1 5728 105 SLEEP QUALITY AND METHYLATION STATUS OF SELECTED TUMOR SUPPRESSOR GENES AMONG NURSES AND MIDWIVES. CHRONIC SLEEP RESTRICTION MAY AFFECT METABOLISM, HORMONE SECRETION PATTERNS AND INFLAMMATORY RESPONSES. LIMITED REPORTS SUGGEST ALSO EPIGENETIC EFFECTS, SUCH AS CHANGES IN DNA METHYLATION PROFILES. THE STUDY AIMS TO ASSESS THE POTENTIAL ASSOCIATION BETWEEN POOR SLEEP QUALITY OR SLEEP DURATION AND THE LEVELS OF 5-METHYLCYTOSINE IN THE PROMOTER REGIONS OF SELECTED TUMOR SUPPRESSOR GENES. A CROSS-SECTIONAL STUDY WAS CONDUCTED ON 710 NURSES AND MIDWIVES AGED 40-60 YEARS. DATA FROM INTERVIEWS REGARDING SLEEP HABITS AND POTENTIAL CONFOUNDERS WERE USED. THE METHYLATION STATUS OF TUMOR SUPPRESSOR GENES WAS DETERMINED VIA QMSP REACTIONS USING DNA SAMPLES DERIVED FROM LEUCOCYTES. NO SIGNIFICANT FINDINGS WERE OBSERVED IN THE TOTAL STUDY POPULATION OR IN THE TWO SUBGROUPS OF WOMEN STRATIFIED BY THE CURRENT SYSTEM OF WORK. A BORDERLINE SIGNIFICANCE ASSOCIATION WAS OBSERVED BETWEEN A SHORTER DURATION OF SLEEP AND AN INCREASED METHYLATION LEVEL IN CDKN2A AMONG DAY WORKING NURSES AND MIDWIVES. FURTHER STUDIES ARE WARRANTED TO EXPLORE THIS UNDER-INVESTIGATED TOPIC. 2018 2 5727 95 SLEEP QUALITY AND METHYLATION STATUS OF CORE CIRCADIAN RHYTHM GENES AMONG NURSES AND MIDWIVES. ABSTARCT POOR SLEEP QUALITY OR SLEEP RESTRICTION IS ASSOCIATED WITH SLEEPINESS AND CONCENTRATION PROBLEMS. MOREOVER, CHRONIC SLEEP RESTRICTION MAY AFFECT METABOLISM, HORMONE SECRETION PATTERNS AND INFLAMMATORY RESPONSES. LIMITED RECENT REPORTS SUGGEST A POTENTIAL LINK BETWEEN SLEEP DEPRIVATION AND EPIGENETIC EFFECTS SUCH AS CHANGES IN DNA METHYLATION PROFILES. THE AIM OF THE PRESENT STUDY WAS TO ASSESS THE POTENTIAL ASSOCIATION BETWEEN POOR SLEEP QUALITY OR SLEEP DURATION AND THE LEVELS OF 5-METHYLCYTOSINE IN THE PROMOTER REGIONS OF PER1, PER2, PER3, BMAL1, CLOCK, CRY1 CRY2 AND NPAS2 GENES, TAKING INTO ACCOUNT ROTATING NIGHT WORK AND CHRONOTYPE AS POTENTIAL CONFOUNDERS OR MODIFIERS. A CROSS-SECTIONAL STUDY WAS CONDUCTED ON 710 NURSES AND MIDWIVES (347 WORKING ON ROTATING NIGHTS AND 363 WORKING ONLY DURING THE DAY) AGED 40-60 YEARS. DATA FROM IN-PERSON INTERVIEWS ABOUT SLEEP QUALITY, CHRONOTYPE AND POTENTIAL CONFOUNDERS WERE USED. SLEEP QUALITY AND CHRONOTYPE WERE ASSESSED USING PITTSBURGH SLEEP QUALITY QUESTIONNAIRE (PSQI) AND MORNINGNESS-EVENINGNESS QUESTIONNAIRE (MEQ), RESPECTIVELY. MORNING BLOOD SAMPLES WERE COLLECTED. THE METHYLATION STATUS OF THE CIRCADIAN RHYTHM GENES WAS DETERMINED VIA QUANTITATIVE METHYLATION-SPECIFIC REAL-TIME PCR ASSAYS (QMSP) REACTIONS USING DNA SAMPLES DERIVED FROM LEUCOCYTES. THE PROPORTIONAL ODDS REGRESSION MODEL WAS FITTED TO QUANTIFY THE RELATIONSHIP BETWEEN METHYLATION INDEX (MI) AS THE DEPENDENT VARIABLE AND SLEEP QUALITY OR SLEEP DURATION AS THE EXPLANATORY VARIABLE. ANALYSES WERE CARRIED OUT FOR THE TOTAL POPULATION AS WELL AS FOR SUBGROUPS OF WOMEN STRATIFIED BY THE CURRENT SYSTEM OF WORK (ROTATING NIGHT