1 3609 132 IN UTERO ARSENIC EXPOSURE AND EPIGENOME-WIDE ASSOCIATIONS IN PLACENTA, UMBILICAL ARTERY, AND HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS. EXPOSURE TO ARSENIC EARLY IN LIFE HAS BEEN ASSOCIATED WITH INCREASED RISK OF SEVERAL CHRONIC DISEASES AND IS BELIEVED TO ALTER EPIGENETIC PROGRAMMING IN UTERO. IN THE PRESENT STUDY, WE EVALUATE THE EPIGENOME-WIDE ASSOCIATION OF ARSENIC EXPOSURE IN UTERO AND DNA METHYLATION IN PLACENTA (N = 37), UMBILICAL ARTERY (N = 45) AND HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS (HUVEC) (N = 52) IN A BIRTH COHORT USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. UNADJUSTED AND CELL MIXTURE ADJUSTED ASSOCIATIONS FOR EACH TISSUE WERE EXAMINED ALONG WITH ENRICHMENT ANALYSES RELATIVE TO CPG ISLAND LOCATION AND OMNIBUS PERMUTATION TESTS OF ASSOCIATION AMONG BIOLOGICAL PATHWAYS. ONE CPG IN ARTERY (CG26587014) AND 4 CPGS IN PLACENTA (CG12825509; CG20554753; CG23439277; CG21055948) REACHED A BONFERRONI ADJUSTED LEVEL OF SIGNIFICANCE. SEVERAL CPGS WERE DIFFERENTIALLY METHYLATED IN ARTERY AND PLACENTA WHEN CONTROLLING THE FALSE DISCOVERY RATE (Q-VALUE<0.05), BUT NONE IN HUVEC. ENRICHMENT OF HYPOMETHYLATED CPG ISLANDS WAS OBSERVED FOR ARTERY WHILE HYPERMETHYLATION OF OPEN SEA REGIONS WERE PRESENT IN PLACENTA RELATIVE TO PRENATAL ARSENIC EXPOSURE. THE MELANOGENESIS PATHWAY WAS DIFFERENTIALLY METHYLATED IN ARTERY (MAX F P < 0.001), PLACENTA (MAX F P < 0.001), AND HUVEC (MAX F P = 0.02). SIMILARLY, THE INSULIN-SIGNALING PATHWAY WAS DIFFERENTIALLY METHYLATED IN ARTERY (MAX F P = 0.02), PLACENTA (MAX F P = 0.02), AND HUVEC (MAX F P = 0.02). OUR RESULTS SHOW THAT PRENATAL ARSENIC EXPOSURE CAN ALTER DNA METHYLATION IN ARTERY AND PLACENTA BUT NOT IN HUVEC. FURTHER STUDIES ARE NEEDED TO DETERMINE IF THESE ALTERATIONS IN DNA METHYLATION MEDIATE THE EFFECT OF PRENATAL ARSENIC EXPOSURE AND HEALTH OUTCOMES LATER IN LIFE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 1573  42 DNA METHYLATION PATTERNS IN NEWBORNS EXPOSED TO TOBACCO IN UTERO. BACKGROUND: MATERNAL SMOKING DURING PREGNANCY IS A MAJOR RISK FACTOR FOR ADVERSE HEALTH OUTCOMES. THE MAIN OBJECTIVE OF THE STUDY WAS TO ASSESS THE IMPACT OF IN UTERO TOBACCO EXPOSURE ON DNA METHYLATION IN CHILDREN BORN AT TERM WITH APPROPRIATE WEIGHT AT BIRTH. METHODS: TWENTY MOTHER-NEWBORN DYADS, AFTER UNCOMPLICATED PREGNANCIES, IN THE ABSENCE OF PERINATAL ILLNESS WERE INCLUDED. ALL MOTHERS WERE HEALTHY WITH NO CARDIOVASCULAR RISK FACTORS, EXCEPT FOR THE ASSOCIATED RISKS AMONG THOSE MOTHERS WHO SMOKED. UMBILICAL CORD BLOOD AND MATERNAL PERIPHERAL VENOUS BLOOD WERE COLLECTED AND AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING A 450 K EPIGENOME-WIDE SCAN (ILLUMINA INFINIUM HUMANMETHYLATION 450BEADCHIP) WITH ADJUSTMENT TO NORMALIZE THE DNA METHYLATION FOR DATA CELL VARIABILITY IN WHOLE BLOOD. RESULTS: THE MATERNAL PLASMATIC COTININE LEVELS RANGED FROM 10.70-115.40 NG/ML IN THE EXPOSED GROUP TO 0-0.59 NG/ML IN THE NON-EXPOSED GROUP. AFTER ADJUSTING FOR MULTIPLE COMPARISONS IN 427102 PROBES, STATISTICALLY SIGNIFICANT DIFFERENCES FOR 31 CPG SITES, ASSOCIATED TO 25 GENES WERE OBSERVED. THERE WAS A GREATER THAN EXPECTED PROPORTION OF STATISTICALLY-SIGNIFICANT LOCI LOCATED IN CPG ISLANDS (FISHER'S EXACT TEST, P = 0.029) AND OF THOSE CPG ISLANDS, 90.3% EXHIBIT HIGHER METHYLATION LEVELS IN THE EXPOSED GROUP. THE MOST STRIKING AND SIGNIFICANT CPG SITE, CG05727225, IS LOCATED IN THE CHROMOSOME 11P15.4, WITHIN THE ADRENOMEDULLIN GENE. CONCLUSIONS: IN UTERO TOBACCO EXPOSURE, EVEN IN THE ABSENCE OF FETAL GROWTH RESTRICTION, MAY ALTER