ILLUMINA GOLDENGATE METHYLATION CANCER PANEL I WERE ANALYZED IN 316 SUBJECTS. ASSOCIATIONS OF FIVE SMOKING BEHAVIORS AND CRP LEVELS WITH INDIVIDUAL CPG SITES AND AVERAGE METHYLATION LEVELS WERE ASSESSED USING NON-PARAMETRIC TESTING, LINEAR REGRESSION AND LINEAR MIXED EFFECT MODELS, WITH AND WITHOUT ADJUSTMENT FOR AGE AND GENDER. UNIVARIATE LINEAR REGRESSION ANALYSIS REVEALED THAT METHYLATION LEVELS OF 16 CPG SITES SIGNIFICANTLY ASSOCIATED WITH EVER-SMOKING STATUS. A CPG SITE IN THE TGFBI GENE WAS THE ONLY SITE ASSOCIATED WITH EVER-SMOKING AFTER ADJUSTMENT FOR AGE AND GENDER. NO HIGHLY SIGNIFICANT ASSOCIATIONS EXISTED BETWEEN AGE AT SMOKING INITIATION, PACK-YEARS SMOKED, DURATION OF SMOKING, AND TIME SINCE QUITTING SMOKING AS PREDICTORS OF INDIVIDUAL CPG SITE METHYLATION LEVELS. HOWEVER, EVER-SMOKING AND YOUNGER AGE AT SMOKING INITIATION ASSOCIATED WITH LOWER METHYLATION LEVEL AVERAGED ACROSS ALL SITES. DNA METHYLATION AT CPG SITES IN THE RUNX3, JAK3 AND KRT1 GENES ASSOCIATED WITH CRP LEVELS. THE MOST SIGNIFICANTLY ASSOCIATED CPG SITES WITH GENDER AND AGE MAPPED TO THE CASP6 AND FZD9 GENES, RESPECTIVELY. IN SUMMARY, THIS STUDY IDENTIFIED MULTIPLE POTENTIAL CANDIDATE CPG SITES ASSOCIATED WITH EVER-SMOKING AND CRP LEVEL IN AAT-DEFICIENT SUBJECTS. PHENOTYPIC VARIABILITY IN MENDELIAN DISEASES MAY BE DUE TO EPIGENETIC FACTORS. 2012 18 2488 38 EPIGENETICALLY DYSREGULATED GENES AND PATHWAYS IMPLICATED IN THE PATHOGENESIS OF NON-SYNDROMIC HIGH MYOPIA. MYOPIA, COMMONLY REFERRED TO AS NEARSIGHTEDNESS, IS ONE OF THE MOST COMMON CAUSES OF VISUAL DISABILITY THROUGHOUT THE WORLD. IT AFFECTS MORE PEOPLE WORLDWIDE THAN ANY OTHER CHRONIC VISUAL IMPAIRMENT CONDITION. ALTHOUGH THE PREVALENCE VARIES AMONG VARIOUS ETHNIC GROUPS, THE INCIDENCE OF MYOPIA IS INCREASING IN ALL POPULATIONS ACROSS GLOBE. THUS, IT IS CONSIDERED A PRESSING PUBLIC HEALTH PROBLEM. BOTH GENETICS AND ENVIRONMENT PLAY A ROLE IN DEVELOPMENT OF MYOPIA. TO ELUCIDATE THE EPIGENETIC MECHANISM(S) UNDERLYING THE PATHOPHYSIOLOGY OF HIGH-MYOPIA, WE CONDUCTED METHYLATION PROFILING IN 18 CASES AND 18 MATCHED CONTROLS (AGED 4-12 YEARS), USING ILLUMINA METHYLATIONEPIC BEADCHIPS ARRAY. THE DEGREE OF MYOPIA WAS VARIABLE AMONG SUBJECTS, RANGING FROM -6 TO -15D. WE IDENTIFIED 1541 HYPERMETHYLATED CPGS, REPRESENTING 1745 GENES (2.0-FOLD OR HIGHER) (FALSE DISCOVERY RATE (FDR) P /= 0.75 IN HIGH-MYOPIA SUBJECTS COMPARED TO CONTROLS. AMONG THESE, 48 CPGS HAD EXCELLENT CORRELATION (AUC >/= 0.90). HEREIN, WE PRESENT THE FIRST GENOME-WIDE DNA METHYLATION ANALYSIS IN A UNIQUE HIGH-MYOPIA COHORT, SHOWING EXTENSIVE AND DISCRETE METHYLATION CHANGES RELATIVE TO CONTROLS. THE GENES WE IDENTIFIED HOLD SIGNIFICANT POTENTIAL AS TARGETS FOR NOVEL THERAPEUTIC INTERVENTION EITHER ALONE, OR IN COMBINATION. 2019 19 6080 40 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION. 2023 20 2628 28 EPIGENOME-WIDE ASSOCIATION STUDY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG FUNCTION IN KOREANS. AIM: TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND REGIONS (DMRS) IN RELATION TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG FUNCTION TRAITS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF COPD AND SPIROMETRIC PARAMETERS, INCLUDING FORCED EXPIRATORY VOLUME IN 1 S (FEV1), FORCED VITAL CAPACITY (FVC) AND FEV1/FVC, IN BLOOD DNA USING THE INFINIUM HUMANMETHYLATION450 (N = 100, A KOREAN COPD COHORT). RESULTS: WE FOUND ONE SIGNIFICANT DMP (CG03559389, DIP2C) AND 104 SIGNIFICANT DMRS AFTER MULTIPLE-TESTING CORRECTION. OF THESE, 34 DMRS MAPPED TO GENES DIFFERENTIAL EXPRESSED WITH RESPECT TO THE SAME TRAIT. FIVE OF THE GENES WERE ASSOCIATED WITH MORE THAN TWO TRAITS: CTU2, USP36, ZNF516, KLK10 AND CPT1B. CONCLUSION: WE IDENTIFIED NOVEL DIFFERENTIAL METHYLATION LOCI RELATED TO COPD AND LUNG FUNCTION IN BLOOD DNA IN KOREANS AND CONFIRMED PREVIOUS FINDINGS IN NON-ASIANS. EPIGENETIC MODIFICATION COULD CONTRIBUTE TO THE ETIOLOGY OF THESE PHENOTYPES. 2017