SHIFT/DAY WORK) AND CHRONOTYPE (MORNING TYPE/INTERMEDIATE TYPE/EVENING TYPE). A POTENTIAL MODIFYING EFFECT OF THE SYSTEM OF WORK OR THE CHRONOTYPE WAS EXAMINED USING THE LIKELIHOOD RATIO TEST. NO SIGNIFICANT FINDINGS WERE OBSERVED IN THE TOTAL STUDY POPULATION. SUBGROUP ANALYSES REVEALED TWO STATISTICALLY SIGNIFICANT ASSOCIATIONS BETWEEN A SHORTER SLEEP DURATION AND 1) METHYLATION LEVEL IN PER2 AMONG DAY WORKERS, ESPECIALLY THOSE WITH THE MORNING CHRONOTYPE (OR = 2.31, 95%CI:1.24-4.33), AND 2) METHYLATION LEVEL IN CRY2 AMONG SUBJECTS WITH THE INTERMEDIATE CHRONOTYPE, PARTICULARLY AMONG DAY WORKERS (OR = 0.52, 95%CI:0.28-0.96). THE STUDY RESULTS DEMONSTRATED A POSITIVE ASSOCIATION BETWEEN AVERAGE SLEEP DURATION OF LESS THAN 6 HOURS AND THE METHYLATION LEVEL OF PER2 AMONG MORNING CHRONOTYPE SUBJECTS, AND AN INVERSE ASSOCIATION FOR CRY2 AMONG INTERMEDIATE CHRONOTYPE SUBJECTS, BUT ONLY AMONG DAY WORKERS. BOTH THE SYSTEM OF WORK AND THE CHRONOTYPE TURNED OUT TO BE IMPORTANT CONFOUNDERS AND MODIFIERS IN A NUMBER OF ANALYSES, MAKING IT NECESSARY TO CONSIDER THEM AS POTENTIAL COVARIATES IN FUTURE RESEARCH ON SLEEP DEFICIENCY OUTCOMES. FURTHER STUDIES ARE WARRANTED TO EXPLORE THIS UNDER-INVESTIGATED TOPIC. 2017 3 6311 31 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP. 2017 4 1599 32 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 5 287 28 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010 6 497 22 ASSOCIATION BETWEEN BMI AND DNA METHYLATION IN BLOOD OR NORMAL ADULT BREAST TISSUE: A SYSTEMATIC REVIEW. BACKGROUND/AIM: SEVERAL STUDIES HAVE INVESTIGATED THE INFLUENCE OF OBESITY ON DNA METHYLATION (DNAM) TO FIND BIOMARKERS ASSOCIATED WITH THE DETECTION OF CHRONIC DISEASES, INCLUDING BREAST CANCER. THE AIM OF THE STUDY WAS TO SYSTEMATICALLY REVIEW STUDIES EXAMINING THE ASSOCIATION OF BODY MASS INDEX (BMI) AND DNAM IN BLOOD OR NORMAL BREAST TISSUE. MATERIALS AND METHODS: THREE SCIENTIFIC LITERATURE DATABASES (PUBMED, EMBASE AND WEB OF SCIENCE) WERE SCREENED UNTIL MAY 2018. RESULTS: TWENTY-FOUR STUDIES WERE INCLUDED ALONG WITH OURS IN WHICH WE INVESTIGATED THIS RELATION IN THE NORMAL BREAST TISSUE OF 40 BREAST CANCER PATIENTS. CONCLUSION: BMI-ASSOCIATED CPG SITES WERE HIGHLY VARIABLE WITH FEW IDENTIFIED IN LESS THAN HALF OF THE STUDIES. NEVERTHELESS, A FEW GENES POTENTIALLY ASSOCIATED WITH BMI WERE HIGHLIGHTED IN BLOOD (CPT1A, ABCG1, SREBF1 AND LGALS3BP) AND IN NORMAL BREAST TISSUE (PTPRN2 AND ABLIM2). THE VARIABILITY OF THE RESULTS COULD BE EXPLAINED BY THE TISSUE AND CELL-SPECIFICITY OF METHYLATION AND DIFFERENCES IN METHODOLOGY. 