1  4339 86 MIGRAINE: A GENETIC DISEASE? MIGRAINES CARRY A SUBSTANTIAL GENETIC LIABILITY, AND IN FAMILIES AFFECTED WITH THE TYPICAL MIGRAINES (MIGRAINE WITH, MA, AND WITHOUT AURA, MO) LINKAGE TO SOME CHROMOSOMAL LOCI HAS BEEN REPORTED. AS YET HOWEVER, NO GENES ARE KNOWN FOR MA/MO, WHILE THE THREE GENES DISCOVERED AS RESPONSIBLE FOR FAMILIAL HEMIPLEGIC MIGRAINE (FHM) ARE NOT INVOLVED IN THE TYPICAL MIGRAINES. ACCORDINGLY, WE PROPOSE TO CONSIDER FHM AS A SYNDROMIC MIGRAINE AND NOT AS A VARIETY OF MA. MOREOVER, WE SUGGEST THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE DETERMINATION OF THE TYPICAL MIGRAINES, AND THAT THE PRIMARY HEADACHES REPRESENT BEHAVIOURAL RESPONSES (SICKNESS BEHAVIOUR, FIGHT-OR-FLIGHT RESPONSES), HAVING ADAPTIVE ADVANTAGE AND HAVING BEEN EVOLUTIONARY CONSERVED, IN WHICH PAIN REPRESENTS A SIGNAL OF HOMEOSTATIC IMBALANCE. EPIGENETIC MECHANISMS AND THIS PROPOSED GENETIC BEHAVIOURAL MODEL COULD BE USEFULLY INCORPORATED INTO HEADACHE GENETIC RESEARCH.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2   404 26 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	
                                                                                                   
3    63 19 A HIGH METHYLATION LEVEL OF A NOVEL -284 BP CPG ISLAND IN THE RAMP1 GENE PROMOTER IS POTENTIALLY ASSOCIATED WITH MIGRAINE IN WOMEN. MIGRAINE IS A COMPLEX NEUROVASCULAR DISORDER AFFECTING ONE BILLION PEOPLE WORLDWIDE, MAINLY FEMALES. IT IS CHARACTERIZED BY ATTACKS OF MODERATE TO SEVERE HEADACHE PAIN, WITH ASSOCIATED SYMPTOMS. RECEPTOR ACTIVITY MODIFYING PROTEIN (RAMP1) IS PART OF THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR, A PHARMACOLOGICAL TARGET FOR MIGRAINE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, PLAY A ROLE IN CLINICAL PRESENTATION OF VARIOUS DISEASES. DNA METHYLATION OCCURS MOSTLY IN THE GENE PROMOTER AND CAN CONTROL GENE EXPRESSION. WE INVESTIGATED THE METHYLATION STATE OF THE RAMP1 PROMOTER IN 104 FEMALE BLOOD DNA SAMPLES: 54 MIGRAINEURS AND 50 CONTROLS. WE TREATED DNA WITH SODIUM BISULFITE AND PERFORMED PCR, SANGER SEQUENCING, AND EPIGENETIC SEQUENCING METHYLATION (ESME) SOFTWARE ANALYSIS. WE IDENTIFIED 51 CPG DINUCLEOTIDES, AND 5 SHOWED METHYLATION VARIABILITY. MIGRAINEURS HAD A HIGHER NUMBER OF INDIVIDUALS WITH ALL FIVE CPG METHYLATED WHEN COMPARED TO CONTROLS (26% VS. 16%), ALTHOUGH NON-SIGNIFICANT (P = 0.216). WE ALSO FOUND THAT CPG -284 BP, RELATED TO THE TRANSCRIPTION START SITE (TSS), SHOWED HIGHER METHYLATION LEVELS IN CASES (P = 0.011). THIS CPG MAY POTENTIALLY PLAY A ROLE IN MIGRAINE, AFFECTING RAMP1 TRANSCRIPTION OR RECEPTOR MALFUNCTIONING AND/OR ALTERED CGRP BINDING. WE HOPE TO CONFIRM THIS FINDING IN A LARGER COHORT AND ESTABLISH AN EPIGENETIC BIOMARKER TO PREDICT FEMALE MIGRAINE RISK.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4  6916 24 [WHAT IS MIGRAINE?]. MIGRAINE IS A MULTIFACTORIAL AND HETEROGENEOUS DISORDER. DIAGNOSTIC CRITERIA HAVE BEEN ESTABLISHED BY THE INTERNATIONAL HEADACHE SOCIETY, HOWEVER THESE ARE ONLY SUPPORTIVE IN TERMS OF DEFINITION. THE PATHOPHYSIOLOGY INVOLVES NEURONAL AND VASCULAR PHENOMENA. THE FORMER IS SUPPORTED BY THE CORTICAL SPREADING DEPRESSION BEING THE AURA CORRELATE AND BY BRAINSTEM AND HYPOTHALAMIC ACTIVATION DURING THE PAIN PHASE; THE LATTER IS SUGGESTED BY THE ASSOCIATION BETWEEN MIGRAINE AND CARDIOVASCULAR DISEASE AND FINDINGS OF PATHOLOGICAL VASOREACTIVITY AND ENDOTHELIAL DYSFUNCTION. TRIPTANS AND CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONISTS SHOW ONLY A RELATIVE MIGRAINE-SPECIFIC ACTION; UP TO 30% OF PATIENTS ARE NONRESPONDERS. DESPITE A CLEAR GENETIC COMPONENT, THE DISCOVERY OF SPECIFIC GENES FOR COMMON FORMS OF MIGRAINE REMAINS ELUSIVE. ELECTROPHYSIOLOGICAL STUDIES CONSISTENTLY INDICATE A