1 2624 168 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 2 2621 37 EPIGENOME-WIDE ASSOCIATION STUDIES IDENTIFY DNA METHYLATION ASSOCIATED WITH KIDNEY FUNCTION. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). PREVIOUS GENETIC STUDIES HAVE IMPLICATED REGULATORY MECHANISMS CONTRIBUTING TO CKD. HERE WE PRESENT EPIGENOME-WIDE ASSOCIATION STUDIES OF EGFR AND CKD USING WHOLE-BLOOD DNA METHYLATION OF 2264 ARIC STUDY AND 2595 FRAMINGHAM HEART STUDY PARTICIPANTS TO IDENTIFY EPIGENETIC SIGNATURES OF KIDNEY FUNCTION. OF 19 CPG SITES SIGNIFICANTLY ASSOCIATED (P < 1E-07) WITH EGFR/CKD AND REPLICATED, FIVE ALSO ASSOCIATE WITH RENAL FIBROSIS IN BIOPSIES FROM CKD PATIENTS AND SHOW CONCORDANT DNA METHYLATION CHANGES IN KIDNEY CORTEX. LEAD CPGS AT PTPN6/PHB2, ANKRD11, AND TNRC18 MAP TO ACTIVE ENHANCERS IN KIDNEY CORTEX. AT PTPN6/PHB2 CG19942083, METHYLATION IN KIDNEY CORTEX ASSOCIATES WITH LOWER RENAL PTPN6 EXPRESSION, HIGHER EGFR, AND LESS RENAL FIBROSIS. THE REGIONS CONTAINING THE 243 EGFR-ASSOCIATED (P < 1E-05) CPGS ARE SIGNIFICANTLY ENRICHED FOR TRANSCRIPTION FACTOR BINDING SITES OF EBF1, EP300, AND CEBPB (P < 5E-6). OUR FINDINGS HIGHLIGHT KIDNEY FUNCTION ASSOCIATED EPIGENETIC VARIATION. 2017 3 2005 39 EPIGENETIC ASSOCIATIONS WITH ESTIMATED GLOMERULAR FILTRATION RATE AMONG MEN WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION. BACKGROUND: PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION HAVE HIGHER RISK FOR CHRONIC KIDNEY DISEASE (CKD), DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). PREVIOUS STUDIES HAVE IMPLICATED EPIGENETIC CHANGES RELATED TO CKD; HOWEVER, THE MECHANISM OF HIV-RELATED CKD HAS NOT BEEN THOROUGHLY INVESTIGATED. METHODS: WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY OF EGFR AMONG 567 HIV-POSITIVE AND 117 HIV-NEGATIVE MALE PARTICIPANTS IN THE VETERANS AGING COHORT STUDY TO IDENTIFY EPIGENETIC SIGNATURES OF KIDNEY FUNCTION. RESULTS: BY SURVEYING MORE THAN 400 000 CYTOSINE GUANINE DINUCLEOTIDE (CPG) SITES MEASURED FROM PERIPHERAL BLOOD MONONUCLEAR CELLS, WE IDENTIFIED 15 SITES THAT WERE SIGNIFICANTLY ASSOCIATED WITH EGFR (FALSE DISCOVERY RATE Q VALUE < 0.05) AMONG HIV-POSITIVE PARTICIPANTS. THE MOST SIGNIFICANT CPG SITES, LOCATED AT MAD1L1, TSNARE1/BAI1, AND LTV1, WERE ALL NEGATIVELY ASSOCIATED WITH EGFR (CG06329547, P = 5.25 X 10-9; CG23281907, P = 1.37 X 10-8; CG18368637, P = 5.17 X 10-8). WE ALSO REPLICATED PREVIOUSLY REPORTED EGFR-ASSOCIATED CPG SITES INCLUDING CG17944885 (P = 2.5 X 10-5) LOCATED BETWEEN ZNF788 AND ZNF20 ON CHROMOSOME 19 IN THE POOLED POPULATION. CONCLUSIONS: IN THIS STUDY WE UNCOVERED NOVEL EPIGENETIC ASSOCIATIONS WITH KIDNEY FUNCTION AMONG PEOPLE LIVING WITH HIV AND SUGGEST POTENTIAL EPIGENETIC MECHANISMS LINKED WITH HIV-RELATED CKD RISK. 2020 4 4730 43 