1  3179 156 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2  5957  36 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3   404  42 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4  2734  42 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  1189  39 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  5395  32 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  3557  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8   325  38 ALLELE-SPECIFIC DNA METHYLATION LEVEL OF FKBP5 IS ASSOCIATED WITH POST-TRAUMATIC STRESS DISORDER. BACKGROUND: FK506-BINDING PROTEIN 5 (FKBP5) BINDS TO GLUCOCORTICOID RECEPTORS AND MODULATES GLUCOCORTICOID SENSITIVITY. THE FKBP5 GENE HAS BEEN IMPLICATED IN THE DYSREGULATION OF HUMAN STRESS RESPONSES, CONTRIBUTING TO THE RISK AND TREATMENT RESPONSE OF STRESS-RELATED DISORDERS. THE PRESENT STUDY EXAMINED WHETHER EPIGENETIC CHANGES IN FKBP5 ARE ASSOCIATED WITH CHRONIC POST-TRAUMATIC STRESS DISORDER (PTSD) STATUS IN THE CONTEXT OF FKBP5 GENETIC VARIATION (RS1360780 POLYMORPHISM) AMONG MALE VETERANS EXPOSED TO COMBAT TRAUMA. METHODS: KOREAN MALE VETERANS WHO SERVED ON ACTIVE DUTY DURING THE VIETNAM WAR WERE CATEGORIZED INTO 2 GROUPS: WITH PTSD (N = 123) AND WITHOUT PTSD (N = 116). THE GENOTYPE OF FKBP5 RS1360780 AND DNA METHYLATION LEVELS OF TWO CPG SITES AT THE FKBP5 INTRON 7 REGION WERE ASSESSED IN PERIPHERAL BLOOD. ANALYSIS OF COVARIANCE WAS PERFORMED TO EXAMINE MAIN AND INTERACTION EFFECTS OF PTSD STATUS AND FKBP5 GENOTYPE ON FKBP5 DNA METHYLATION LEVEL, WITH AGE, TRAUMA LEVELS, AND ALCOHOL USE AS COVARIATES. RESULTS: A SIGNIFICANT MAIN EFFECT OF FKBP5 RS1360780 AND PTSD AND AN INTERACTION EFFECT BETWEEN GENOTYPE AND PTSD STATUS WERE FOUND ON MEAN FKBP5 DNA METHYLATION LEVEL. THE T ALLELE OF RS1360780 WAS ASSOCIATED WITH LOWER FKBP5 METHYLATION LEVEL. IN ADDITION, THE PTSD GROUP SHOWED SIGNIFICANTLY HIGHER METHYLATION THAN DID THE NON-PTSD GROUP AMONG VETERANS CARRYING THE RISK T ALLELE (N = 96), WHILE NO GROUP DIFFERENCE WAS OBSERVED ON METHYLATION LEVELS AMONG VETERANS WITH THE CC GENOTYPE (N = 143). AMONG VETERANS CARRYING THE T ALLELE, FKBP5 METHYLATION LEVELS WERE POSITIVELY CORRELATED WITH THE SEVERITY OF PTSD SYMPTOMS. CONCLUSIONS: THE PRESENT STUDY DEMONSTRATED DIFFERENT FKBP5 METHYLATION LEVELS IN PTSD DEPENDING ON FKBP5 GENETIC VARIATION AMONG VETERANS EXPOSED TO COMBAT TRAUMA. THE PRESENT FINDING SUGGESTS THAT THE GENETIC AND EPIGENETIC MODULATION OF FKBP5 IS INVOLVED IN THE PATHOPHYSIOLOGY OF PTSD. FURTHER LONGITUDINAL RESEARCH INVOLVING PEOPLE EXPOSED TO TRAUMA IS REQUIRED TO UNDERSTAND CAUSAL RELATIONSHIPS