2020 7 2677 26 EVALUATING THE CHALLENGES AND REPRODUCIBILITY OF STUDIES INVESTIGATING DNA METHYLATION SIGNATURES OF PSYCHOLOGICAL STRESS. PSYCHOLOGICAL STRESS CAN INCREASE THE RISK OF A WIDE RANGE OF NEGATIVE HEALTH OUTCOMES. STUDIES HAVE BEEN COMPLETED TO DETERMINE IF DNA METHYLATION CHANGES OCCUR IN THE HUMAN BRAIN BECAUSE OF STRESS AND ARE ASSOCIATED WITH LONG-TERM EFFECTS AND DISEASE, BUT RESULTS HAVE BEEN INCONSISTENT. HUMAN CANDIDATE GENE STUDIES (150) AND EPIGENOME-WIDE ASSOCIATION STUDIES (67) WERE SYSTEMATICALLY EVALUATED TO ASSESS HOW DNA METHYLATION IS IMPACTED BY STRESS DURING THE PRENATAL PERIOD, EARLY CHILDHOOD AND ADULTHOOD. THE ASSOCIATION BETWEEN DNA METHYLATION OF NR3C1 EXON 1F AND CHILD MALTREATMENT AND EARLY LIFE ADVERSITY WAS WELL DEMONSTRATED, BUT OTHER GENES DID NOT EXHIBIT A CLEAR ASSOCIATION. THE REPRODUCIBILITY OF INDIVIDUAL CPG SITES IN EPIGENOME-WIDE ASSOCIATION STUDIES WAS ALSO POOR. HOWEVER, BIOLOGICAL PATHWAYS, INCLUDING STRESS RESPONSE, BRAIN DEVELOPMENT AND IMMUNITY, HAVE BEEN CONSISTENTLY IDENTIFIED ACROSS DIFFERENT STRESSORS THROUGHOUT THE LIFE SPAN. FUTURE STUDIES WOULD BENEFIT FROM THE INCREASED SAMPLE SIZE, LONGITUDINAL DESIGN, STANDARDIZED METHODOLOGY, OPTIMAL QUALITY CONTROL, AND IMPROVED STATISTICAL PROCEDURES. 2022 8 70 19 A METHOD TO DETECT DIFFERENTIALLY METHYLATED LOCI WITH NEXT-GENERATION SEQUENCING. EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION AT CPG LOCI HAVE IMPORTANT IMPLICATIONS IN CANCER AND OTHER COMPLEX DISEASES. WITH THE DEVELOPMENT OF NEXT-GENERATION SEQUENCING (NGS), IT IS FEASIBLE TO GENERATE DATA TO INTERROGATE THE DIFFERENCE IN METHYLATION STATUS FOR GENOME-WIDE LOCI USING CASE-CONTROL DESIGN. HOWEVER, A PROPER AND EFFICIENT STATISTICAL TEST IS LACKING. THERE ARE SEVERAL CHALLENGES. FIRST, UNLIKE METHYLATION EXPERIMENTS USING MICROARRAYS, WHERE THERE IS ONE MEASURE OF METHYLATION FOR ONE INDIVIDUAL AT A PARTICULAR CPG SITE, HERE WE HAVE THE COUNTS OF METHYLATION ALLELE AND UNMETHYLATION ALLELE FOR EACH INDIVIDUAL. SECOND, DUE TO THE NATURE OF SAMPLE PREPARATION, THE MEASURED METHYLATION REFLECTS THE METHYLATION STATUS OF A MIXTURE OF CELLS INVOLVED IN SAMPLE PREPARATION. THEREFORE, THE UNDERLYING DISTRIBUTION OF THE MEASURED METHYLATION LEVEL IS UNKNOWN, AND A ROBUST TEST IS MORE DESIRABLE THAN PARAMETRIC APPROACH. THIRD, CURRENTLY NGS MEASURES METHYLATION AT OVER 2 MILLION CPG SITES. ANY STATISTICAL TESTS HAVE TO BE COMPUTATIONALLY EFFICIENT IN ORDER TO BE APPLIED TO THE NGS DATA. TAKING THESE CHALLENGES INTO ACCOUNT, WE PROPOSE A TEST FOR DIFFERENTIAL METHYLATION BASED ON CLUSTERED DATA ANALYSIS BY MODELING THE METHYLATION COUNTS. WE PERFORMED SIMULATIONS TO SHOW THAT IT IS ROBUST UNDER SEVERAL DISTRIBUTIONS FOR THE MEASURED METHYLATION LEVELS. IT HAS GOOD POWER AND IS COMPUTATIONALLY EFFICIENT. FINALLY, WE APPLY THE TEST TO OUR NGS DATA ON CHRONIC LYMPHOCYTIC LEUKEMIA. THE RESULTS INDICATE THAT IT IS A PROMISING AND PRACTICAL TEST. 2013 9 1967 35 EPIGENETIC ALTERATION OF THE DOPAMINE TRANSPORTER GENE IN ALCOHOL-DEPENDENT PATIENTS IS ASSOCIATED WITH AGE. CHRONIC ALCOHOL ABUSE AND DEPENDENCE ARE ASSOCIATED WITH DYSFUNCTIONAL DOPAMINERGIC NEUROTRANSMISSION IN MESOCORTICOLIMBIC CIRCUITS. GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN SHOWN TO MODULATE SUSCEPTIBILITY TO ALCOHOL