THE EPIGENOME, CONTRIBUTING TO GLOBAL DNA HYPOMETHYLATION. THEREFORE, DNA STATUS CAN BE USED AS A BIOMARKER OF PRENATAL INSULTS. CONSIDERING THE POSSIBILITY TO REVERSE EPIGENETIC MODIFICATIONS, A WINDOW OF OPPORTUNITY EXISTS TO CHANGE THE PROGRAMMED CHRONIC DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3 2921  41 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	
                                                                                                                                                                                                                                                                                                                                                    
4  382  47 AN EPIGENOME-WIDE STUDY OF BODY MASS INDEX AND DNA METHYLATION IN BLOOD USING PARTICIPANTS FROM THE SISTER STUDY COHORT. BACKGROUND/OBJECTIVES: THE RELATIONSHIP BETWEEN OBESITY AND CHRONIC DISEASE RISK IS WELL-ESTABLISHED; THE UNDERLYING BIOLOGICAL MECHANISMS DRIVING THIS RISK INCREASE MAY INCLUDE OBESITY-RELATED EPIGENETIC MODIFICATIONS. TO EXPLORE THIS HYPOTHESIS, WE CONDUCTED A GENOME-WIDE ANALYSIS OF DNA METHYLATION AND BODY MASS INDEX (BMI) USING DATA FROM A SUBSET OF WOMEN IN THE SISTER STUDY. SUBJECTS/METHODS: THE SISTER STUDY IS A COHORT OF 50 884 US WOMEN WHO HAD A SISTER WITH BREAST CANCER BUT WERE FREE OF BREAST CANCER THEMSELVES AT ENROLLMENT. STUDY PARTICIPANTS COMPLETED EXAMINATIONS WHICH INCLUDED MEASUREMENTS OF HEIGHT AND WEIGHT, AND PROVIDED BLOOD SAMPLES. BLOOD DNA METHYLATION DATA GENERATED WITH THE ILLUMINA INFINIUM HUMANMETHYLATION27 BEADCHIP ARRAY COVERING 27,589 CPG SITES WAS AVAILABLE FOR 871 WOMEN FROM A PRIOR STUDY OF BREAST CANCER AND DNA METHYLATION. TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH BMI, WE ANALYZED THIS METHYLATION DATA USING ROBUST LINEAR REGRESSION WITH ADJUSTMENT FOR AGE AND CASE STATUS. FOR THOSE CPGS PASSING THE FALSE DISCOVERY RATE SIGNIFICANCE LEVEL, WE EXAMINED THE ASSOCIATION IN A REPLICATION SET COMPRISED OF A NON-OVERLAPPING GROUP OF 187 WOMEN FROM THE SISTER STUDY WHO HAD DNA METHYLATION DATA GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. ANALYSIS OF THIS EXPANDED 450 K ARRAY IDENTIFIED ADDITIONAL BMI-ASSOCIATED SITES WHICH WERE INVESTIGATED WITH TARGETED PYROSEQUENCING. RESULTS: FOUR CPG SITES REACHED GENOME-WIDE SIGNIFICANCE (FALSE DISCOVERY RATE (FDR) Q<0.05) IN THE DISCOVERY SET AND ASSOCIATIONS FOR ALL FOUR WERE SIGNIFICANT AT STRICT BONFERRONI CORRECTION IN THE REPLICATION SET. AN ADDITIONAL 23 SITES PASSED FDR IN THE REPLICATION SET AND FIVE WERE REPLICATED BY PYROSEQUENCING IN THE DISCOVERY SET. SEVERAL OF THE GENES IDENTIFIED INCLUDING ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 AND CRHR2 HAVE BEEN LINKED TO OBESITY AND OBESITY-RELATED CHRONIC DISEASES. CONCLUSIONS: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT OBESITY-RELATED EPIGENETIC DIFFERENCES ARE DETECTABLE IN BLOOD AND MAY BE RELATED TO RISK OF CHRONIC DISEASE.	2017	
                                                                                                                        
5 3951  48 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	