OF FKBP5 IN THE DEVELOPMENT AND RECOVERY OF PTSD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  6418  39 THE TEMPORAL EXPRESSION OF CIRCULATING MICRORNAS AFTER ACUTE EXPERIMENTAL PAIN IN HUMANS. BACKGROUND: MICRORNAS (MIRNAS) CAN MODULATE SEVERAL BIOLOGICAL SYSTEMS, INCLUDING THE PAIN SYSTEM. THIS STUDY AIMED TO EVALUATE THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY VOLUNTEERS AS A MARKER FOR EPIGENETIC CHANGES BEFORE AND AFTER AN ACUTE, EXPERIMENTAL, PAIN PROVOCATION BY INTRAMUSCULAR HYPERTONIC SALINE INJECTION. METHODS: TWENTY VOLUNTEERS WERE RANDOMLY ALLOCATED INTO TWO GROUPS AND RECEIVED EITHER HYPERTONIC (PAIN) OR ISOTONIC (CONTROL) SALINE INJECTION IN THE FIRST DORSAL INTEROSSEOUS MUSCLE OF THEIR DOMINANT HAND. PAIN INTENSITY WAS CONTINUOUSLY RECORDED FOR 20 MINUTES AFTER INJECTION ON A VAS SCALE FROM 0 TO 100 (0 INDICATES NO PAIN AND 100 THE WORST IMAGINABLE PAIN). BLOOD SAMPLES WERE TAKEN AT BASELINE, 30 MINUTES, 3 HOURS, AND 24 HOURS POST-INJECTION, AND PLASMA WAS SEPARATED. MIRNA EXTRACTS WERE USED FOR RNA SEQUENCING WITH THE ILLUMINA NEXTSEQ PLATFORM. MIRNA TRANSCRIPTS WERE COMPARED BETWEEN THE PAIN AND THE NO-PAIN, CONTROL GROUP AT EVERY TIME POINT. SIGNIFICANT DIFFERENCES WERE CONSIDERED WHEN FOLDS WERE >2 AND THE FALSE DISCOVERY RATE WAS P < 0.05. RESULTS: AFTER 30 MINUTES, 4 MIRNAS WERE SIGNIFICANTLY ALTERED IN THE PAIN GROUP COMPARED TO CONTROLS, WHICH INCREASED TO 24 AFTER 3 HOURS AND TO 42 AFTER 24 HOURS FROM BASELINE (P < 0.0001). TWO MIRNAS WERE CONSISTENTLY UPREGULATED THROUGHOUT THE EXPERIMENT. ENRICHMENT ANALYSIS SHOWED SIGNIFICANT MIRNAS INVOLVED IN BRAIN PERCEPTION OF PAIN, BRAIN SIGNALLING AND RESPONSE TO STIMULI. CONCLUSIONS: THIS EXPLORATORY STUDY IS THE FIRST TO REPORT ON THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS AFTER AN ACUTE, HUMAN EXPERIMENTAL MUSCLE PAIN MODEL. SIGNIFICANCE: THIS EXPLORATORY STUDY EVALUATED THE TEMPORAL PROFILE OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY SUBJECTS AFTER ACUTE EXPERIMENTAL PAIN. SEVERAL MIRNAS WERE ALTERED IN SUBJECTS AT THE TIMES OF FOLLOW-UP AFTER THE ACUTE PAIN MODEL WHEN COMPARED TO CONTROLS. MIRNAS PREVIOUSLY ASSOCIATED WITH PAIN PROCESSES WERE ALTERED IN THE PAIN GROUP. OUR RESULTS, BY SHOWING THE FAST AND PROLONGED MODIFICATIONS OF MIRNA ELICITED BY THE ACUTE EXPERIMENTAL PAIN MODEL, ADD NEW PERSPECTIVES TO THE TOPIC OF EPIGENETICS AND PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  1497  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11   521  41 ASSOCIATIONS BETWEEN MATERNAL PSYCHOSOCIAL STRESS, DNA METHYLATION, AND NEWBORN BIRTH WEIGHT