DEPENDENCE, AND BOTH MAY ACT THROUGH EPIGENETIC MECHANISMS THAT CAN MODULATE GENE EXPRESSION, E.G. DNA METHYLATION AT CPG SITES. RECENT STUDIES HAVE SUGGESTED THAT DNA METHYLATION PATTERNS MAY CHANGE OVER TIME. HOWEVER, FEW DATA ARE AVAILABLE CONCERNING THE RATE OF THESE CHANGES IN SPECIFIC GENES. A RECENT STUDY FOUND THAT HYPERMETHYLATION OF THE PROMOTER OF THE DOPAMINE TRANSPORTER (DAT) GENE WAS POSITIVELY CORRELATED WITH ALCOHOL DEPENDENCE AND NEGATIVELY CORRELATED WITH ALCOHOL CRAVING. THE AIM OF THE PRESENT STUDY WAS TO REPLICATE THESE FINDINGS IN A LARGER SAMPLE OF ALCOHOL-DEPENDENT PATIENTS AND POPULATION-BASED CONTROLS MATCHED FOR AGE AND SEX. NO DIFFERENCE IN METHYLATION LEVEL WAS OBSERVED BETWEEN PATIENTS AND CONTROLS, AND NO DIFFERENCE IN METHYLATION LEVEL WAS OBSERVED BEFORE AND AFTER ALCOHOL WITHDRAWAL IN PATIENTS. HOWEVER, PATIENTS WITH MORE SEVERE CRAVING SHOWED A TREND TOWARDS LOWER DAT METHYLATION LEVELS (P = 0.07), WHICH IS CONSISTENT WITH PREVIOUS FINDINGS. FURTHERMORE, IN OUR OVERALL SAMPLE, DAT METHYLATION LEVELS INCREASED WITH AGE. INTERESTINGLY, A SEPARATE ANALYSIS OF PATIENTS SUGGESTED THAT THIS FINDING WAS MAINLY DRIVEN BY THE PATIENT GROUP. ALTHOUGH THE PRESENT DATA DO NOT CLARIFY WHETHER CHRONIC ALCOHOL ABUSE IS RESPONSIBLE FOR THIS PHENOMENON OR MERELY ENHANCES AN AGEING-SPECIFIC PROCESS, OUR FINDINGS SUGGEST THAT HYPERMETHYLATION IN ALCOHOL-DEPENDENT PATIENTS IS A CONSEQUENCE, RATHER THAN A CAUSE, OF THE DISORDER. 2014 10 1583 25 DNA METHYLATION PROFILES OF BLOOD CELLS ARE DISTINCT BETWEEN EARLY-ONSET OBESE AND CONTROL INDIVIDUALS. OBESITY IS A HIGHLY PREVALENT, CHRONIC DISORDER THAT HAS BEEN INCREASING IN INCIDENCE IN YOUNG PATIENTS. BOTH EPIGENETIC AND GENETIC ABERRATIONS MAY PLAY A ROLE IN THE PATHOGENESIS OF OBESITY. THEREFORE, IN-DEPTH EPIGENOMIC AND GENOMIC ANALYSES WILL ADVANCE OUR UNDERSTANDING OF THE DETAILED MOLECULAR MECHANISMS UNDERLYING OBESITY AND AID IN THE SELECTION OF POTENTIAL BIOMARKERS FOR OBESITY IN YOUTH. HERE, WE PERFORMED MICROARRAY-BASED DNA METHYLATION AND GENE EXPRESSION PROFILING OF PERIPHERAL WHITE BLOOD CELLS OBTAINED FROM SIX YOUNG, OBESE INDIVIDUALS AND SIX HEALTHY CONTROLS. WE OBSERVED THAT THE HIERARCHICAL CLUSTERING OF DNA METHYLATION, BUT NOT GENE EXPRESSION, CLEARLY SEGREGATES THE OBESE INDIVIDUALS FROM THE CONTROLS, SUGGESTING THAT THE METABOLIC DISTURBANCE THAT OCCURS AS A RESULT OF OBESITY AT A YOUNG AGE MAY AFFECT THE DNA METHYLATION OF PERIPHERAL BLOOD CELLS WITHOUT ACCOMPANYING TRANSCRIPTIONAL CHANGES. TO EXAMINE THE GENOME-WIDE DIFFERENCES IN THE DNA METHYLATION PROFILES OF YOUNG OBESE AND CONTROL INDIVIDUALS, WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES AND INVESTIGATED THEIR GENOMIC AND EPIGENOMIC CONTEXTS. THE ABERRANT DNA METHYLATION PATTERNS IN OBESE INDIVIDUALS CAN BE SUMMARIZED AS RELATIVE GAINS AND LOSSES OF DNA METHYLATION IN GENE PROMOTERS AND GENE BODIES, RESPECTIVELY. WE ALSO OBSERVED THAT THE CPG ISLANDS OF OBESE INDIVIDUALS ARE MORE SUSCEPTIBLE TO DNA METHYLATION COMPARED TO CONTROLS. OUR PILOT STUDY SUGGESTS THAT THE GENOME-WIDE ABERRANT DNA METHYLATION PATTERNS OF OBESE INDIVIDUALS MAY ADVANCE NOT ONLY OUR UNDERSTANDING OF THE EPIGENOMIC PATHOGENESIS BUT ALSO EARLY SCREENING OF OBESITY IN YOUTH. 