CHARACTERISTIC "DYSHABITUATION" CONCURRING WITH CLINICAL FEATURES OF ALTERED SENSORY PERCEPTION. THE AGE- AND SEX-SPECIFIC PATTERN ALONG WITH THE EFFECT OF EXTERNAL FACTORS ON THE COURSE OF MIGRAINE ARGUE IN FAVOR OF THE INVOLVEMENT OF EPIGENETIC MECHANISMS. KNOWLEDGE ABOUT MIGRAINE IS STILL LIMITED, WHICH HAMPERS A DEFINITION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  3929 19 LIVER EPIGENOME CHANGES IN PATIENTS WITH HEPATOPULMONARY SYNDROME: A PILOT STUDY. THE HEPATOPULMONARY SYNDROME (HPS) IS DEFINED BY THE PRESENCE OF PULMONARY GAS EXCHANGE ABNORMALITIES DUE TO INTRAPULMONARY VASCULAR DILATATIONS IN PATIENTS WITH CHRONIC LIVER DISEASE. CHANGES IN DNA METHYLATION REFLECT THE GENOMIC VARIATION. SINCE LIVER TRANSPLANT (LT) REVERTS HPS WE HYPOTHESIZED THAT IT MAY BE ASSOCIATED WITH SPECIFIC LIVER EPIGENETIC CHANGES. THUS, THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF THE LIVER EPIGENOME IN PATIENTS WITH HPS. WE EXTRACTED DNA FROM PARAFFIN EMBEDDED LIVER TISSUE SAMPLES FROM 10 PATIENTS WITH HPS AND 10 AGE-, SEX- AND MELD (MODEL FOR END-STAGE LIVER DISEASE)-MATCHED CONTROLS. DNA METHYLATION WAS DETERMINED USING THE 850K ARRAY (ILLUMINA). WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA) WAS USED TO IDENTIFY MODULES RELATED TO DEFINING PHYSIOLOGIC CHARACTERISTICS OF HPS. ONLY 12 OUT OF THE 20 LIVER BIOPSIES (7 HPS AND 5 CONTROLS) HAD SUFFICIENT QUALITY TO BE ANALYZED. NONE OF THE 802,688 DNA PROBES ANALYZED IN THE CASE CONTROL COMPARISON ACHIEVED A SIGNIFICANT FALSE DISCOVERY RATE (FDR). WGCNA IDENTIFIED 5 CO-METHYLATED GENE-MODULES ASSOCIATED TO HPS MARKERS, MAINLY RELATED TO NERVOUS AND NEUROENDOCRINE SYSTEM, APOPTOTIC PROCESSES, GUT BACTERIAL TRANSLOCATION, ANGIOGENESIS AND VASCULAR REMODELING ONTOLOGIES. TO CONCLUDE, HPS IS ASSOCIATED WITH NERVOUS/NEUROENDOCRINE SYSTEM AND VASCULAR REMODELING RELATED LIVER EPIGENETIC CHANGES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  2623 18 EPIGENOME-WIDE ASSOCIATION STUDIES OF THE FRACTIONAL EXHALED NITRIC OXIDE AND BRONCHODILATOR DRUG RESPONSE IN MODERATE-TO-SEVERE PEDIATRIC ASTHMA. ASTHMA IS THE MOST PREVALENT PEDIATRIC CHRONIC DISEASE. BRONCHODILATOR DRUG RESPONSE (BDR) AND FRACTIONAL EXHALED NITRIC OXIDE (FENO) ARE CLINICAL BIOMARKERS OF ASTHMA. ALTHOUGH DNA METHYLATION (DNAM) CONTRIBUTES TO ASTHMA PATHOGENESIS, THE INFLUENCE OF DNAM ON BDR AND FENO IS SCARCELY INVESTIGATED. THIS STUDY AIMS TO IDENTIFY DNAM MARKERS IN WHOLE BLOOD ASSOCIATED EITHER WITH BDR OR FENO IN PEDIATRIC ASTHMA. WE ANALYZED 121 SAMPLES FROM CHILDREN WITH MODERATE-TO-SEVERE ASTHMA. THE ASSOCIATION OF GENOME-WIDE DNAM WITH BDR AND FENO HAS BEEN ASSESSED USING REGRESSION MODELS, ADJUSTING FOR AGE, SEX, ANCESTRY, AND TISSUE HETEROGENEITY. CROSS-TISSUE VALIDATION WAS ASSESSED IN 50 NASAL SAMPLES. DIFFERENTIALLY METHYLATED REGIONS (DMRS) AND ENRICHMENT IN TRAITS AND BIOLOGICAL PATHWAYS WERE ASSESSED. A FALSE DISCOVERY RATE (FDR) < 0.1 AND A GENOME-WIDE SIGNIFICANCE THRESHOLD OF P < 9 X 10(-8) WERE USED TO CONTROL FOR FALSE-POSITIVE RESULTS. THE CPG CG12835256 (PLA2G12A) WAS GENOME-WIDE ASSOCIATED WITH FENO IN BLOOD SAMPLES (COEFFICIENT= -0.015, P = 2.53 X 10(-9)) AND NOMINALLY ASSOCIATED IN NASAL SAMPLES (COEFFICIENT = -0.015, P = 0.045). ADDITIONALLY, THREE CPGS WERE SUGGESTIVELY ASSOCIATED WITH BDR (FDR < 0.1). WE IDENTIFIED 12 AND FOUR DMRS ASSOCIATED WITH FENO AND BDR (FDR < 0.05), RESPECTIVELY. AN ENRICHMENT IN ALLERGIC AND INFLAMMATORY PROCESSES, SMOKING, AND AGING WAS OBSERVED. WE REPORTED NOVEL ASSOCIATIONS OF DNAM MARKERS ASSOCIATED WITH BDR AND FENO ENRICHED IN ASTHMA-RELATED PROCESSES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  1962 24 EPIGENETIC AGING IS ASSOCIATED WITH CLINICAL AND EXPERIMENTAL PAIN IN COMMUNITY-DWELLING OLDER ADULTS. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, WHICH HAS MOTIVATED RESEARCH EFFORTS TO IDENTIFY "AGING BIOMARKERS." AGING BIOMARKERS ARE USED TO CALCULATE BIOLOGICAL AGE, WHICH ARE BETTER PREDICTORS OF DISEASE RISK AND RESIDUAL LIFESPAN WHEN COMPARED TO CHRONOLOGICAL AGE ALONE. EMERGING EVIDENCE USING THE EPIGENETIC CLOCK AS AN AGING BIOMARKER SUPPORTS HIGHLY RELIABLE INDIVIDUALIZED PREDICTIONS ABOUT FUTURE HEALTH. THIS STUDY AIMED TO DETERMINE WHETHER AN EPIGENETIC AGING BIOMARKER WAS ASSOCIATED WITH CHRONIC PAIN IN OLDER ADULTS (60-83 YEARS OLD). A SUBSET OF PARTICIPANTS (N = 29) IN THE NEUROMODULATORY EXAMINATION OF PAIN AND MOBILITY ACROSS THE LIFESPAN STUDY UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOLOGICAL, COGNITIVE, AND PAIN ASSESSMENTS. WE ESTIMATED HORVATH'S EPIGENETIC CLOCK AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE THAT HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK. OLDER INDIVIDUALS WITHOUT CHRONIC PAIN (N = 9) HAD SIGNIFICANTLY "YOUNGER" EPIGENETIC AGE COMPARED TO THOSE WITH CHRONIC PAIN (N = 20, P < 0.05). OLDER EPIGENETIC AGE WAS ASSOCIATED WITH GREATER PAIN DURING DAILY ACTIVITIES (R = 0.494, P = 0.010) AND ANATOMICAL PAIN SITES (R = 0.741, P < 0.001) BUT NOT PAIN FREQUENCY/DURATION. AN OLDER EPIGENETIC AGE WAS ALSO ASSOCIATED WITH HIGHER VIBRATORY DETECTION THRESHOLDS (R = 0.490, P = 0.021), HEAT PAIN THRESHOLDS (R = -0.478, P = 0.028), AND PRESSURE PAIN THRESHOLDS AT THE TRAPEZIUS (R = -0.571, P = 0.006) BUT NOT THERMAL DETECTION, PRESSURE PAIN AT THE QUADRICEPS OR PAIN INHIBITION (P'S > 0.05). EPIGENETIC AGING WAS ASSOCIATED WITH GREATER EMOTIONAL STABILITY (R = -0.461, P = 0.027), CONSCIENTIOUSNESS (R = -0.549, P = 0.007), AND LOWER EXTRAVERSION (R = 0.414, P = 0.049) BUT NOT DEPRESSION OR AFFECT (P'S > 0.05). EPIGENETIC AGING WAS ALSO ASSOCIATED WITH LOWER EPISODIC (R = -0.698, P = 0.001) AND WORKING MEMORY (R = -0.760, P < 0.001). OUR FINDINGS SUGGEST THAT CHRONIC PAIN IS ASSOCIATED WITH ACCELERATED EPIGENETIC AGING IN HEALTHY, COMMUNITY-DWELLING OLDER INDIVIDUALS, AND FUTURE STUDIES WITH LARGER SAMPLES ARE NEEDED TO CONFIRM OUR FINDINGS. AN AGING BIOMARKER SUCH AS THE EPIGENETIC CLOCK MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2019	
       
8  5537 24 ROLE OF CALCITONIN GENE-RELATED PEPTIDE IN LIGHT-AVERSIVE BEHAVIOR: IMPLICATIONS FOR MIGRAINE. MIGRAINE IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRENT EPISODES OF SEVERE UNILATERAL THROBBING HEAD PAIN AND ASSOCIATED SYMPTOMS, SUCH AS PHOTOPHOBIA. OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING MIGRAINE HAS BEEN HAMPERED BY LIMITATIONS IN ASCERTAINING MIGRAINE SYMPTOMS IN ANIMAL MODELS. CLINICAL STUDIES HAVE ESTABLISHED THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A KEY PLAYER IN MIGRAINE. HERE, WE ESTABLISH A GENETIC MODEL OF PHOTOPHOBIA BY ENGINEERING INCREASED SENSITIVITY TO CGRP IN MICE. THESE TRANSGENIC MICE (NESTIN/HRAMP1) DISPLAY LIGHT-AVERSIVE BEHAVIOR THAT IS GREATLY ENHANCED BY INTRACEREBROVENTRICULAR INJECTION OF CGRP AND BLOCKED BY COADMINISTRATION OF THE CGRP RECEPTOR ANTAGONIST OLCEGEPANT. THIS BEHAVIOR APPEARS TO BE AN INDICATOR OF PHOTOPHOBIA AND CANNOT BE FULLY EXPLAINED BY GROSS ABNORMALITY OF OCULAR ANATOMY OR DIFFERENCES IN GENERAL ANXIETY OR MOTOR ACTIVITY. OUR FINDINGS DEMONSTRATE THAT A SINGLE GENE, RECEPTOR ACTIVITY-MODIFYING PROTEIN 1 (RAMP1), CAN BE A MODIFIER OF PHOTOPHOBIA AND, BY EXTENSION, SUGGEST THAT GENETIC OR EPIGENETIC MODULATION OF RAMP1 LEVELS MAY CONTRIBUTE TO MIGRAINE SUSCEPTIBILITY. MOREOVER, THEY VALIDATE CGRP HYPERSENSITIVE MICE AS A TOOL FOR EXPLORING THE NEUROBIOLOGY AND NOVEL THERAPIES FOR MIGRAINE AND OTHER DISORDERS INVOLVING PHOTOPHOBIA.