IDENTIFIED BY INVESTIGATING METHYLATION AT INDIVIDUAL, REGIONAL, AND GENOME LEVELS. STRESS IS KNOWN TO AFFECT HEALTH THROUGHOUT LIFE AND INTO FUTURE GENERATIONS, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNKNOWN. WE TESTED THE HYPOTHESIS THAT MATERNAL PSYCHOSOCIAL STRESS INFLUENCES DNA METHYLATION (DNAM), WHICH IN TURN IMPACTS NEWBORN HEALTH OUTCOMES. SPECIFICALLY, WE ANALYZED DNAM AT INDIVIDUAL, REGIONAL, AND GENOME-WIDE LEVELS TO TEST FOR ASSOCIATIONS WITH MATERNAL STRESS AND NEWBORN BIRTH WEIGHT. MATERNAL VENOUS BLOOD AND NEWBORN CORD BLOOD (N = 24 AND 22, RESPECTIVELY) WERE ASSAYED FOR METHYLATION AT APPROXIMATELY 450,000 CPG SITES. METHYLATION WAS ANALYZED BY EXAMINING CPG SITES INDIVIDUALLY IN AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), AS REGIONAL GROUPS USING VARIABLY METHYLATED REGION (VMR) ANALYSIS IN MATERNAL BLOOD ONLY, AND THROUGH THE EPIGENOME-WIDE MEASURES USING GENOME-WIDE MEAN METHYLATION (GMM), HORVATH'S EPIGENETIC CLOCK, AND MITOTIC AGE. THESE METHYLATION MEASURES WERE TESTED FOR ASSOCIATION WITH THREE MEASURES OF MATERNAL STRESS (MATERNAL WAR TRAUMA, CHRONIC STRESS, AND EXPERIENCE OF SEXUAL VIOLENCE) AND ONE HEALTH OUTCOME (NEWBORN BIRTH WEIGHT). WE OBSERVED THAT MATERNAL EXPERIENCES OF WAR TRAUMA, CHRONIC STRESS, AND SEXUAL ASSAULT WERE EACH ASSOCIATED WITH DECREASED NEWBORN BIRTH WEIGHT (P < 1.95 X 10(-7) IN ALL CASES). TESTING INDIVIDUAL CPG SITES USING EWAS, WE OBSERVED NO ASSOCIATIONS BETWEEN DNAM AND ANY MEASURE OF MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER MATERNAL OR CORD BLOOD, AFTER BONFERRONI MULTIPLE TESTING CORRECTION. HOWEVER, THE TOP-RANKED CPG SITE IN MATERNAL BLOOD THAT ASSOCIATED WITH MATERNAL CHRONIC STRESS AND SEXUAL VIOLENCE BEFORE MULTIPLE TESTING CORRECTION IS LOCATED NEAR THE SPON1 GENE. TESTING AT A REGIONAL LEVEL, WE FOUND INCREASED METHYLATION OF A VMR IN MATERNAL BLOOD NEAR SPON1 THAT WAS ASSOCIATED WITH CHRONIC STRESS AND SEXUAL VIOLENCE AFTER BONFERRONI MULTIPLE TESTING CORRECTION (P = 1.95 X 10(-7) AND 8.3 X 10(-6), RESPECTIVELY). AT THE EPIGENOMIC LEVEL, CORD BLOOD GMM WAS ASSOCIATED WITH SIGNIFICANTLY HIGHER LEVELS OF WAR TRAUMA (P = 0.025) AND WAS SUGGESTIVELY ASSOCIATED WITH SEXUAL VIOLENCE (P = 0.053). THE OTHER TWO EPIGENOME-WIDE MEASURES WERE NOT ASSOCIATED WITH MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER TISSUE TYPE. DESPITE OUR SMALL SAMPLE SIZE, WE IDENTIFIED ASSOCIATIONS EVEN AFTER CONSERVATIVE MULTIPLE TESTING CORRECTION. SPECIFICALLY, WE FOUND ASSOCIATIONS BETWEEN DNAM AND THE THREE MEASURES OF MATERNAL STRESS ACROSS BOTH TISSUES; SPECIFICALLY, A VMR IN MATERNAL