2017 11 1503 32 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION. 2009 12 2075 32 EPIGENETIC DIFFERENCES IN INFLAMMATION GENES OF MONOZYGOTIC TWINS ARE RELATED TO PARENT-CHILD EMOTIONAL AVAILABILITY AND HEALTH. THE INFLAMMATORY RESPONSE IS AN IMMUNE DEFENSE ENGAGED IMMEDIATELY AFTER INJURY OR INFECTION. CHRONIC INFLAMMATION CAN BE DELETERIOUS FOR VARIOUS HEALTH OUTCOMES AND IS CHARACTERIZED BY HIGH LEVELS OF PRO-INFLAMMATORY MARKERS SUCH AS C-REACTIVE PROTEIN (CRP), INTERLEUKIN 6 (IL-6), AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA). A LARGE BODY OF RESEARCH DEMONSTRATES THESE INFLAMMATORY MARKERS ARE RESPONSIVE TO STRESS AND QUALITY OF SOCIAL RELATIONSHIPS THROUGHOUT THE LIFESPAN. FOR EXAMPLE, THE QUALITY OF THE EARLY PARENTAL BOND PREDICTS VARIOUS HEALTH OUTCOMES AND MAY BE DRIVEN BY CHANGES IN IMMUNE FUNCTION. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, MAY BE ONE MECHANISM BY WHICH EARLY SOCIAL EXPERIENCES SHAPE IMMUNE FUNCTIONING. THE PRESENT STUDY USED A MONOZYGOTIC TWIN DIFFERENCE DESIGN TO ASSESS IF MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR AND 2.5 YEARS PREDICTED IMMUNE GENE METHYLATION AT 8 YEARS OF AGE. FURTHER, WE ASSESSED IF INFLAMMATION GENE METHYLATION WAS RELATED TO GENERAL HEALTH PROBLEMS (E.G. INFECTIONS, ALLERGIES, ETC.). WE FOUND THAT MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR, BUT NOT 2.5 YEARS, WAS RELATED TO METHYLATION OF VARIOUS IMMUNE GENES IN MONOZYGOTIC TWINS. FURTHERMORE, TWIN PAIRS DISCORDANT IN HEALTH PROBLEMS HAVE MORE DIFFERENCE IN IMMUNE GENE METHYLATION COMPARED TO TWIN PAIRS CONCORDANT FOR HEALTH PROBLEMS, SUGGESTING THAT METHYLATION OF IMMUNE GENES MAY HAVE FUNCTIONAL CONSEQUENCES FOR GENERAL HEALTH. THESE RESULTS SUGGEST THAT THE EMOTIONAL COMPONENT OF ATTACHMENT QUALITY DURING INFANCY CONTRIBUTES TO IMMUNE EPIGENETIC PROFILES IN CHILDHOOD, WHICH MAY INFLUENCE GENERAL HEALTH. 2020 13 5882 34 SYSTEMATIC REVIEW OF LUNG FUNCTION AND COPD WITH PERIPHERAL BLOOD DNA METHYLATION IN POPULATION BASED STUDIES. BACKGROUND: EPIGENETIC VARIATIONS IN PERIPHERAL BLOOD HAVE POTENTIAL AS BIOMARKERS FOR DISEASE. THIS SYSTEMATIC REVIEW ASSESSES THE ASSOCIATION OF LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WITH DNA METHYLATION PROFILES IN PERIPHERAL BLOOD FROM POPULATION-BASED STUDIES. METHODS: ONLINE DATABASES MEDLINE, EMBASE, AND WEB OF SCIENCE WERE SEARCHED. GOOGLE SCHOLAR WAS SEARCHED TO IDENTIFY GREY LITERATURE. AFTER REMOVING DUPLICATE ARTICLES, 1155 ARTICLES WERE INDEPENDENTLY SCREENED BY TWO INVESTIGATORS. PEER REVIEWED REPORTS ON POPULATION-BASED STUDIES THAT EXAMINED PERIPHERAL BLOOD DNA METHYLATION IN PARTICIPANTS WITH