6 3414  30 HSD11B2, RUNX3, AND LINE-1 METHYLATION IN PLACENTAL DNA OF HYPERTENSIVE DISORDERS OF PREGNANCY PATIENTS. HYPERTENSIVE DISORDERS OF PREGNANCY (HDSP) REMAIN LEADING CAUSES OF MATERNAL AND PERINATAL MORBIDITY AND MORTALITY. GROWING EVIDENCE SUGGESTS THE INVOLVEMENT OF EPIGENETIC FACTORS, SUCH AS GENE-SPECIFIC AND GLOBAL DNA METHYLATION CHANGES, BOTH IN THE ETIOLOGY AND AS AN EFFECT OF HDSP. IN THIS STUDY, WE INVESTIGATED THE POTENTIAL ASSOCIATION BETWEEN PLACENTAL DNA METHYLATION STATUS IN SELECTED CPGS OF HSD11B2 CORTISOL LEVEL CONTROLLING GENE, RUNX3 TUMOR SUPPRESSOR GENE, AND LONG INTERSPERSED NUCLEOTIDE ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS AND HDSP-PREECLAMPSIA (PE), GESTATIONAL HYPERTENSION (GH), AND CHRONIC HYPERTENSION (CH). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND PYROSEQUENCING (PSQ) WERE USED TO ANALYZE PLACENTAL DNA METHYLATION. PLASMA AND URINE CORTISOL AND CORTISONE LEVELS WERE MEASURED USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH FLUORESCENCE DETECTION (HPLC-FLD), WHEREAS SERUM PROGESTERONE LEVEL WAS DETERMINED BY ELECTROCHEMILUMINESCENCE IMMUNOASSAY. THE MEAN PERCENTAGE OF HSD11B2, RUNX3, AND LINE-1 METHYLATION WAS NOT ALTERED IN THE PLACENTAS OF PATIENTS WITH HDSP, AS COMPARED TO THE CONTROLS. HOWEVER, AMONG PATIENTS FROM PE, GH, AND CH GROUPS, SEVERAL SIGNIFICANT CORRELATIONS WERE OBSERVED BETWEEN THE METHYLATION STATUS OF HSD11B2, RUNX3, OR LINE-1 AND CHILDREN'S BIRTH WEIGHT, GESTATIONAL AGE AT DELIVERY, MOTHER'S AGE, AND BODY MASS INDEX AS WELL AS HORMONES LEVELS. THESE RESULTS INDICATE LACK OF ASSOCIATION BETWEEN METHYLATION STATUS OF HSD11B2, RUNX3, OR LINE-1 REPETITIVE ELEMENTS AND HDSP. HOWEVER, ASSOCIATION OF THESE PARAMETERS WITH SOME CLINICAL VARIABLES MAY SUGGEST THE ROLE OF PLACENTAL DNA METHYLATION IN FETAL DEVELOPMENT AND SHOULD BE FURTHER EXPLORED.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 2903  39 GENDER-SPECIFIC METHYLATION DIFFERENCES IN RELATION TO PRENATAL EXPOSURE TO CIGARETTE SMOKE. EPIGENETIC ALTERATIONS MAY MECHANISTICALLY EXPLAIN THE DEVELOPMENTAL ORIGINS OF ADULT DISEASE, NAMELY THE HYPOTHESIS THAT MANY COMPLEX ADULT CHRONIC DISEASES ORIGINATE AS A RESULT OF CONDITIONS ENCOUNTERED IN UTERO. IF TRUE, EPIGENETICALLY REGULATED IMPRINTED GENES, CRITICAL TO NORMAL GROWTH AND DEVELOPMENT, MAY PARTIALLY MEDIATE THESE OUTCOMES. WE DETERMINED THE INFLUENCE OF IN UTERO EXPOSURE TO CIGARETTE SMOKING ON METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) REGULATING INSULIN-LIKE GROWTH FACTOR 2 (IGF2) AND H19, AND HOW THIS MIGHT RELATE TO BIRTH WEIGHT OF INFANTS BORN TO 418 PREGNANT WOMEN. SMOKING STATUS WAS ASCERTAINED THROUGH SELF-REPORT AND MEDICAL RECORDS. BISULFITE PYROSEQUENCING WAS USED TO MEASURE METHYLATION IN UMBILICAL CORD BLOOD DNAS. LEAST SQUARES DNA METHYLATION MEANS AT EACH DMR AND BIRTH WEIGHT WERE COMPARED BETWEEN INFANTS OF SMOKERS AND NON-SMOKERS, USING GENERALIZED LINEAR MODELS. WHILE THERE WERE NO SIGNIFICANT DIFFERENCES AT THE H19 DMR, INFANTS BORN TO SMOKERS HAD HIGHER METHYLATION AT THE IGF2 DMR THAN THOSE BORN TO NEVER SMOKERS OR THOSE WHO QUIT DURING PREGNANCY (49.5%, SD=8.0 VERSUS 46.6%, SD=5.6 AND 45.8%, SD=6.3, RESPECTIVELY; P=0.0002). THE SMOKING-RELATED INCREASE IN METHYLATION WAS MOST PRONOUNCED IN MALE OFFSPRING (P FOR SEX INTERACTION=0.03), FOR WHOM APPROXIMATELY 20% OF SMOKING-RELATED LOW BIRTH WEIGHT WAS MEDIATED BY DNA METHYLATION AT THE IGF2 DMR. OUR FINDINGS SUGGEST THAT IGF2 DMR PLASTICITY IS AN IMPORTANT MECHANISM BY WHICH IN UTERO ADJUSTMENTS TO ENVIRONMENTAL TOXICANTS ARE CONFERRED. LARGER STUDIES TO REPLICATE THESE FINDINGS ARE REQUIRED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8 3117  45 GESTATIONAL DIABETES MELLITUS EPIGENETICALLY AFFECTS GENES PREDOMINANTLY INVOLVED IN METABOLIC DISEASES. OFFSPRING EXPOSED TO GESTATIONAL DIABETES MELLITUS (GDM) HAVE AN INCREASED RISK FOR CHRONIC DISEASES, AND ONE PROMISING MECHANISM FOR FETAL METABOLIC PROGRAMMING IS