BLOOD AND GMM IN CORD BLOOD WERE BOTH ASSOCIATED WITH DIFFERENT MEASURES OF MATERNAL STRESS. THE ASSOCIATION OF CORD BLOOD GMM, BUT NOT MATERNAL BLOOD GMM, WITH MATERNAL STRESS MAY SUGGEST DIFFERENT RESPONSES TO STRESS IN MOTHER AND NEWBORN. IT IS NOTEWORTHY THAT WE FOUND ASSOCIATIONS ONLY WHEN CPG SITES WERE ANALYZED IN AGGREGATE, EITHER AS VMRS OR AS A BROAD SUMMARY MEASURE OF GMM.	2019	

12  3841  41 IRON SUPPLEMENTATION REVERSES THE REDUCTION OF HYDROXYMETHYLCYTOSINE IN HEPATIC DNA ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION IN RATS. BACKGROUND: ALCOHOL IS KNOWN TO AFFECT TWO EPIGENETIC PHENOMENA, DNA METHYLATION AND DNA HYDROXYMETHYLATION, AND IRON IS A COFACTOR OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES THAT CATALYZE THE CONVERSION FROM METHYLCYTOSINE TO HYDROXYMETHYLCYTOSINE. IN THE PRESENT STUDY WE AIMED TO DETERMINE THE EFFECTS OF ALCOHOL ON DNA HYDROXYMETHYLATION AND FURTHER EFFECTS OF IRON ON ALCOHOL ASSOCIATED EPIGENETIC CHANGES. METHODS: TWENTY-FOUR MALE SPRAGUE-DAWLEY RATS WERE FED EITHER LIEBER-DECARLI ALCOHOL DIET (36% CALORIES FROM ETHANOL) OR LIEBER-DECARLI CONTROL DIET ALONG WITH OR WITHOUT IRON SUPPLEMENTATION (0.6% CARBONYL IRON) FOR 8 WEEKS. HEPATIC NON-HEME IRON CONCENTRATIONS WERE MEASURED BY COLORIMETRIC ASSAYS. PROTEIN LEVELS OF HEPATIC FERRITIN AND TRANSFERRIN RECEPTOR WERE DETERMINED BY WESTERN BLOTTING. METHYLCYTOSINE, HYDROXYMETHYLCYTOSINE AND UNMODIFIED CYTOSINE IN DNA WERE SIMULTANEOUSLY MEASURED BY LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY METHOD. RESULTS: IRON SUPPLEMENTATION SIGNIFICANTLY INCREASED HEPATIC NON-HEME IRON CONTENTS (P < 0.05) BUT ALCOHOL ALONE DID NOT. HOWEVER, BOTH ALCOHOL AND IRON SIGNIFICANTLY INCREASED HEPATIC FERRITIN LEVELS AND DECREASED HEPATIC TRANSFERRIN RECEPTOR LEVELS (P < 0.05). ALCOHOL REDUCED HEPATIC DNA HYDROXYMETHYLATION (0.21% +/- 0.04% VS. 0.33% +/- 0.04%, P = 0.01) COMPARED TO CONTROL, WHILE IRON SUPPLEMENTATION TO ALCOHOL DIET DID NOT CHANGE DNA HYDROXYMETHYLATION. THERE WAS NO SIGNIFICANT DIFFERENCE IN METHYLCYTOSINE LEVELS, WHILE UNMODIFIED CYTOSINE LEVELS WERE SIGNIFICANTLY INCREASED IN ALCOHOL-FED GROUPS COMPARED TO CONTROL (95.61% +/- 0.08% VS. 95.26% +/- 0.12%, P = 0.03), SUGGESTING THAT ALCOHOL FURTHER INCREASES THE CONVERSION FROM HYDROXYMETHYLCYTOSINE TO UNMODIFIED CYTOSINE. CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION ALTERS GLOBAL DNA HYDROXYMETHYLATION IN THE LIVER BUT IRON SUPPLEMENTATION REVERSES THE EPIGENETIC EFFECT OF ALCOHOL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   173  30 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  