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 5 2628 33 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 6 3557 45 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 7 5745 43 SMOKING-RELATED CHANGES IN DNA METHYLATION AND GENE EXPRESSION ARE ASSOCIATED WITH CARDIO-METABOLIC TRAITS. BACKGROUND: TOBACCO SMOKING IS A WELL-KNOWN MODIFIABLE RISK FACTOR FOR MANY CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASE (CVD). ONE OF THE PROPOSED UNDERLYING MECHANISM LINKING SMOKING TO DISEASE IS VIA EPIGENETIC MODIFICATIONS, WHICH COULD AFFECT THE EXPRESSION OF DISEASE-ASSOCIATED GENES. HERE, WE CONDUCTED A THREE-WAY ASSOCIATION STUDY TO IDENTIFY THE RELATIONSHIP BETWEEN SMOKING-RELATED CHANGES IN DNA METHYLATION AND GENE EXPRESSION AND THEIR ASSOCIATIONS WITH CARDIO-METABOLIC TRAITS. RESULTS: WE SELECTED 2549 CPG SITES AND 443 GENE EXPRESSION PROBES ASSOCIATED WITH CURRENT VERSUS NEVER SMOKERS, FROM THE LARGEST EPIGENOME-WIDE ASSOCIATION STUDY AND TRANSCRIPTOME-WIDE ASSOCIATION STUDY TO DATE. WE EXAMINED THREE-WAY ASSOCIATIONS, INCLUDING CPG VERSUS GENE EXPRESSION, CARDIO-METABOLIC TRAIT VERSUS CPG, AND CARDIO-METABOLIC TRAIT VERSUS GENE EXPRESSION, IN THE ROTTERDAM STUDY. SUBSEQUENTLY, WE REPLICATED OUR FINDINGS IN THE COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG (KORA) STUDY. AFTER CORRECTION FOR MULTIPLE TESTING, WE IDENTIFIED BOTH CIS- AND TRANS-EXPRESSION QUANTITATIVE TRAIT METHYLATION (EQTM) ASSOCIATIONS IN BLOOD. SPECIFICALLY, WE FOUND 1224 SMOKING-RELATED CPGS ASSOCIATED WITH AT LEAST ONE OF THE 443 GENE EXPRESSION PROBES, AND 200 SMOKING-RELATED GENE EXPRESSION PROBES TO BE ASSOCIATED WITH AT LEAST ONE OF THE 2549 CPGS. OUT OF THESE, 109 CPGS AND 27 GENES WERE ASSOCIATED WITH AT LEAST ONE CARDIO-METABOLIC TRAIT IN THE ROTTERDAM STUDY. WE WERE ABLE TO REPLICATE THE ASSOCIATIONS WITH CARDIO-METABOLIC TRAITS OF 26 CPGS AND 19 GENES IN THE KORA STUDY. FURTHERMORE, WE IDENTIFIED A THREE-WAY ASSOCIATION OF TRIGLYCERIDES WITH TWO CPGS AND TWO GENES (GZMA; CLDND1), AND BMI WITH SIX CPGS AND TWO GENES (PID1; LRRN3). FINALLY, OUR RESULTS REVEALED THE MEDIATION EFFECT OF CG03636183 (F2RL3), CG06096336 (PSMD1), CG13708645 (KDM2B), AND CG17287155 (AHRR) WITHIN THE ASSOCIATION BETWEEN SMOKING AND LRRN3 EXPRESSION. CONCLUSIONS: OUR STUDY INDICATES THAT SMOKING-RELATED CHANGES IN DNA METHYLATION AND GENE EXPRESSION ARE ASSOCIATED WITH CARDIO-METABOLIC RISK FACTORS. THESE FINDINGS MAY PROVIDE ADDITIONAL INSIGHTS INTO THE MOLECULAR MECHANISMS LINKING SMOKING TO THE DEVELOPMENT OF CVD. 2020 8 3992 34 LONGITUDINAL EPIGENOME-WIDE ANALYSIS OF KIDNEY TRANSPLANT RECIPIENTS PRETRANSPLANT AND POSTTRANSPLANT. INTRODUCTION: KIDNEY TRANSPLANTATION REMAINS THE GOLD STANDARD OF TREATMENT FOR END-STAGE RENAL DISEASE (ESRD), WITH IMPROVED PATIENT OUTCOMES COMPARED WITH