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9   173 14 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  4502 18 MORTALITY ASSOCIATIONS WITH DNA METHYLATION-BASED BIOLOGICAL AGING AND PHYSICAL FUNCTIONING MEASURES ACROSS A 20-YEAR FOLLOW-UP PERIOD. BACKGROUND: MEASURES OF BIOLOGICAL AGING RANGE FROM DNA METHYLATION (DNAM)-BASED ESTIMATES TO MEASURES OF PHYSICAL ABILITIES. THE PURPOSE OF THIS STUDY WAS TO COMPARE DNAM- AND PHYSICAL FUNCTIONING-BASED MEASURES OF BIOLOGICAL AGING IN PREDICTING MORTALITY. METHODS: WE STUDIED 63- TO 76-YEAR-OLD WOMEN (N = 395) FROM THE FINNISH TWIN STUDY ON AGING (FITSA). PARTICIPANTS' BIOLOGICAL AGE (EPIGENETIC CLOCKS DNAM GRIMAGE AND DUNEDINPACE) WAS ESTIMATED USING BLOOD DNAM DATA. TESTS OF PHYSICAL FUNCTIONING CONDUCTED UNDER STANDARDIZED LABORATORY CONDITIONS INCLUDED THE TIMED UP AND GO (TUG) TEST AND 10-M WALK TEST. MORTALITY HAZARD RATIOS WERE CALCULATED PER EVERY 1 STANDARD DEVIATION (SD) INCREASE IN THE PREDICTOR. COX REGRESSION MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS, THE LATTER CONTROLLING FOR UNDERLYING GENETIC EFFECTS. THE MODELS WERE ADJUSTED FOR KNOWN LIFESTYLE PREDICTORS OF MORTALITY. RESULTS: DURING THE FOLLOW-UP PERIOD (MEAN 17.0 YEARS, RANGE 0.2-20.3), 187 PARTICIPANTS DIED. IN BOTH THE INDIVIDUAL-BASED AND PAIRWISE ANALYSES, GRIMAGE AND BOTH FUNCTIONAL BIOMARKERS OF AGING WERE ASSOCIATED WITH MORTALITY INDEPENDENT OF FAMILY RELATEDNESS, CHRONOLOGICAL AGE, PHYSICAL ACTIVITY, BODY MASS INDEX, SMOKING, EDUCATION, OR CHRONIC DISEASES. IN A MODEL INCLUDING BOTH THE DNAM-BASED MEASURES AND FUNCTIONAL BIOMARKERS OF AGING, GRIMAGE AND TUG REMAINED PREDICTIVE. CONCLUSIONS: THE FINDINGS SUGGEST THAT DNAM GRIMAGE AND THE TUG TEST ARE STRONG PREDICTORS OF MORTALITY INDEPENDENT OF EACH OTHERS AND GENETIC INFLUENCES. DNAM-BASED MEASURES AND FUNCTIONAL TESTS CAPTURE DIFFERENT ASPECTS OF THE AGING PROCESS AND THUS COMPLEMENT EACH OTHER AS MEASURES OF BIOLOGICAL AGING IN PREDICTING MORTALITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  2079 18 EPIGENETIC DNA METHYLATION CHANGES ASSOCIATED WITH HEADACHE CHRONIFICATION: A RETROSPECTIVE CASE-CONTROL STUDY. BACKGROUND THE BIOLOGICAL MECHANISMS OF HEADACHE CHRONIFICATION ARE POORLY UNDERSTOOD. WE AIMED TO IDENTIFY CHANGES IN DNA METHYLATION ASSOCIATED WITH THE TRANSFORMATION FROM EPISODIC TO CHRONIC HEADACHE. METHODS PARTICIPANTS WERE RECRUITED FROM THE POPULATION-BASED NORWEGIAN HUNT STUDY. THIRTY-SIX FEMALE HEADACHE PATIENTS WHO TRANSFORMED FROM EPISODIC TO CHRONIC HEADACHE BETWEEN BASELINE AND FOLLOW-UP 11 YEARS LATER WERE MATCHED AGAINST 35 CONTROLS WITH EPISODIC HEADACHE. DNA METHYLATION WAS QUANTIFIED AT 485,000 CPG SITES, AND CHANGES IN METHYLATION LEVEL AT THESE SITES WERE COMPARED BETWEEN CASES AND CONTROLS BY LINEAR REGRESSION ANALYSIS. DATA WERE ANALYZED IN TWO STAGES (STAGES 1 AND 2) AND IN A COMBINED META-ANALYSIS. RESULTS NONE OF THE TOP 20 CPG SITES IDENTIFIED IN STAGE 1 REPLICATED IN STAGE 2 AFTER MULTIPLE TESTING CORRECTION. IN THE COMBINED META-ANALYSIS THE STRONGEST ASSOCIATED CPG SITES WERE RELATED TO SH2D5 AND NPTX2, TWO BRAIN-EXPRESSED GENES INVOLVED IN THE REGULATION OF SYNAPTIC PLASTICITY. FUNCTIONAL ENRICHMENT ANALYSIS POINTED TO PROCESSES INCLUDING CALCIUM ION BINDING AND ESTROGEN RECEPTOR PATHWAYS. CONCLUSION IN THIS FIRST GENOME-WIDE STUDY OF DNA METHYLATION IN HEADACHE CHRONIFICATION SEVERAL POTENTIALLY IMPLICATED LOCI AND PROCESSES WERE IDENTIFIED. THE STUDY EXEMPLIFIES THE USE OF PROSPECTIVELY COLLECTED POPULATION COHORTS TO SEARCH FOR EPIGENETIC MECHANISMS OF DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  1952  9 EPIGENETIC AGE ACCELERATION AMONG SURVIVORS OF PEDIATRIC MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMOR. SURVIVORS OF CHILDHOOD CENTRAL NERVOUS SYSTEM (CNS) TUMORS EXPERIENCE EARLY-ONSET