3063  39 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  5728  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16   286  40 AGING AND ALCOHOL INTERACT TO ALTER HEPATIC DNA HYDROXYMETHYLATION. BACKGROUND: AGING AND CHRONIC ALCOHOL CONSUMPTION ARE BOTH MODIFIERS OF DNA METHYLATION, BUT IT IS NOT YET KNOWN WHETHER CHRONIC ALCOHOL CONSUMPTION ALSO ALTERS DNA HYDROXYMETHYLATION, A NEWLY DISCOVERED EPIGENETIC MARK PRODUCED BY OXIDATION OF METHYLCYTOSINE. FURTHERMORE, IT HAS NOT BEEN TESTED WHETHER AGING AND ALCOHOL INTERACT TO MODIFY THIS EPIGENETIC PHENOMENON, THEREBY HAVING AN INDEPENDENT EFFECT ON GENE EXPRESSION. METHODS: OLD (18 MONTHS) AND YOUNG (4 MONTHS) MALE C57BL/6 MICE WERE PAIR-FED EITHER A LIEBER-DECARLI LIQUID DIET WITH ALCOHOL (18% OF ENERGY) OR AN ISOCALORIC LIEBER-DECARLI CONTROL DIET FOR 5 WEEKS. GLOBAL DNA HYDROXYMETHYLATION AND DNA METHYLATION WERE ANALYZED FROM HEPATIC DNA USING A NEW LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY METHOD. HEPATIC MRNA EXPRESSION OF THE TET ENZYMES WERE MEASURED VIA QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: IN YOUNG MICE, MILD CHRONIC ALCOHOL EXPOSURE SIGNIFICANTLY REDUCED GLOBAL DNA HYDROXYMETHYLATION COMPARED WITH CONTROL MICE (0.22 +/- 0.01 VS. 0.29 +/- 0.06%, P = 0.004). ALCOHOL DID NOT SIGNIFICANTLY ALTER HYDROXYMETHYLCYTOSINE LEVELS IN OLD MICE. OLD MICE FED THE CONTROL DIET SHOWED DECREASED GLOBAL DNA HYDROXYMETHYLATION COMPARED WITH YOUNG MICE FED THE CONTROL DIET (0.24 +/- 0.02 VS. 0.29 +/- 0.06%, P = 0.04). THIS MODEL SUGGESTS AN INTERACTION BETWEEN AGING AND ALCOHOL IN DETERMINING DNA HYDROXYMETHYLATION (PINTERACTION = 0.009). EXPRESSION OF TET2 AND TET3 WAS DECREASED IN THE OLD MICE RELATIVE TO THE YOUNG (P < 0.005). CONCLUSIONS: THE OBSERVATION THAT ALCOHOL ALTERS DNA HYDROXYMETHYLATION INDICATES A NEW EPIGENETIC EFFECT OF ALCOHOL. THIS IS THE FIRST STUDY DEMONSTRATING THE INTERACTIVE EFFECTS OF CHRONIC ALCOHOL CONSUMPTION AND AGING ON DNA HYDROXYMETHYLATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   524  36 ASSOCIATIONS OF BDNF GENOTYPE AND PROMOTER METHYLATION WITH ACUTE AND LONG-TERM STROKE OUTCOMES IN AN EAST ASIAN COHORT. BACKGROUND: BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN POSTSTROKE RECOVERY. BDNF SECRETION IS INFLUENCED BY GENETIC AND EPIGENETIC PROFILES. THIS STUDY AIMED TO INVESTIGATE WHETHER BDNF VAL66MET POLYMORPHISM AND PROMOTER METHYLATION STATUS WERE ASSOCIATED WITH OUTCOMES AT TWO WEEKS AND ONE YEAR AFTER STROKE. METHODS AND FINDINGS: A TOTAL OF 286 PATIENTS WERE EVALUATED AT THE TIME OF ADMISSION AND TWO WEEKS AFTER STROKE, AND 222 (78%) WERE FOLLOWED ONE YEAR LATER IN ORDER TO EVALUATE CONSEQUENCES OF STROKE AT BOTH ACUTE AND CHRONIC STAGES. STROKE OUTCOMES WERE DICHOTOMISED INTO GOOD AND POOR BY THE MODIFIED RANKIN SCALE. STROKE SEVERITY (NATIONAL INSTITUTES OF HEALTH STROKE SCALE), PHYSICAL DISABILITY (BARTHEL INDEX), AND COGNITIVE FUNCTION (MINI-MENTAL STATE EXAMINATION) WERE MEASURED. ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION STATUS ON STROKE OUTCOMES AND ASSESSMENT SCALE SCORES WERE INVESTIGATED USING LOGISTIC REGRESSION, REPEATED MEASURES ANOVA AND PARTIAL CORRELATION TESTS. BDNF VAL66MET POLYMORPHISM WAS INDEPENDENTLY ASSOCIATED WITH POOR OUTCOME AT 2 WEEKS AND AT 1 YEAR, AND WITH WORSENING PHYSICAL DISABILITY AND COGNITIVE FUNCTION OVER THAT PERIOD. HIGHER BDNF PROMOTER METHYLATION STATUS WAS INDEPENDENTLY ASSOCIATED WITH WORSE OUTCOMES AT 1 YEAR, AND WITH THE WORSENING OF PHYSICAL DISABILITY AND COGNITIVE FUNCTION. NO SIGNIFICANT GENOTYPE-METHYLATION INTERACTIONS WERE FOUND. CONCLUSIONS: A ROLE FOR BDNF IN POSTSTROKE RECOVERY WAS SUPPORTED, AND CLINICAL UTILITY OF BDNF GENETIC AND EPIGENETIC PROFILE AS PROGNOSTIC BIOMARKERS AND A TARGET FOR DRUG DEVELOPMENT WAS SUGGESTED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  2960  30 GENETIC AND EPIGENETIC MARKERS IN THE EVALUATION OF PANCREATIC MASSES. BACKGROUND: METHYLATION MARKERS HAVE SHOWN PROMISE IN THE EARLY DIAGNOSIS OF PANCREATIC CARCINOMA. THE AIM OF THIS STUDY WAS TO ASSESS THE DIAGNOSTIC UTILITY OF HYPERMETHYLATION STATUS OF CANDIDATE GENES IN COMBINATION WITH KRAS MUTATION DETECTION IN THE EVALUATION OF PANCREATIC MASSES. EXPERIMENTAL DESIGN: SIXTY-ONE FINE NEEDLE ASPIRATES OF PANCREATIC MASSES (43 PANCREATIC ADENOCARCINOMAS AND 18 CHRONIC PANCREATITIS) WERE STUDIED. METHYLATION STATUS OF HRH2, EN1, SPARC, CDH13 AND APC WERE ANALYSED USING MELTING CURVE ANALYSIS AFTER DNA BISULFITE TREATMENT. KRAS MUTATIONS WERE ALSO ANALYSED. RESULTS: THE METHYLATION PANEL HAD A SENSITIVITY OF 73% (27 OF 37, CI 95% 56 TO 86%) AND A SPECIFICITY OF 100% WHENEVER TWO OR MORE PROMOTERS WERE FOUND HYPERMETHYLATED. KRAS MUTATIONS SHOWED A SENSITIVITY OF 77% (33 OF 43, CI 95% 62 TO 88%) AND A SPECIFICITY OF 100%. BOTH MOLECULAR ANALYSES ADDED USEFUL INFORMATION TO CYTOLOGY BY INCREASING THE NUMBER OF INFORMATIVE CASES. WHEN GENETIC AND EPIGENETIC ANALYSES WERE COMBINED SENSITIVITY WAS 84% (36 OF 43 CI 95% 69 TO 93%) MAINTAINING A 100% SPECIFICITY. CONCLUSIONS: ANALYSIS OF HYPERMETHYLATION STATUS OF A PANEL OF GENES AND KRAS MUTATION DETECTION OFFER A SIMILAR DIAGNOSTIC YIELD IN THE EVALUATION OF PANCREATIC MASSES. THE COMBINED