EPIGENETICS. THEREFORE, WE POSTULATED THAT GDM EXPOSURE IMPACTS THE OFFSPRING'S METHYLOME AND USED AN EPIGENOMIC APPROACH TO EXPLORE THIS HYPOTHESIS. PLACENTA AND CORD BLOOD SAMPLES WERE OBTAINED FROM 44 NEWBORNS, INCLUDING 30 EXPOSED TO GDM. WOMEN WERE RECRUITED AT FIRST TRIMESTER OF PREGNANCY AND FOLLOWED UNTIL DELIVERY. GDM WAS ASSESSED AFTER A 75-G ORAL GLUCOSE TOLERANCE TEST AT 24-28 WEEKS OF PREGNANCY. DNA METHYLATION WAS MEASURED AT>485,000 CPG SITES (INFINIUM HUMANMETHYLATION450 BEADCHIPS). INGENUITY PATHWAY ANALYSIS WAS CONDUCTED TO IDENTIFY METABOLIC PATHWAYS EPIGENETICALLY AFFECTED BY GDM. OUR RESULTS SHOWED THAT 3,271 AND 3,758 GENES IN PLACENTA AND CORD BLOOD, RESPECTIVELY, WERE POTENTIALLY DIFFERENTIALLY METHYLATED BETWEEN SAMPLES EXPOSED OR NOT TO GDM (P-VALUES DOWN TO 1 X 10(-06); NONE REACHED THE GENOME-WIDE SIGNIFICANCE LEVELS), WITH MORE THAN 25% (N = 1,029) BEING COMMON TO BOTH TISSUES. MEAN DNA METHYLATION DIFFERENCES BETWEEN GROUPS WERE 5.7 +/- 3.2% AND 3.4 +/- 1.9% FOR PLACENTA AND CORD BLOOD, RESPECTIVELY. THESE GENES WERE LIKELY INVOLVED IN THE METABOLIC DISEASES PATHWAY (UP TO 115 GENES (11%), P-VALUES FOR PATHWAYS = 1.9 X 10(-13)<P<4.0 X 10(-03); INCLUDING DIABETES MELLITUS P = 4.3 X 10(-11)). AMONG THE DIFFERENTIALLY METHYLATED GENES, 326 IN PLACENTA AND 117 IN CORD BLOOD WERE ALSO ASSOCIATED WITH NEWBORN WEIGHT. OUR RESULTS THEREFORE SUGGEST THAT GDM HAS EPIGENETIC EFFECTS ON GENES PREFERENTIALLY INVOLVED IN THE METABOLIC DISEASES PATHWAY, WITH CONSEQUENCES ON FETAL GROWTH AND DEVELOPMENT, AND PROVIDE SUPPORTIVE EVIDENCE THAT DNA METHYLATION IS INVOLVED IN FETAL METABOLIC PROGRAMMING.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9 1849  33 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 4072  39 MATERNAL DNA METHYLATION SIGNATURES OF ARSENIC EXPOSURE IS ASSOCIATED WITH ADULT OFFSPRING INSULIN RESISTANCE IN THE STRONG HEART STUDY. EXPOSURE TO LOW TO MODERATE ARSENIC (AS) LEVELS HAS BEEN ASSOCIATED WITH TYPE 2 DIABETES (T2D) AND OTHER CHRONIC DISEASES IN AMERICAN INDIAN COMMUNITIES. PRENATAL EXPOSURE TO AS MAY ALSO INCREASE THE RISK FOR T2D IN ADULTHOOD, AND MATERNAL AS HAS BEEN ASSOCIATED WITH ADULT OFFSPRING METABOLIC HEALTH MEASUREMENTS. WE HYPOTHESIZED THAT T2D-RELATED OUTCOMES IN ADULT OFFSPRING BORN TO WOMEN EXPOSED TO LOW TO MODERATE AS CAN BE EVALUATED UTILIZING A MATERNALLY-DERIVED MOLECULAR BIOSIGNATURE OF AS EXPOSURE. HEREIN, WE EVALUATED THE ASSOCIATION OF MATERNAL DNA METHYLATION WITH INCIDENT T2D AND INSULIN RESISTANCE (HOMEOSTATIC MODEL ASSESSMENT OF INSULIN RESISTANCE [HOMA2-IR]) IN ADULT OFFSPRING. FOR DNA METHYLATION, WE USED 20 DIFFERENTIALLY METHYLATED CYTOSINE-GUANINE DINUCLEOTIDES (CPG) PREVIOUSLY ASSOCIATED WITH THE SUM OF INORGANIC AND METHYLATED AS SPECIES (SIGMAAS) IN URINE IN THE STRONG HEART STUDY (SHS). OF THESE 20 CPGS, WE FOUND SIX CPGS NOMINALLY ASSOCIATED (P < 0.05) WITH HOMA2-IR IN A FULLY ADJUSTED MODEL THAT INCLUDED CLINICALLY RELEVANT COVARIATES AND OFFSPRING ADIPOSITY MEASUREMENTS; A SIMILAR MODEL THAT ADJUSTED INSTEAD FOR MATERNAL ADIPOSITY MEASUREMENTS FOUND THREE CPGS NOMINALLY ASSOCIATED WITH HOMA2-IR, TWO OF WHICH OVERLAPPED THE OFFSPRING ADIPOSITY MODEL. AFTER ADJUSTING FOR MULTIPLE COMPARISONS, CG03036214 REMAINED ASSOCIATED WITH HOMA2-IR (Q < 0.10) IN THE OFFSPRING ADIPOSITY MODEL. THE ODDS RATIO OF INCIDENT T2D INCREASED WITH AN INCREASE IN MATERNAL DNA METHYLATION AT ONE HOMA2-IR ASSOCIATED CPG IN THE MODEL ADJUSTING FOR OFFSPRING ADIPOSITY, CG12116137, WHEREAS ADJUSTING FOR MATERNAL ADIPOSITY HAD A MINIMAL EFFECT ON THE