MEASURED LUNG FUNCTION (FEV1, FEV1/FVC RATIO) OR KNOWN COPD STATUS WERE SELECTED FOR FULL-TEXT REVIEW. SIX ARTICLES WERE SUITABLE FOR INCLUSION. INFORMATION REGARDING STUDY CHARACTERISTICS, DESIGNS, METHODOLOGIES AND CONCLUSIONS WAS EXTRACTED. A NARRATIVE SYNTHESIS WAS PERFORMED BASED ON PUBLISHED RESULTS. RESULTS: THREE OF THE SIX ARTICLES ASSESSED THE ASSOCIATION OF COPD WITH DNA METHYLATION, AND TWO OF THESE ALSO INCLUDED ASSOCIATIONS WITH LUNG FUNCTION. OVERALL, FIVE REPORTS EXAMINED THE ASSOCIATION OF LUNG FUNCTION WITH DNA METHYLATION PROFILES. FIVE OF THE SIX ARTICLES REPORTED 'SIGNIFICANT' RESULTS. HOWEVER, NO CONSISTENT CPG SITES WERE IDENTIFIED ACROSS STUDIES FOR COPD STATUS OR LUNG FUNCTION VALUES. CONCLUSIONS: DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD FROM INDIVIDUALS WITH REDUCED LUNG FUNCTION OR COPD MAY BE DIFFERENT TO THOSE IN PEOPLE WITH NORMAL LUNG FUNCTION. HOWEVER, THIS SYSTEMATIC REVIEW DID NOT FIND ANY CONSISTENT ASSOCIATIONS OF LUNG FUNCTION OR COPD WITH DIFFERENTIALLY METHYLATED CPG SITES. LARGE STUDIES WITH A LONGITUDINAL DESIGN TO ADDRESS REVERSE CAUSALITY MAY PROVE A MORE FRUITFUL AREA OF RESEARCH. TRIAL REGISTRATION: PROSPERO 2016: CRD42016037352 . 2017 14 4607 39 NEIGHBORHOOD ENVIRONMENT AND DNA METHYLATION: IMPLICATIONS FOR CARDIOVASCULAR DISEASE RISK. EXPOSURE TO CHRONIC STRESS SUCH AS LIVING IN DISADVANTAGED NEIGHBORHOODS HAS BEEN RELATED TO CARDIOVASCULAR DISEASE (CVD). CHRONIC STRESS MAY INCREASE THE RISK FOR CVD BY INCREASING LEVELS OF SYSTEMIC INFLAMMATION (E.G., HIGHER LEVELS OF PRO-INFLAMMATORY CYTOKINES). DIFFERENTIAL DNA METHYLATION OF INFLAMMATION-RELATED CANDIDATE GENES IS ALSO RELATED TO HIGHER RISK FOR CVD. THUS, THE PURPOSE OF THIS REVIEW WAS TO EXAMINE THE ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH DNA METHYLATION. A SEARCH OF LITERATURE WAS CONDUCTED USING SCOPUS, CINAHL, PUBMED, MEDLINE, AND EMBASE DATABASES. THE KEYWORDS NEIGHBORHOOD, NEIGHBORHOOD DISORDER, NEIGHBORHOOD CRIME, NEIGHBORHOOD VIOLENCE, NEIGHBORHOOD SAFETY, BUILT ENVIRONMENT, AND HOUSING VACANCY WERE COMBINED WITH THE KEYWORDS DNA METHYLATION AND EPIGENETICS. FIVE STUDIES WERE INCLUDED IN THIS REVIEW (N = 3 ADULT BLOOD SAMPLES AND N = 2 FETAL BLOOD SAMPLES). FOUR OF THE FIVE STUDIES REPORTED AN ASSOCIATION OF NEIGHBORHOOD SOCIOECONOMIC STATUS, SOCIAL ENVIRONMENT, AND CRIME WITH EITHER GLOBAL OR GENE-SPECIFIC DNA METHYLATION. ONLY TWO STUDIES EXAMINED THE ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH INFLAMMATION-RELATED CANDIDATE GENES. ONE OF THESE STUDIES FOUND A SIGNIFICANT ASSOCIATION OF NEIGHBORHOOD SOCIOECONOMIC DISADVANTAGE AND SOCIAL ENVIRONMENT WITH DNA METHYLATION IN INFLAMMATION-RELATED CANDIDATE GENES. THUS, DATA ARE LIMITED ON THE ASSOCIATION BETWEEN NEIGHBORHOOD DISADVANTAGE AND DNA METHYLATION OF INFLAMMATION-RELATED CANDIDATE GENES, AS WELL AS GENES IN OTHER POTENTIAL MECHANISTIC PATHWAYS INCLUDING PSYCHOSOCIAL STRESS, TOXIN RESPONSE, AND