MOLECULAR ANALYSIS INCREASES THE NUMBER OF INFORMATIVE CASES WITHOUT DIMINISHING SPECIFICITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  3850  38 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20  1343  45 DETECTING CORD BLOOD CELL TYPE-SPECIFIC EPIGENETIC ASSOCIATIONS WITH GESTATIONAL DIABETES MELLITUS AND EARLY CHILDHOOD GROWTH. BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE PROVIDED OPPORTUNITIES TO UNDERSTAND THE ROLE OF EPIGENETIC MECHANISMS IN DEVELOPMENT AND PATHOPHYSIOLOGY OF MANY CHRONIC DISEASES. HOWEVER, AN IMPORTANT LIMITATION OF CONVENTIONAL EWAS IS THAT PROFILES OF EPIGENETIC VARIABILITY ARE OFTEN OBTAINED IN SAMPLES OF MIXED CELL TYPES. HERE, WE AIM TO ASSESS WHETHER CHANGES IN CORD BLOOD DNA METHYLATION (DNAM) ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) EXPOSURE AND EARLY CHILDHOOD GROWTH MARKERS OCCUR IN A CELL TYPE-SPECIFIC MANNER. RESULTS: WE ANALYZED 275 CORD BLOOD SAMPLES COLLECTED AT DELIVERY FROM A PROSPECTIVE PRE-BIRTH COHORT WITH GENOME-WIDE DNAM PROFILED BY THE ILLUMINA METHYLATIONEPIC ARRAY. WE ESTIMATED PROPORTIONS OF SEVEN COMMON CELL TYPES IN EACH SAMPLE USING A CORD BLOOD-SPECIFIC DNAM REFERENCE PANEL. LEVERAGING A RECENTLY DEVELOPED APPROACH NAMED CELLDMC, WE PERFORMED CELL TYPE-SPECIFIC EWAS TO IDENTIFY CPG LOCI SIGNIFICANTLY ASSOCIATED WITH GDM, OR 3-YEAR-OLD BODY MASS INDEX (BMI) Z-SCORE. A TOTAL OF 1410 CPG LOCI DISPLAYED SIGNIFICANT CELL TYPE-SPECIFIC DIFFERENCES IN METHYLATION LEVEL BETWEEN 23 GDM CASES AND 252 CONTROLS WITH A FALSE DISCOVERY RATE < 0.05. GENE ONTOLOGY ENRICHMENT ANALYSIS INDICATED THAT LDL TRANSPORTATION EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM B-CELLS DNAM ANALYSES AND THE MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM NATURAL KILLER CELLS DNAM ANALYSES. IN ADDITION, WE IDENTIFIED FOUR AND SIX LOCI ASSOCIATED WITH 3-YEAR-OLD BMI Z-SCORE THAT WERE SPECIFIC TO CD8+ T-CELLS AND MONOCYTES, RESPECTIVELY. BY PERFORMING GENOME-WIDE PERMUTATION TESTS, WE VALIDATED THAT MOST OF OUR DETECTED SIGNALS HAD LOW FALSE POSITIVE RATES. CONCLUSION: COMPARED TO CONVENTIONAL EWAS ADJUSTING FOR THE EFFECTS OF CELL TYPE HETEROGENEITY, THE PROPOSED APPROACH BASED ON CELL TYPE-SPECIFIC EWAS COULD PROVIDE ADDITIONAL BIOLOGICALLY MEANINGFUL ASSOCIATIONS BETWEEN CPG METHYLATION, PRENATAL MATERNAL GDM OR 3-YEAR-OLD BMI. WITH CAREFUL VALIDATION, THESE FINDINGS MAY PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS, PROGRAMMING, AND CONSEQUENCES OF RELATED CHILDHOOD METABOLIC DYSREGULATION. THEREFORE, WE PROPOSE THAT CELL TYPE-SPECIFIC ANALYSES ARE WORTH CAUTIOUS EXPLORATIONS.	2021