AGING-RELATED PHENOTYPES. DNA METHYLATION (DNAM) AGE IS AN EMERGING EPIGENETIC BIOMARKER OF PHYSIOLOGIC AGE AND MAY BE PREDICTIVE OF CHRONIC HEALTH CONDITIONS IN LONG-TERM SURVIVORS. THIS REPORT DESCRIBES THE COURSE OF EPIGENETIC AGE ACCELERATION USING POST-DIAGNOSIS BLOOD SAMPLES (MEDIAN: 3.9 YEARS POST-DIAGNOSIS; RANGE: 0.04-15.96) FROM 83 SURVIVORS OF PEDIATRIC CNS TUMORS. EPIGENETIC AGE ACCELERATION WAS DETECTED IN 72% OF PATIENTS, WITH AN AVERAGE DIFFERENCE BETWEEN CHRONOLOGIC AND DNAM AGE OF 2.58 YEARS (95% CI: 1.75-3.41, P < 0.001). TIME FROM DIAGNOSIS TO SAMPLE COLLECTION CORRELATED WITH THE MAGNITUDE OF EPIGENETIC AGE ACCELERATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  1645 28 DOES THE EPIGENETIC CLOCK GRIMAGE PREDICT MORTALITY INDEPENDENT OF GENETIC INFLUENCES: AN 18 YEAR FOLLOW-UP STUDY IN OLDER FEMALE TWIN PAIRS. BACKGROUND: EPIGENETIC CLOCKS ARE BASED ON DNA METHYLATION (DNAM). IT HAS BEEN SUGGESTED THAT THESE CLOCKS ARE USEABLE MARKERS OF BIOLOGICAL AGING AND PREMATURE MORTALITY. BECAUSE GENETIC FACTORS EXPLAIN VARIATIONS IN BOTH EPIGENETIC AGING AND MORTALITY, THIS ASSOCIATION COULD ALSO BE EXPLAINED BY SHARED GENETIC FACTORS. WE INVESTIGATED THE INFLUENCE OF GENETIC AND LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, CHRONIC DISEASES, BODY MASS INDEX) AND EDUCATION ON THE ASSOCIATION OF ACCELERATED EPIGENETIC AGING WITH MORTALITY USING A LONGITUDINAL TWIN DESIGN. UTILIZING A PUBLICLY AVAILABLE ONLINE TOOL, WE CALCULATED THE EPIGENETIC AGE USING TWO EPIGENETIC CLOCKS, HORVATH DNAMAGE AND DNAM GRIMAGE, IN 413 FINNISH TWIN SISTERS, AGED 63-76 YEARS, AT THE BEGINNING OF THE 18-YEAR MORTALITY FOLLOW-UP. EPIGENETIC AGE ACCELERATION WAS CALCULATED AS THE RESIDUALS FROM A LINEAR REGRESSION MODEL OF EPIGENETIC AGE ESTIMATED ON CHRONOLOGICAL AGE (AA(HORVATH), AA(GRIMAGE), RESPECTIVELY). COX PROPORTIONAL HAZARD MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS. RESULTS: THE RESULTS OF THE INDIVIDUAL-BASED ANALYSES SHOWED AN INCREASED MORTALITY HAZARD RATIO (HR) OF 1.31 (CI(95): 1.13-1.53) PER ONE STANDARD DEVIATION (SD) INCREASE IN AA(GRIMAGE). THE RESULTS INDICATED NO SIGNIFICANT ASSOCIATIONS OF AA(HORVATH) WITH MORTALITY. PAIRWISE MORTALITY ANALYSES SHOWED AN HR OF 1.50 (CI(95): 1.02-2.20) PER 1 SD INCREASE IN AA(GRIMAGE). HOWEVER, AFTER ADJUSTING FOR SMOKING, THE HR ATTENUATED SUBSTANTIALLY AND WAS STATISTICALLY NON-SIGNIFICANT (1.29; CI(95): 0.84-1.99). SIMILARLY, IN MULTIVARIABLE ADJUSTED MODELS THE HR (1.42-1.49) WAS NON-SIGNIFICANT. IN AA(HORVATH), THE NON-SIGNIFICANT HRS WERE LOWER AMONG MONOZYGOTIC PAIRS IN COMPARISON TO DIZYGOTIC PAIRS, WHILE IN AA(GRIMAGE) THERE WERE NO SYSTEMATIC DIFFERENCES BY ZYGOSITY. FURTHER, THE PAIRWISE ANALYSIS IN QUARTILES SHOWED THAT THE INCREASED WITHIN PAIR DIFFERENCE IN AA(GRIMAGE) WAS ASSOCIATED WITH A HIGHER ALL-CAUSE MORTALITY RISK. CONCLUSIONS: IN CONCLUSION, THE FINDINGS SUGGEST THAT DNAM GRIMAGE IS A STRONG PREDICTOR OF MORTALITY INDEPENDENT OF GENETIC INFLUENCES. SMOKING, WHICH IS KNOWN TO ALTER DNAM LEVELS AND IS BUILT INTO THE DNAM GRIMAGE ALGORITHM, ATTENUATED THE ASSOCIATION BETWEEN EPIGENETIC AGING AND MORTALITY RISK.	2021	

14  2029 18 EPIGENETIC CHANGES IN HEADACHE. INTRODUCTION: MULTIPLE FACTORS, INCLUDING BOTH GENETIC AND ENVIRONMENTAL MECHANISMS, APPEAR TO PLAY A ROLE IN THE AETIOLOGY OF HEADACHE. AN INTERESTING AREA OF STUDY IS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN HEADACHE DEVELOPMENT AND THE TRANSFORMATION TO CHRONIC HEADACHE, AND THE POTENTIAL ROLE OF THESE FACTORS AS A THERAPEUTIC TARGET. METHODS: WE PERFORMED A LITERATURE REVIEW OF THE INVOLVEMENT OF DIFFERENT EPIGENETIC MECHANISMS IN HEADACHE, MAINLY USING THE MEDLINE/PUBMED DATABASE. TO THIS END, WE USED THE FOLLOWING ENGLISH SEARCH