DIALYSIS. EPIGENOME-WIDE ASSOCIATION ANALYSIS (EWAS) OF DNA METHYLATION MAY IDENTIFY MARKERS THAT CONTRIBUTE TO AN INDIVIDUAL'S RISK OF ADVERSE TRANSPLANT OUTCOMES, YET ONLY A LIMITED NUMBER OF EWAS HAVE BEEN CONDUCTED IN KIDNEY TRANSPLANT RECIPIENTS. THIS EWAS AIMED TO INTERROGATE THE METHYLATION PROFILE OF A KIDNEY TRANSPLANT RECIPIENT COHORT WITH MINIMAL POSTTRANSPLANT COMPLICATIONS, EXPLORING DIFFERENCES IN SAMPLES PRETRANSPLANT AND POSTTRANSPLANT. METHODS: WE COMPARED DIFFERENTIALLY METHYLATED CYTOSINE-PHOSPHATE-GUANINE SITES (DMCPGS) IN SAMPLES DERIVED FROM PERIPHERAL BLOOD MONONUCLEAR CELLS OF THE SAME KIDNEY TRANSPLANT RECIPIENTS, COLLECTED BOTH PRETRANSPLANT AND POSTTRANSPLANT (N = 154), USING THE INFINIUM METHYLATIONEPIC MICROARRAY (ILLUMINA, SAN DIEGO, CA). RECIPIENTS RECEIVED KIDNEYS FROM DECEASED DONORS AND HAD A MEAN OF 17 YEARS OF FOLLOW-UP. RESULTS: FIVE TOP-RANKED DMCPGS WERE SIGNIFICANTLY DIFFERENT AT FALSE DISCOVERY RATE (FDR) ADJUSTED P /= 0.05), THEREBY THIS STUDY ESTABLISHES AN IMPORTANT REFERENCE FOR FUTURE EPIGENETIC STUDIES THAT SEEK TO IDENTIFY MARKERS OF POSTTRANSPLANT COMPLICATIONS. 2023 9 382 51 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 10 2623 40 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 11 5463 40 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 12 3420 37 HUMAN LUNG DNA METHYLATION QUANTITATIVE TRAIT LOCI COLOCALIZE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE GENOME-WIDE ASSOCIATION LOCI. RATIONALE: AS THE THIRD LEADING CAUSE OF DEATH IN THE UNITED STATES, THE IMPACT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) MAKES IDENTIFICATION OF ITS MOLECULAR MECHANISMS OF GREAT IMPORTANCE. GENOME-WIDE ASSOCIATION STUDIES (GWASS) HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS ASSOCIATED WITH COPD. HOWEVER, GENETIC VARIATION ONLY EXPLAINS A SMALL FRACTION OF THE SUSCEPTIBILITY TO COPD, AND SUB-GENOME-WIDE SIGNIFICANT LOCI MAY PLAY A ROLE IN PATHOGENESIS. OBJECTIVES: REGULATORY ANNOTATION WITH EPIGENETIC EVIDENCE MAY GIVE PRIORITY FOR FURTHER INVESTIGATION, PARTICULARLY FOR GWAS ASSOCIATIONS IN NONCODING REGIONS. WE PERFORMED INTEGRATIVE GENOMICS ANALYSES USING DNA METHYLATION PROFILING AND GENOME-WIDE SNP GENOTYPING FROM LUNG TISSUE SAMPLES FROM 90 SUBJECTS WITH COPD AND 36 CONTROL SUBJECTS. METHODS: WE PERFORMED METHYLATION QUANTITATIVE TRAIT LOCI (MQTL) ANALYSES, TESTING FOR SNPS ASSOCIATED WITH PERCENT DNA METHYLATION AND ASSESSED THE COLOCALIZATION OF THESE RESULTS WITH PREVIOUS COPD GWAS FINDINGS USING BAYESIAN METHODS IN THE R PACKAGE COLOC TO HIGHLIGHT POTENTIAL REGULATORY FEATURES OF THE LOCI. MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED 942,068 UNIQUE SNPS AND 33,996 UNIQUE CPG SITES AMONG THE SIGNIFICANT (5% FALSE DISCOVERY RATE) CIS-MQTL RESULTS. THE