ASSOCIATION. OUR DATA SUGGESTS OFFSPRING ADIPOSITY, RATHER THAN MATERNAL ADIPOSITY, POTENTIALLY INFLUENCES THE EFFECTS OF MATERNAL DNAM SIGNATURES ON OFFSPRING METABOLIC HEALTH PARAMETERS. HERE, WE HAVE PRESENTED EVIDENCE SUPPORTING A ROLE FOR EPIGENETIC BIOSIGNATURES OF MATERNAL AS EXPOSURE AS A POTENTIAL BIOMARKER FOR EVALUATING RISK OF T2D-RELATED OUTCOMES IN OFFSPRING LATER IN LIFE.	2023	
                                                                                                                                                                                       
11 6089  42 THE EFFECTS OF DEPRESSION AND USE OF ANTIDEPRESSIVE MEDICINES DURING PREGNANCY ON THE METHYLATION STATUS OF THE IGF2 IMPRINTED CONTROL REGIONS IN THE OFFSPRING. IN UTERO EXPOSURES TO ENVIRONMENTAL FACTORS MAY RESULT IN PERSISTENT EPIGENETIC MODIFICATIONS AFFECTING NORMAL DEVELOPMENT AND SUSCEPTIBILITY TO CHRONIC DISEASES IN LATER LIFE. WE EXPLORED THE RELATIONSHIP BETWEEN EXPOSURE OF THE GROWING FETUS TO MATERNAL DEPRESSION OR ANTIDEPRESSANTS AND DNA METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF THE IMPRINTED INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. ABERRANT DNA METHYLATION AT THE IGF2 AND NEIGHBORING H19 DMRS HAS BEEN ASSOCIATED WITH DEREGULATED IGF2 EXPRESSION, CHILDHOOD CANCERS AND SEVERAL CHRONIC DISEASES DURING ADULTHOOD. OUR STUDY POPULATION IS COMPRISED OF PREGNANT MOTHERS AND THEIR NEWBORNS (N = 436), AS PART OF THE NEWBORN EPIGENETICS STUDY (NEST). A STANDARDIZED QUESTIONNAIRE WAS COMPLETED AND MEDICAL RECORD DATA WERE ABSTRACTED TO ASCERTAIN MATERNAL DEPRESSION AND ANTIDEPRESSIVE DRUG USE. DMR METHYLATION LEVELS IN UMBILICAL CORD BLOOD LEUKOCYTES WERE QUANTIFIED USING PYROSEQUENCING. FROM THE 436 NEWBORNS, LABORATORY DATA WERE OBTAINED FOR 356 INDIVIDUALS AT THE IGF2 DMRS, AND FOR 411 INDIVIDUALS AT THE H19 DMRS; ABOUT HALF OF EACH GROUP WAS AFRICAN AMERICAN OR CAUCASIAN. WHILE OVERALL NO ASSOCIATION BETWEEN DEPRESSION AND METHYLATION PROFILES WAS FOUND, WE OBSERVED A SIGNIFICANT HYPERMETHYLATION OF THE H19 DMRS IN NEWBORNS OF AFRICAN AMERICAN (N = 177) BUT NOT CAUCASIAN (N = 168) MOTHERS WHO REPORTED THE USE OF ANTIDEPRESSIVE DRUGS DURING PREGNANCY (BETA = +6.89, P = 0.01). OF NOTE, OUR DATA REVEAL A RACE-INDEPENDENT ASSOCIATION BETWEEN SMOKING DURING PREGNANCY AND METHYLATION AT THE IGF2 DMR (+3.05%, P = 0.01). IN CONCLUSION, OUR FINDINGS SUGGEST A RACE-DEPENDENT RESPONSE RELATED TO MATERNAL USE OF ANTIDEPRESSANTS AT ONE OF THE IGF2 DMRS IN THE OFFSPRING.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12 1537  35 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13 4091  37 MATERNAL PRECONCEPTION BODY MASS INDEX AND OFFSPRING CORD BLOOD DNA METHYLATION: EXPLORATION OF EARLY LIFE ORIGINS OF DISEASE. MATERNAL OBESITY IS ASSOCIATED WITH A VARIETY OF COMMON DISEASES IN THE OFFSPRING. ONE POSSIBLE UNDERLYING MECHANISM COULD BE MATERNAL OBESITY INDUCED ALTERATIONS IN DNA METHYLATION. HOWEVER, THIS HYPOTHESIS IS YET TO BE TESTED. WE PERFORMED EPIGENOMIC MAPPING OF CORD BLOOD AMONG 308 BLACK MOTHER-INFANT PAIRS DELIVERED AT TERM AT THE BOSTON MEDICAL CENTER USING THE ILLUMINA HUMANMETHYLATION27 BEADCHIP. LINEAR REGRESSION AND PATHWAY ANALYSES WERE CONDUCTED TO EVALUATE THE ASSOCIATIONS BETWEEN DNA METHYLATION LEVELS AND PREPREGNANCY MATERNAL BMI (<25, 25-30, >/=30 KG/M(2) ). THE METHYLATION LEVELS OF 20 CPG SITES WERE ASSOCIATED WITH MATERNAL BMI AT A SIGNIFICANCE LEVEL OF P-VALUE <10(-4) IN THE OVERALL SAMPLE, AND BOYS AND GIRLS, SEPARATELY. ONE CPG SITE REMAINED STATISTICALLY SIGNIFICANT AFTER