TERMS: HEADACHE, MIGRAINE, EPIGENETICS, DNA METHYLATION, HISTONES, NON-CODING RNA, AND MIRNA. RESULTS: A TOTAL OF 15 ENGLISH-LANGUAGE PUBLICATIONS RELATED TO THE ABOVE TERMS WERE OBTAINED. CONCLUSION: THERE IS LIMITED BUT CONSISTENT EVIDENCE OF THE RELATIONSHIP BETWEEN EPIGENETICS AND HEADACHE; IT IS THEREFORE ESSENTIAL TO CONTINUE RESEARCH OF EPIGENETIC CHANGES IN HEADACHE. THIS MAY HELP TO UNDERSTAND THE PATHOPHYSIOLOGY OF HEADACHE AND EVEN TO IDENTIFY CANDIDATE BIOMARKERS AND NEW, MORE EFFECTIVE, THERAPEUTIC TARGETS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  1954 19 EPIGENETIC AGE ACCELERATION MEDIATES THE RELATIONSHIP BETWEEN NEIGHBORHOOD DEPRIVATION AND PAIN SEVERITY IN ADULTS WITH OR AT RISK FOR KNEE OSTEOARTHRITIS PAIN. AN ESTIMATED 250 MILLION PEOPLE WORLDWIDE SUFFER FROM KNEE OSTEOARTHRITIS (KOA), WITH OLDER ADULTS HAVING GREATER RISK. LIKE OTHER AGE-RELATED DISEASES, RESIDENTS OF HIGH-DEPRIVATION NEIGHBORHOODS EXPERIENCE WORSE KOA PAIN OUTCOMES COMPARED TO THEIR MORE AFFLUENT NEIGHBORS. THE PURPOSE OF THIS STUDY WAS TO EXAMINE THE RELATIONSHIP BETWEEN NEIGHBORHOOD DEPRIVATION AND PAIN SEVERITY IN KOA AND THE INFLUENCE OF EPIGENETIC AGE ACCELERATION (EPAA) ON THAT RELATIONSHIP. THE SAMPLE OF 128 PARTICIPANTS WAS MOSTLY FEMALE (60.9%), APPROXIMATELY HALF NON-HISPANIC BLACK (49.2%), AND HAD A MEAN AGE OF 58 YEARS. SPEARMAN BIVARIATE CORRELATIONS REVEALED THAT PAIN SEVERITY POSITIVELY CORRELATED WITH EPAA (RHO = 0.47, P </= 0.001) AND NEIGHBORHOOD DEPRIVATION (RHO = 0.25, P = 0.004). WE FOUND A POSITIVE SIGNIFICANT RELATIONSHIP BETWEEN NEIGHBORHOOD DEPRIVATION AND EPAA (RHO = 0.47, P </= 0.001). RESULTS INDICATE A MEDIATING RELATIONSHIP BETWEEN NEIGHBORHOOD DEPRIVATION (PREDICTOR), EPAA (MEDIATOR), AND PAIN SEVERITY (OUTCOME VARIABLE). THERE WAS A SIGNIFICANT INDIRECT EFFECT OF NEIGHBORHOOD DEPRIVATION ON PAIN SEVERITY THROUGH EPAA, AS THE MEDIATOR ACCOUNTED FOR A MODERATE PORTION OF THE TOTAL EFFECT, PM = 0.44. EPIGENETIC AGE ACCELERATION MAY ACT AS A MECHANISM THROUGH WHICH NEIGHBORHOOD DEPRIVATION LEADS TO WORSE KOA PAIN OUTCOMES AND MAY PLAY A ROLE IN THE WELL-DOCUMENTED RELATIONSHIP BETWEEN THE NEIGHBORHOOD OF RESIDENCE AND AGE-RELATED DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  2485 19 EPIGENETIC-BASED AGE ACCELERATION IN A REPRESENTATIVE SAMPLE OF OLDER AMERICANS: ASSOCIATIONS WITH AGING-RELATED MORBIDITY AND MORTALITY. BIOMARKERS DEVELOPED FROM DNA METHYLATION (DNAM) DATA ARE OF GROWING INTEREST AS PREDICTORS OF HEALTH OUTCOMES AND MORTALITY IN OLDER POPULATIONS. HOWEVER, IT IS UNKNOWN HOW EPIGENETIC AGING FITS WITHIN THE CONTEXT OF KNOWN SOCIOECONOMIC AND BEHAVIORAL ASSOCIATIONS WITH AGING-RELATED HEALTH OUTCOMES IN A LARGE, POPULATION-BASED, AND DIVERSE SAMPLE. THIS STUDY USES DATA FROM A REPRESENTATIVE, PANEL STUDY OF US OLDER ADULTS TO EXAMINE THE RELATIONSHIP BETWEEN DNAM-BASED AGE ACCELERATION MEASURES IN THE PREDICTION OF CROSS-SECTIONAL AND LONGITUDINAL HEALTH OUTCOMES AND MORTALITY. WE EXAMINE WHETHER RECENT IMPROVEMENTS TO THESE SCORES, USING PRINCIPAL COMPONENT (PC)-BASED MEASURES DESIGNED TO REMOVE SOME OF THE TECHNICAL NOISE AND UNRELIABILITY IN MEASUREMENT, IMPROVE THE PREDICTIVE CAPABILITY OF THESE MEASURES. WE ALSO EXAMINE HOW WELL DNAM-BASED MEASURES PERFORM AGAINST WELL-KNOWN PREDICTORS OF HEALTH OUTCOMES SUCH AS DEMOGRAPHICS, SES, AND HEALTH BEHAVIORS. IN OUR SAMPLE, AGE ACCELERATION CALCULATED USING "SECOND AND THIRD GENERATION CLOCKS," PHENOAGE, GRIMAGE, AND DUNEDINPACE, IS CONSISTENTLY A SIGNIFICANT PREDICTOR OF HEALTH OUTCOMES INCLUDING CROSS-SECTIONAL COGNITIVE DYSFUNCTION, FUNCTIONAL LIMITATIONS AND CHRONIC CONDITIONS ASSESSED 2 Y AFTER DNAM MEASUREMENT, AND 4-Y MORTALITY. PC-BASED EPIGENETIC AGE ACCELERATION MEASURES DO NOT SIGNIFICANTLY