GENOME-WIDE SIGNIFICANT AND SUBTHRESHOLD (P < 10(-4)) GWAS SNPS WERE ENRICHED IN THE SIGNIFICANT MQTL SNPS (HYPERGEOMETRIC TEST P < 0.00001). WE OBSERVED ENRICHMENT FOR SITES LOCATED IN CPG SHORES AND SHELVES, BUT NOT CPG ISLANDS. USING BAYESIAN COLOCALIZATION, WE IDENTIFIED LOCI IN REGIONS NEAR KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, AND IL27. CONCLUSIONS: COLOCALIZATION OF MQTL AND GWAS LOCI PROVIDES REGULATORY CHARACTERIZATION OF SIGNIFICANT AND SUBTHRESHOLD GWAS FINDINGS, SUPPORTING A ROLE FOR GENETIC CONTROL OF METHYLATION IN COPD PATHOGENESIS. 2018 13 5070 38 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 14 3951 51 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 15 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 16 335 42 ALTERATIONS IN DNA METHYLATION ASSOCIATE WITH FATTY LIVER AND METABOLIC ABNORMALITIES IN A MULTI-ETHNIC COHORT OF PRE-TEENAGE CHILDREN. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN. EPIGENETIC ALTERATIONS, SUCH AS THROUGH DNA METHYLATION (DNAM), MAY LINK ADVERSE CHILDHOOD EXPOSURES AND FATTY LIVER AND PROVIDE NON-INVASIVE METHODS FOR IDENTIFYING CHILDREN AT HIGH RISK FOR NAFLD AND ASSOCIATED METABOLIC DYSFUNCTION. WE INVESTIGATED THE ASSOCIATION BETWEEN DIFFERENTIAL DNAM AND LIVER FAT CONTENT (LFC) AND LIVER INJURY IN PRE-ADOLESCENT CHILDREN. LEVERAGING DATA FROM THE NEWBORN EPIGENETICS STUDY (NEST), WE ENROLLED 90 MOTHER-CHILD DYADS AND USED LINEAR REGRESSION TO IDENTIFY CPG SITES AND DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN PERIPHERAL BLOOD ASSOCIATED WITH LFC AND ALANINE AMINOTRANSFERASE (ALT) LEVELS IN 7-12YO CHILDREN. DNAM WAS MEASURED USING INFINIUM HUMANMETHYLATIONEPIC BEADCHIPS (ILLUMINA). LFC AND FIBROSIS WERE QUANTIFIED BY MAGNETIC RESONANCE IMAGING PROTON DENSITY FAT FRACTION AND ELASTOGRAPHY. MEDIAN LFC WAS 1.4% (RANGE, 0.3-13.4%) AND MRE WAS 2.5 KPA (RANGE, 1.5-3.6KPA). THREE CHILDREN HAD LFC >/= 5%, WHILE SIX (7.6%) MET OUR DEFINITION OF NAFLD (LFC >/= 3.7%). ALL CHILDREN WITH NAFLD WERE OBESE AND FIVE WERE BLACK. LFC WAS ASSOCIATED WITH 88 DMRS AND 106 CPGS (FDR<5%). THE TOP TWO CPGS, CG25474373 AND CG07264203, MAPPED TO OR NEAR RFTN2 AND PRICKLE2 GENES. THESE TWO CPG SITES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH A NAFLD DIAGNOSIS. AS HIGHER LFC ASSOCIATES WITH AN ADVERSE CARDIOMETABOLIC PROFILE ALREADY IN CHILDHOOD, ALTERED DNAM MAY IDENTIFY THESE CHILDREN EARLY IN DISEASE COURSE FOR TARGETED INTERVENTION. LARGER, LONGITUDINAL STUDIES ARE NEEDED TO VALIDATE THESE FINDINGS AND DETERMINE MECHANISTIC RELEVANCE. 