CORRECTION FOR MULTIPLE COMPARISONS (FDR CORRECTED P-VALUE = 0.04) AND WAS ANNOTATED TO A POTENTIAL CANCER GENE, ZCCHC10. SOME OF THE OTHER CPG SITE ANNOTATED GENES APPEAR TO BE CRITICAL TO THE DEVELOPMENT OF CANCERS AND CARDIOVASCULAR DISEASES (I.E., WNT16, C18ORF8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). SIGNIFICANT FINDINGS FROM PATHWAY ANALYSIS, SUCH AS INFECTIOUS AND INFLAMMATORY AND LIPID METABOLISM PATHWAYS, LENDS SUPPORT FOR THE POTENTIAL IMPACT OF MATERNAL BMI ON THE ABOVE STATED DISORDERS. THIS STUDY DEMONSTRATES THAT PREPREGNANCY MATERNAL BMI MIGHT LEAD TO ALTERATIONS IN OFFSPRING DNA METHYLATION IN GENES RELEVANT TO THE DEVELOPMENT OF A RANGE OF COMPLEX CHRONIC DISEASES, PROVIDING EVIDENCE OF TRANS-GENERATIONAL INFLUENCE ON DISEASE SUSCEPTIBILITY VIA EPIGENETIC MECHANISM.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 1497  31 DNA METHYLATION AGE IS ACCELERATED IN ALCOHOL DEPENDENCE. ALCOHOL DEPENDENCE (ALC) IS A CHRONIC, RELAPSING DISORDER THAT INCREASES THE BURDEN OF CHRONIC DISEASE AND SIGNIFICANTLY CONTRIBUTES TO NUMEROUS PREMATURE DEATHS EACH YEAR. PREVIOUS RESEARCH SUGGESTS THAT CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION PATTERNS. IN ADDITION, DNA METHYLATION LEVELS AT CERTAIN CPG SITES HAVE BEEN CORRELATED WITH AGE. WE USED AN EPIGENETIC CLOCK TO INVESTIGATE THE POTENTIAL ROLE OF EXCESSIVE ALCOHOL CONSUMPTION IN EPIGENETIC AGING. WE EXPLORED THIS QUESTION IN FIVE INDEPENDENT COHORTS, INCLUDING DNA METHYLATION DATA DERIVED FROM DATASETS FROM BLOOD (N = 129, N = 329), LIVER (N = 92, N = 49), AND POSTMORTEM PREFRONTAL CORTEX (N = 46). ONE BLOOD DATASET AND ONE LIVER TISSUE DATASET OF INDIVIDUALS WITH ALC EXHIBITED POSITIVE AGE ACCELERATION (P < 0.0001 AND P = 0.0069, RESPECTIVELY), WHEREAS THE OTHER BLOOD AND LIVER TISSUE DATASETS BOTH EXHIBITED TRENDS OF POSITIVE AGE ACCELERATION THAT WERE NOT SIGNIFICANT (P = 0.83 AND P = 0.57, RESPECTIVELY). PREFRONTAL CORTEX TISSUE EXHIBITED A TREND OF NEGATIVE AGE ACCELERATION (P = 0.19). THESE RESULTS SUGGEST THAT EXCESSIVE ALCOHOL CONSUMPTION MAY BE ASSOCIATED WITH EPIGENETIC AGING IN A TISSUE-SPECIFIC MANNER AND WARRANTS FURTHER INVESTIGATION USING MULTIPLE TISSUE SAMPLES FROM THE SAME INDIVIDUALS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 6080  33 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	
                                                                                      
16 1910  36 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH KNEE OSTEOARTHRITIS PAIN. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (I.E., GENOMIC REGION WHERE MULTIPLE ADJACENT CPG SITES SHOW DIFFERENTIAL METHYLATION) AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH KNEE OSTEOARTHRITIS PAIN (KOA). WE RECRUITED COGNITIVELY HEALTHY MIDDLE TO OLDER AGED (AGE 45-85) ADULTS WITH (N = 182) AND WITHOUT (N = 31) SELF-REPORTED KOA PAIN. WE ALSO EXTRACTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. THE R PACKAGE MINFI (ARYEE ET AL., 2014) WAS USED TO PERFORM METHYLATION DATA PREPROCESSING AND QUALITY CONTROL. TO INVESTIGATE BIOLOGICAL PATHWAYS IMPACTED BY DIFFERENTIAL METHYLATION, WE PERFORMED PATHWAY ENRICHMENT ANALYSIS USING INGENUITY PATHWAY ANALYSIS (IPA) TO IDENTIFY CANONICAL PATHWAYS AND UPSTREAM REGULATORS. ANNOTATED GENES WITHIN +/- 5 KB OF THE PUTATIVE DIFFERENTIALLY METHYLATED REGIONS (DMRS, P < 0.05) WERE SUBJECTED TO THE IPA ANALYSIS. THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE, SEX, STUDY SITE BETWEEN NO PAIN AND PAIN GROUP (P > 0.05). NON-HISPANIC BLACK INDIVIDUALS WERE OVERREPRESENTED