CHANGE THE RELATIONSHIP OF DNAM-BASED AGE ACCELERATION MEASURES TO HEALTH OUTCOMES OR MORTALITY COMPARED TO EARLIER VERSIONS OF THESE MEASURES. WHILE THE USEFULNESS OF DNAM-BASED AGE ACCELERATION AS A PREDICTOR OF LATER LIFE HEALTH OUTCOMES IS QUITE CLEAR, OTHER FACTORS SUCH AS DEMOGRAPHICS, SES, MENTAL HEALTH, AND HEALTH BEHAVIORS REMAIN EQUALLY, IF NOT MORE ROBUST, PREDICTORS OF LATER LIFE OUTCOMES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  1963 18 EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN PAIN IMPACT AND BRAIN AGING IN MIDDLE TO OLDER AGE INDIVIDUALS WITH KNEE PAIN. CHRONIC MUSCULOSKELETAL PAIN IS A HEALTH BURDEN THAT MAY ACCELERATE THE AGING PROCESS. ACCELERATED BRAIN AGING AND EPIGENETIC AGING HAVE SEPARATELY BEEN OBSERVED IN THOSE WITH CHRONIC PAIN. HOWEVER, IT IS UNKNOWN WHETHER THESE BIOLOGICAL MARKERS OF AGING ARE ASSOCIATED WITH EACH OTHER IN THOSE WITH CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND BRAIN AGING IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS (57.91 +/- 8.04 Y) WITH LOW IMPACT KNEE PAIN (N = 95), HIGH IMPACT KNEE PAIN (N = 53), AND PAIN-FREE CONTROLS (N = 26) COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW, AND AN MRI SCAN. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AND BRAIN AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD, RESPECTIVELY). THERE WAS A SIGNIFICANT MAIN EFFECT FOR PAIN IMPACT GROUP (F (2,167) = 3.847, P = 0.023, ROTATIONAL ENERGY = 1 / 2IOMEGA2 = 0.038, ANCOVA) ON BRAIN-PAD AND DNAMGRIMAGE-DIFFERENCE (F (2,167) = 6.800, P = 0.001, I = MK2 = 0.075, ANCOVA) AFTER CONTROLLING FOR COVARIATES. DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD WERE MODESTLY CORRELATED (R =0.198; P =0.010). EXPLORATORY ANALYSIS REVEALED THAT DNAMGRIMAGE-DIFFERENCE MEDIATED GCPS PAIN IMPACT, GCPS PAIN SEVERITY, AND PAIN-RELATED DISABILITY SCORES ON BRAIN-PAD. BASED UPON THE CURRENT STUDY FINDINGS, WE SUGGEST THAT PAIN COULD BE A DRIVER FOR ACCELERATED BRAIN AGING VIA EPIGENOME INTERACTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  1969 23 EPIGENETIC ALTERATIONS AND AN INCREASED FREQUENCY OF MICRONUCLEI IN WOMEN WITH FIBROMYALGIA. FIBROMYALGIA (FM), CHARACTERIZED BY CHRONIC WIDESPREAD PAIN, FATIGUE, AND COGNITIVE/MOOD DISTURBANCES, LEADS TO REDUCED WORKPLACE PRODUCTIVITY AND INCREASED HEALTHCARE EXPENSES. TO DETERMINE IF ACQUIRED EPIGENETIC/GENETIC CHANGES ARE ASSOCIATED WITH FM, WE COMPARED THE FREQUENCY OF SPONTANEOUSLY OCCURRING MICRONUCLEI (MN) AND GENOME-WIDE METHYLATION PATTERNS IN WOMEN WITH FM (N = 10) TO THOSE SEEN IN COMPARABLY AGED HEALTHY CONTROLS (N = 42 (MN); N = 8 (METHYLATION)). THE MEAN (SD) MN FREQUENCY OF WOMEN WITH FM (51.4 (21.9)) WAS SIGNIFICANTLY HIGHER THAN THAT OF CONTROLS (15.8 (8.5)) (CHI (2) = 45.552; DF = 1; P = 1.49 X 10(-11)). SIGNIFICANT DIFFERENCES (N = 69 SITES) IN METHYLATION PATTERNS WERE OBSERVED BETWEEN CASES AND CONTROLS CONSIDERING A 5% FALSE DISCOVERY RATE. THE MAJORITY OF DIFFERENTIALLY METHYLATED (DM) SITES (91%) WERE ATTRIBUTABLE TO INCREASED VALUES IN THE WOMEN WITH FM. THE DM SITES INCLUDED SIGNIFICANT BIOLOGICAL CLUSTERS INVOLVED IN NEURON DIFFERENTIATION/NERVOUS SYSTEM DEVELOPMENT, SKELETAL/ORGAN SYSTEM DEVELOPMENT, AND CHROMATIN COMPACTION. GENES ASSOCIATED WITH DM SITES WHOSE FUNCTION HAS PARTICULAR RELEVANCE TO FM INCLUDED BDNF, NAT15, HDAC4, PRKCA, RTN1, AND PRKG1. RESULTS SUPPORT THE NEED FOR FUTURE RESEARCH TO FURTHER EXAMINE THE POTENTIAL ROLE OF EPIGENETIC AND ACQUIRED CHROMOSOMAL ALTERATIONS AS A POSSIBLE BIOLOGICAL MECHANISM UNDERLYING FM.