2022 17 1576 32 DNA METHYLATION PROFILE ASSOCIATED WITH RAPID DECLINE IN KIDNEY FUNCTION: FINDINGS FROM THE CRIC STUDY. BACKGROUND: EPIGENETIC MECHANISMS MAY BE IMPORTANT IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). METHODS: WE STUDIED THE GENOME-WIDE DNA METHYLATION PATTERN ASSOCIATED WITH RAPID LOSS OF KIDNEY FUNCTION USING THE INFINIUM HUMANMETHYLATION 450 K BEADCHIP IN 40 CHRONIC RENAL INSUFFICIENCY (CRIC) STUDY PARTICIPANTS (N = 3939) WITH THE HIGHEST AND LOWEST RATES OF DECLINE IN ESTIMATED GLOMERULAR FILTRATION RATE. RESULTS: THE MEAN EGFR SLOPE WAS 2.2 (1.4) AND -5.1 (1.2) ML/MIN/1.73 M(2) IN THE STABLE KIDNEY FUNCTION GROUP AND THE RAPID PROGRESSION GROUP, RESPECTIVELY. CPG ISLANDS IN NPHP4, IQSEC1 AND TCF3 WERE HYPERMETHYLATED TO A LARGER EXTENT IN SUBJECTS WITH STABLE KIDNEY FUNCTION (P-VALUES OF 7.8E-05 TO 9.5E-05). THESE GENES ARE INVOLVED IN PATHWAYS KNOWN TO PROMOTE THE EPITHELIAL TO MESENCHYMAL TRANSITION AND RENAL FIBROSIS. OTHER CKD-RELATED GENES THAT WERE DIFFERENTIALLY METHYLATED ARE NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 AND TGFBI, WHICH ARE INVOLVED IN OXIDATIVE STRESS AND INFLAMMATORY PATHWAYS (P-VALUES OF 4.5E-03 TO 0.046). PATHWAY ANALYSIS USING INGENUITY PATHWAY ANALYSIS SHOWED THAT GENE NETWORKS RELATED TO CELL SIGNALING, CARBOHYDRATE METABOLISM AND HUMAN BEHAVIOR ARE EPIGENETICALLY REGULATED IN CKD. CONCLUSIONS: EPIGENETIC MODIFICATIONS MAY BE IMPORTANT IN DETERMINING THE RATE OF LOSS OF KIDNEY FUNCTION IN PATIENTS WITH ESTABLISHED CKD. 2014 18 4240 23 METHYLATION QUANTITATIVE TRAIT LOCUS ANALYSIS OF CHRONIC POSTSURGICAL PAIN UNCOVERS EPIGENETIC MEDIATORS OF GENETIC RISK. BACKGROUND: OVERLAP OF PATHWAYS ENRICHED BY SINGLE NUCLEOTIDE POLYMORPHISMS AND DNA-METHYLATION UNDERLYING CHRONIC POSTSURGICAL PAIN (CPSP), PROMPTED PILOT STUDY OF CPSP-ASSOCIATED METHYLATION QUANTITATIVE TRAIT LOCI (MEQTL). MATERIALS & METHODS: CHILDREN UNDERGOING SPINE-FUSION WERE RECRUITED PROSPECTIVELY. LOGISTIC-REGRESSION FOR GENOME- AND EPIGENOME-WIDE CPSP ASSOCIATION AND DNA-METHYLATION-SINGLE NUCLEOTIDE POLYMORPHISM ASSOCIATION/MEDIATION ANALYSES TO IDENTIFY MEQTLS WERE FOLLOWED BY FUNCTIONAL GENOMICS ANALYSES. RESULTS: CPSP (N = 20/58) AND NON-CPSP GROUPS DIFFERED IN PAIN-MEASURES. OF 2753 MEQTLS, DNA-METHYLATION AT 127 CYTOSINE-GUANINE DINUCLEOTIDES MEDIATED ASSOCIATION OF 470 MEQTLS WITH CPSP (P < 0.05). AT PARK16 LOCUS, CPSP RISK MEQTLS WERE ASSOCIATED WITH DECREASED DNA-METHYLATION AT RAB7L1 AND INCREASED DNA-METHYLATION AT PM20D1. CORRESPONDING RAB7L1/PM20D1 BLOOD EQTLS (GTEX) AND CYTOSINE-GUANINE DINUCLEOTIDE-LOCI ENRICHMENT FOR HISTONE MARKS, TRANSCRIPTION FACTOR BINDING SITES AND ATAC-SEQ PEAKS SUGGEST ALTERED TRANSCRIPTION FACTOR-BINDING. CONCLUSION: CPSP-ASSOCIATED MEQTLS INDICATE EPIGENETIC MECHANISMS MEDIATE GENETIC RISK. CLINICAL TRIAL REGISTRATION: NCT01839461, NCT01731873 (CLINICALTRIALS.GOV). 2021 19 525 36 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE. 2021 20 6190 46 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