IN THE PAIN GROUP (P = 0.003). AT RAW P < 0.05 CUTOFF, WE IDENTIFIED A TOTAL OF 19,710 CPG PROBES, INCLUDING 13,951 HYPERMETHYLATED CPG PROBES, FOR WHICH DNA METHYLATION LEVEL WAS HIGHER IN THE GROUPS WITH HIGHEST PAIN GRADES. WE ALSO IDENTIFIED 5,759 HYPOMETHYLATED CPG PROBES FOR WHICH DNA METHYLATION LEVEL WAS LOWER IN THE PAIN GROUPS WITH HIGHER PAIN GRADES. IPA REVEALED THAT PAIN-RELATED DMRS WERE ENRICHED ACROSS MULTIPLE PATHWAYS AND UPSTREAM REGULATORS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E., ANTIGEN PRESENTATION, PD-1, PD-L1 CANCER IMMUNOTHERAPY, B CELL DEVELOPMENT, IL-4 SIGNALING, TH1 AND TH2 ACTIVATION PATHWAY, AND PHAGOSOME MATURATION). MOREOVER, IN TERMS OF UPSTREAM REGULATORS, NDUFAF3 WAS THE MOST SIGNIFICANT (P = 8.6E-04) UPSTREAM REGULATOR. OUR FINDINGS SUPPORT PREVIOUS PRELIMINARY WORK SUGGESTING THE IMPORTANCE OF EPIGENETIC REGULATION OF THE IMMUNE SYSTEM IN KNEE PAIN AND THE NEED FOR FUTURE WORK TO UNDERSTAND THE EPIGENETIC CONTRIBUTIONS TO CHRONIC PAIN.	2022	
                                                                                                                                      
17 1580  44 DNA METHYLATION PROFILES ARE ASSOCIATED WITH COMPLEX REGIONAL PAIN SYNDROME AFTER TRAUMATIC INJURY. FACTORS CONTRIBUTING TO DEVELOPMENT OF COMPLEX REGIONAL PAIN SYNDROME (CRPS) ARE NOT FULLY UNDERSTOOD. THIS STUDY EXAMINED POSSIBLE EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO CRPS AFTER TRAUMATIC INJURY. DNA METHYLATION PROFILES WERE COMPARED BETWEEN INDIVIDUALS DEVELOPING CRPS (N = 9) AND THOSE DEVELOPING NON-CRPS NEUROPATHIC PAIN (N = 38) AFTER UNDERGOING AMPUTATION FOLLOWING MILITARY TRAUMA. LINEAR MODELS FOR MICROARRAY (LIMMA) ANALYSES REVEALED 48 DIFFERENTIALLY METHYLATED CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES BETWEEN GROUPS (UNADJUSTED P'S < 0.005), WITH THE TOP GENE COL11A1 MEETING BONFERRONI-ADJUSTED P < 0.05. THE SECOND LARGEST DIFFERENTIAL METHYLATION WAS OBSERVED FOR THE HLA-DRB6 GENE, AN IMMUNE-RELATED GENE LINKED PREVIOUSLY TO CRPS IN A SMALL GENE EXPRESSION STUDY. FOR ALL BUT 7 OF THE SIGNIFICANT CPG SITES, THE CRPS GROUP WAS HYPOMETHYLATED. NUMEROUS FUNCTIONAL GENE ONTOLOGY-BIOLOGICAL PROCESS CATEGORIES WERE SIGNIFICANTLY ENRICHED (FALSE DISCOVERY RATE-ADJUSTED Q VALUE <0.15), INCLUDING MULTIPLE IMMUNE-RELATED CATEGORIES (EG, ACTIVATION OF IMMUNE RESPONSE, IMMUNE SYSTEM DEVELOPMENT, REGULATION OF IMMUNE SYSTEM PROCESSES, AND ANTIGEN PROCESSING AND PRESENTATION). DIFFERENTIALLY METHYLATED GENES WERE MORE HIGHLY CONNECTED IN HUMAN PROTEIN-PROTEIN NETWORKS THAN EXPECTED BY CHANCE (P < 0.05), SUPPORTING THE BIOLOGICAL RELEVANCE OF THE FINDINGS. RESULTS WERE VALIDATED IN AN INDEPENDENT SAMPLE LINKING A DNA BIOBANK WITH ELECTRONIC HEALTH RECORDS (N = 126 CRPS PHENOTYPE, N = 19,768 NON-CRPS CHRONIC PAIN PHENOTYPE). ANALYSES USING PREDIXCAN METHODOLOGY INDICATED DIFFERENCES IN THE GENETICALLY DETERMINED COMPONENT OF GENE EXPRESSION IN 7 OF 48 GENES IDENTIFIED IN METHYLATION ANALYSES (P'S < 0.02). RESULTS SUGGEST THAT IMMUNE- AND INFLAMMATORY-RELATED FACTORS MIGHT CONFER RISK OF DEVELOPING CRPS AFTER TRAUMATIC INJURY. VALIDATION FINDINGS DEMONSTRATE THE POTENTIAL OF USING ELECTRONIC HEALTH RECORDS LINKED TO DNA FOR GENOMIC STUDIES OF CRPS.	2019	
                                                                                                                                                                                                                                                                                            