ADIPOSITY. FUTURE STUDIES SHOULD EXAMINE THESE ASSOCIATIONS AND THE POTENTIAL EPIGENETIC MECHANISMS BY WHICH NEIGHBORHOOD DISADVANTAGE INCREASES THE RISK FOR CVD. 2019 15 5748 33 SOCIAL AND PHYSICAL ENVIRONMENTS EARLY IN DEVELOPMENT PREDICT DNA METHYLATION OF INFLAMMATORY GENES IN YOUNG ADULTHOOD. CHRONIC INFLAMMATION CONTRIBUTES TO A WIDE RANGE OF HUMAN DISEASES, AND ENVIRONMENTS IN INFANCY AND CHILDHOOD ARE IMPORTANT DETERMINANTS OF INFLAMMATORY PHENOTYPES. THE UNDERLYING BIOLOGICAL MECHANISMS CONNECTING EARLY ENVIRONMENTS WITH THE REGULATION OF INFLAMMATION IN ADULTHOOD ARE NOT KNOWN, BUT EPIGENETIC PROCESSES ARE PLAUSIBLE CANDIDATES. WE TESTED THE HYPOTHESIS THAT PATTERNS OF DNA METHYLATION (DNAM) IN INFLAMMATORY GENES IN YOUNG ADULTHOOD WOULD BE PREDICTED BY EARLY LIFE NUTRITIONAL, MICROBIAL, AND PSYCHOSOCIAL EXPOSURES PREVIOUSLY ASSOCIATED WITH LEVELS OF INFLAMMATION. DATA COME FROM A POPULATION-BASED LONGITUDINAL BIRTH COHORT STUDY IN METROPOLITAN CEBU, THE PHILIPPINES, AND DNAM WAS CHARACTERIZED IN WHOLE BLOOD SAMPLES FROM 494 PARTICIPANTS (AGE 20-22 Y). ANALYSES FOCUSED ON PROBES IN 114 TARGET GENES INVOLVED IN THE REGULATION OF INFLAMMATION, AND WE IDENTIFIED 10 SITES ACROSS NINE GENES WHERE THE LEVEL OF DNAM WAS SIGNIFICANTLY PREDICTED BY THE FOLLOWING VARIABLES: HOUSEHOLD SOCIOECONOMIC STATUS IN CHILDHOOD, EXTENDED ABSENCE OF A PARENT IN CHILDHOOD, EXPOSURE TO ANIMAL FECES IN INFANCY, BIRTH IN THE DRY SEASON, OR DURATION OF EXCLUSIVE BREASTFEEDING. TO EVALUATE THE BIOLOGICAL SIGNIFICANCE OF THESE SITES, WE TESTED FOR ASSOCIATIONS WITH A PANEL OF INFLAMMATORY BIOMARKERS MEASURED IN PLASMA OBTAINED AT THE SAME AGE AS DNAM ASSESSMENT. THREE SITES PREDICTED ELEVATED INFLAMMATION, AND ONE SITE PREDICTED LOWER INFLAMMATION, CONSISTENT WITH THE INTERPRETATION THAT LEVELS OF DNAM AT THESE SITES ARE FUNCTIONALLY RELEVANT. THIS PATTERN OF RESULTS POINTS TOWARD DNAM AS A POTENTIALLY IMPORTANT BIOLOGICAL MECHANISM THROUGH WHICH DEVELOPMENTAL ENVIRONMENTS SHAPE INFLAMMATORY PHENOTYPES ACROSS THE LIFE COURSE. 2017 16 3652 28 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION. 2021 17 1563 27 DNA METHYLATION OF METHYLATION COMPLEX GENES IN RELATION TO STRESS AND GENOME-WIDE METHYLATION IN MOTHER-NEWBORN DYADS. OBJECTIVES: EARLY LIFE STRESS IS KNOWN TO HAVE ENDURING BIOLOGICAL EFFECTS, PARTICULARLY WITH RESPECT TO HEALTH. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE A POSSIBLE MECHANISM TO MEDIATE THE BIOLOGICAL EFFECT OF STRESS. WE PREVIOUSLY FOUND CORRELATIONS BETWEEN MATERNAL STRESS, NEWBORN BIRTHWEIGHT, AND GENOME-WIDE MEASURES OF DNA METHYLATION. HERE WE INVESTIGATE TEN GENES RELATED TO THE METHYLATION/DEMETHYLATION COMPLEX IN ORDER TO BETTER UNDERSTAND THE IMPACT OF STRESS ON HEALTH. MATERIALS AND METHODS: DNA METHYLATION AND GENETIC VARIANTS AT METHYLATION/DEMETHYLATION GENES WERE ASSAYED. MEAN METHYLATION MEASURES WERE CONSTRUCTED FOR EACH GENE AND TESTED, IN ADDITION TO GENETIC