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19  3078 22 GENOME-WIDE METHYLATION ANALYSIS OF A LARGE POPULATION SAMPLE SHOWS NEUROLOGICAL PATHWAYS INVOLVEMENT IN CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN. CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN (CWP), HAS A CONSIDERABLE HERITABLE COMPONENT, WHICH REMAINS TO BE EXPLAINED. EPIGENETIC FACTORS MAY CONTRIBUTE TO AND ACCOUNT FOR SOME OF THE HERITABILITY ESTIMATE. WE ANALYSED EPIGENOME-WIDE METHYLATION USING MEDIPSEQ IN WHOLE BLOOD DNA FROM 1708 MONOZYGOTIC AND DIZYGOTIC CAUCASIAN TWINS HAVING CWP PREVALENCE OF 19.9%. LONGITUDINALLY STABLE METHYLATION BINS (LSBINS), WERE ESTABLISHED BY TESTING REPEATED MEASUREMENTS CONDUCTED >/=3 YEARS APART, N = 292. DNA METHYLATION VARIATION AT LSBINS WAS TESTED FOR ASSOCIATION WITH CWP IN A DISCOVERY SET OF 50 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR CWP, AND IN AN INDEPENDENT DATASET (N = 1608 TWINS), AND THE RESULTS FROM THE 2 SAMPLES WERE COMBINED USING FISHER METHOD. FUNCTIONAL INTERPRETATION OF THE MOST ASSOCIATED SIGNALS WAS BASED ON FUNCTIONAL GENOMIC ANNOTATIONS, GENE ONTOLOGY, AND PATHWAY ANALYSES. OF 723,029 SIGNALS IDENTIFIED AS LSBINS, 26,399 LSBINS DEMONSTRATED THE SAME DIRECTION OF ASSOCIATION IN BOTH DISCOVERY AND REPLICATION DATASETS AT NOMINAL SIGNIFICANCE (P </= 0.05). IN THE COMBINED ANALYSIS ACROSS 1708 INDIVIDUALS, WHEREAS NO LSBINS SHOWED GENOME-WIDE SIGNIFICANCE (P < 10-8), 24 SIGNALS REACHED P</=9E-5, AND THESE INCLUDED ASSOCIATION SIGNALS MAPPING IN OR NEAR TO IL17A, ADIPOR2, AND TNFRSF13B. BIOINFORMATICS ANALYSES OF THE ASSOCIATED METHYLATION BINS SHOWED ENRICHMENT FOR NEUROLOGICAL PATHWAYS IN CWP. WE ESTIMATE THAT THE VARIANCE EXPLAINED BY EPIGENETIC FACTORS IN CWP IS 6%. THIS, THE LARGEST STUDY TO DATE OF DNA METHYLATION IN CWP, POINTS TOWARDS EPIGENETIC MODIFICATION OF NEUROLOGICAL PATHWAYS IN CWP AND PROVIDES PROOF OF PRINCIPLE OF THIS METHOD IN TEASING APART THE COMPLEX RISK FACTORS FOR CWP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20  3334 24 HISTONE DEACETYLASE INHIBITORS COUNTERACT CGRP SIGNALING AND PRONOCICEPTIVE SENSITIZATION IN A RAT MODEL OF MEDICATION OVERUSE HEADACHE. CHRONIC TRIPTAN EXPOSURE IN RODENTS RECAPITULATES MEDICATION OVERUSE HEADACHE (MOH), CAUSING CEPHALIC PAIN SENSITIZATION AND TRIGEMINAL GANGLION OVEREXPRESSION OF PRONOCICEPTIVE PROTEINS INCLUDING CGRP. BECAUSE OF THESE TRANSCRIPTIONAL DERANGEMENTS, AS WELL AS THE EMERGING ROLE OF EPIGENETICS IN CHRONIC PAIN, IN THE PRESENT STUDY, WE EVALUATED THE EFFECTS OF THE HISTONE DEACETYLASE INHIBITORS (HDACIS) PANOBINOSTAT AND GIVINOSTAT, IN RATS CHRONICALLY EXPOSED TO ELETRIPTAN FOR 1 MONTH. BOTH PANOBINOSTAT AND GIVINOSTAT COUNTERACTED OVEREXPRESSION OF GENES CODING FOR CGRP AND ITS RECEPTOR SUBUNIT RAMP1, HAVING NO EFFECTS ON CLR AND RCP RECEPTOR SUBUNITS IN THE TRIGEMINAL GANGLION (TG) OF ELETRIPTAN-EXPOSED RATS. WITHIN THE TRIGEMINAL NUCLEUS CAUDALIS (TNC), TRANSCRIPTS FOR THESE GENES WERE NEITHER UPREGULATED BY ELETRIPTAN NOR ALTERED BY CONCOMITANT TREATMENT WITH PANOBINOSTAT OR GIVINOSTAT. HDACIS COUNTERACTED HYPERSENSITIVITY TO CAPSAICIN-INDUCED VASODILATATION IN THE TRIGEMINAL TERRITORY, AS WELL AS PHOTOPHOBIC BEHAVIOR AND CEPHALIC ALLODYNIAIN ELETRIPTAN-EXPOSED RATS. ELETRIPTAN DID NOT AFFECT CGRP, CLR, AND RAMP1 EXPRESSION IN CULTURED TRIGEMINAL GANGLIA, WHEREAS BOTH INHIBITORS REDUCED TRANSCRIPTS FOR CLR AND RAMP-1. THE DRUGS, HOWEVER, INCREASED LUCIFERASE EXPRESSION DRIVEN BY CGRP PROMOTER IN CULTURED CELLS. OUR FINDINGS PROVIDE EVIDENCE FOR A KEY ROLE OF HDACS AND EPIGENETICS IN MOH PATHOGENESIS, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE PREVENTION OF MIGRAINE CHRONIFICATION. PERSPECTIVE: THE PRESENT STUDY HIGHLIGHTS A KEY EPIGENETIC ROLE OF HDAC IN THE RODENT MODEL OF MEDICATION OVERUSE HEADACHE, FURTHERING OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS RESPONSIBLE FOR PRONOCICEPTIVE SENSITIZATION DURING HEADACHE CHRONIFICATION.	2022