18  490  39 ASSESSING THE IMPACT OF ARSENIC METABOLISM EFFICIENCY ON DNA METHYLATION USING MENDELIAN RANDOMIZATION. BACKGROUND: ARSENIC EXPOSURE AFFECTS >100 MILLION PEOPLE GLOBALLY AND INCREASES RISK FOR CHRONIC DISEASES. ONE POSSIBLE TOXICITY MECHANISM IS EPIGENETIC MODIFICATION. PREVIOUS EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG-SPECIFIC DNA METHYLATION. TO PROVIDE ADDITIONAL EVIDENCE THAT OBSERVED ASSOCIATIONS REPRESENT CAUSAL RELATIONSHIPS, WE EXAMINE THE ASSOCIATION BETWEEN GENETIC DETERMINANTS OF ARSENIC METABOLISM EFFICIENCY (PERCENT DIMETHYLARSINIC ACID, DMA%, IN URINE) AND DNA METHYLATION AMONG INDIVIDUALS FROM THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (N = 379) AND BANGLADESH VITAMIN E AND SELENIUM TRIAL (N = 393). METHODS: WE USED MULTIVARIATE LINEAR MODELS TO ASSESS THE ASSOCIATION OF METHYLATION AT 221 ARSENIC-ASSOCIATED CPGS WITH DMA% AND MEASURES OF GENETICALLY PREDICTED DMA% DERIVED FROM THREE SNPS (RS9527, RS11191527, AND RS61735836). WE ALSO CONDUCTED TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES TO ESTIMATE THE ASSOCIATION BETWEEN ARSENIC METABOLISM EFFICIENCY AND CPG METHYLATION. RESULTS: AMONG THE ASSOCIATIONS BETWEEN DMA% AND METHYLATION AT EACH OF 221 CPGS, 64% WERE DIRECTIONALLY CONSISTENT WITH ASSOCIATIONS OBSERVED BETWEEN ARSENIC EXPOSURE AND THE 221 CPGS FROM A PRIOR EWAS. SIMILARLY, AMONG THE ASSOCIATIONS BETWEEN GENETICALLY PREDICTED DMA% AND EACH CPG, 62% WERE DIRECTIONALLY CONSISTENT WITH THE PRIOR EWAS RESULTS. TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES PRODUCED SIMILAR CONCLUSIONS. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT ARSENIC EXPOSURE EFFECTS DNA METHYLATION AT SPECIFIC CPGS IN WHOLE BLOOD. OUR NOVEL APPROACH FOR ASSESSING THE IMPACT OF ARSENIC EXPOSURE ON DNA METHYLATION REQUIRES LARGER SAMPLES IN ORDER TO DRAW MORE ROBUST CONCLUSIONS FOR SPECIFIC CPG SITES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19 2079  29 EPIGENETIC DNA METHYLATION CHANGES ASSOCIATED WITH HEADACHE CHRONIFICATION: A RETROSPECTIVE CASE-CONTROL STUDY. BACKGROUND THE BIOLOGICAL MECHANISMS OF HEADACHE CHRONIFICATION ARE POORLY UNDERSTOOD. WE AIMED TO IDENTIFY CHANGES IN DNA METHYLATION ASSOCIATED WITH THE TRANSFORMATION FROM EPISODIC TO CHRONIC HEADACHE. METHODS PARTICIPANTS WERE RECRUITED FROM THE POPULATION-BASED NORWEGIAN HUNT STUDY. THIRTY-SIX FEMALE HEADACHE PATIENTS WHO TRANSFORMED FROM EPISODIC TO CHRONIC HEADACHE BETWEEN BASELINE AND FOLLOW-UP 11 YEARS LATER WERE MATCHED AGAINST 35 CONTROLS WITH EPISODIC HEADACHE. DNA METHYLATION WAS QUANTIFIED AT 485,000 CPG SITES, AND CHANGES IN METHYLATION LEVEL AT THESE SITES WERE COMPARED BETWEEN CASES AND CONTROLS BY LINEAR REGRESSION ANALYSIS. DATA WERE ANALYZED IN TWO STAGES (STAGES 1 AND 2) AND IN A COMBINED META-ANALYSIS. RESULTS NONE OF THE TOP 20 CPG SITES IDENTIFIED IN STAGE 1 REPLICATED IN STAGE 2 AFTER MULTIPLE TESTING CORRECTION. IN THE COMBINED META-ANALYSIS THE STRONGEST ASSOCIATED CPG SITES WERE RELATED TO SH2D5 AND NPTX2, TWO BRAIN-EXPRESSED GENES INVOLVED IN THE REGULATION OF SYNAPTIC PLASTICITY. FUNCTIONAL ENRICHMENT ANALYSIS POINTED TO PROCESSES INCLUDING CALCIUM ION BINDING AND ESTROGEN RECEPTOR PATHWAYS. CONCLUSION IN THIS FIRST GENOME-WIDE STUDY OF DNA METHYLATION IN HEADACHE CHRONIFICATION SEVERAL POTENTIALLY IMPLICATED LOCI AND PROCESSES WERE IDENTIFIED. THE STUDY EXEMPLIFIES THE USE OF PROSPECTIVELY COLLECTED POPULATION COHORTS TO SEARCH FOR EPIGENETIC MECHANISMS OF DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 3991  34 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS.	2018