VARIANTS, FOR ASSOCIATION WITH MATERNAL STRESS MEASURES BASED ON INTERVIEW AND SURVEY DATA (CHRONIC STRESS AND WAR TRAUMA), MATERNAL VENOUS, AND NEWBORN CORD GENOME-WIDE MEAN METHYLATION (GMM), AND BIRTHWEIGHT. RESULTS: AFTER CELL TYPE CORRECTION, WE FOUND MULTIPLE PAIRWISE ASSOCIATIONS BETWEEN WAR TRAUMA, MATERNAL GMM, MATERNAL METHYLATION AT DNMT1, DNMT3A, TET3, AND MBD2, AND BIRTHWEIGHT. CONCLUSIONS: THE ASSOCIATION OF MATERNAL GMM AND MATERNAL METHYLATION AT DNMT1, DNMT3A, TET3, AND MBD2 IS CONSISTENT WITH THE ROLE OF THESE GENES IN ESTABLISHING, MAINTAINING AND ALTERING GENOME-WIDE METHYLATION PATTERNS, IN SOME CASES IN RESPONSE TO STRESS. DNMT1 PRODUCES ONE OF THE PRIMARY ENZYMES THAT REPRODUCES METHYLATION PATTERNS DURING DNA REPLICATION. DNMT3A AND TET3 HAVE BEEN IMPLICATED IN GENOME-WIDE HYPOMETHYLATION IN RESPONSE TO GLUCOCORTICOID HORMONES. ALTHOUGH WE CANNOT DETERMINE THE DIRECTIONALITY OF THE GENIC AND GENOME-WIDE CHANGES IN METHYLATION, OUR RESULTS SUGGEST THAT ALTERED METHYLATION OF SPECIFIC METHYLATION GENES MAY BE PART OF THE MOLECULAR MECHANISM UNDERLYING THE HUMAN BIOLOGICAL RESPONSE TO STRESS. 2018 18 311 35 ALCOHOL AND THE METHYLOME: DESIGN AND ANALYSIS CONSIDERATIONS FOR RESEARCH USING HUMAN SAMPLES. BACKGROUND: A GROWING NUMBER OF STUDIES IN HUMAN SAMPLES HAVE SOUGHT TO DETERMINE WHETHER CHRONIC ALCOHOL USE AND ALCOHOL USE DISORDERS (AUDS) MAY BE ASSOCIATED WITH EPIGENETIC FACTORS, SUCH AS DNA METHYLATION. WE REVIEW THE EXTANT LITERATURE IN LIGHT OF SOME OF THE CHALLENGES THAT CURRENTLY AFFECT THE DESIGN AND INTERPRETATION OF EPIGENETIC RESEARCH IN HUMAN SAMPLES. METHOD: A LITERATURE SEARCH WAS USED TO IDENTIFY STUDIES THAT HAVE EXAMINED DNA METHYLATION IN RELATION TO ALCOHOL USE OR AUDS IN HUMAN SAMPLES (THROUGH JULY 2013). A TOTAL OF 22 STUDIES WERE IDENTIFIED. RESULTS: ASSOCIATIONS WITH QUANTITATIVE OR DIAGNOSTIC PHENOTYPES OF ALCOHOL USE OR AUDS HAVE BEEN REPORTED FOR SEVERAL GENES. HOWEVER, ALL STUDIES TO DATE HAVE RELIED ON RELATIVELY SMALL SAMPLES AND CROSS-SECTIONAL STUDY DESIGNS. ADDITIONALLY, ATTEMPTS TO REPLICATE RESULTS HAVE BEEN RARE. MORE GENERALLY, RESEARCH PROGRESS IS HAMPERED BY SEVERAL ISSUES, INCLUDING LIMITATIONS OF THE TECHNOLOGIES USED TO ASSESS DNA METHYLATION, TISSUE- AND CELL-SPECIFICITY OF METHYLATION PATTERNS, THE DIFFICULTIES OF RELATING OBSERVED METHYLATION DIFFERENCES AT A GIVEN LOCUS TO A FUNCTIONAL EFFECT, AND LIMITED KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF ALCOHOL ON DNA METHYLATION. CONCLUSIONS: ALTHOUGH WE SHARE THE OPTIMISM THAT EPIGENETICS MAY LEAD TO NEW INSIGHTS INTO THE ETIOLOGY AND PATHOPHYSIOLOGY OF AUDS, THE METHODOLOGICAL AND SCIENTIFIC CHALLENGES ASSOCIATED WITH CONDUCTING METHYLOMIC RESEARCH IN HUMAN SAMPLES NEED TO BE CAREFULLY CONSIDERED WHEN DESIGNING AND EVALUATING SUCH STUDIES. 2013 19 344 33 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY. 2020 20 1497 28 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