1  1908 163 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH CHRONIC POSTSURGICAL PAIN AND ANXIETY IN CHILDREN: A PROSPECTIVE, PILOT STUDY. WE HAVE REPORTED CHILD ANXIETY SENSITIVITY (CHILD ANXIETY SENSITIVITY INDEX [CASI]) PREDICTS CHRONIC POSTSURGICAL PAIN (CPSP). HEREIN, WE EVALUATED DNA METHYLATION PROFILES TO UNDERSTAND THE GENE-ENVIRONMENT INTERACTIONS UNDERLYING CPSP AND CASI, TO IDENTIFY SHARED, ENRICHED, GENOMIC PATHWAYS. IN 73 PROSPECTIVELY RECRUITED ADOLESCENTS UNDERGOING SPINE FUSION, PREOPERATIVE CASI AND PAIN DATA OVER 12 MONTHS AFTER SURGERY WERE COLLECTED. DNA FROM THE PERIPHERAL BLOOD OF EVALUABLE SUBJECTS WITH (N = 16) AND WITHOUT CPSP (N = 40) WERE ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 637 AND 2,445 DIFFERENTIALLY DNA METHYLATED POSITIONS (DMPS) ASSOCIATED WITH CPSP AND CASI, RESPECTIVELY (P </= .05). INGENUITY PATHWAY ANALYSIS OF 39 GENES WITH DMPS FOR BOTH CPSP AND CASI REVEALED ENRICHMENT OF SEVERAL CANONICAL PATHWAYS, INCLUDING GABA RECEPTOR (P = .00016 FOR CPSP; P =.0008 FOR CASI) AND DOPAMINE-DARPP32 FEEDBACK IN CYCLIC ADENOSINE MONOPHOSPHATE (P = .004 FOR CPSP AND P =.00003 FOR CASI) SIGNALING. GENE-GENE INTERACTION NETWORK ENRICHMENT ANALYSIS REVEALED PARTICIPATION OF PATHWAYS IN CELL SIGNALING, MOLECULAR TRANSPORT, METABOLISM, AND NEUROLOGIC DISEASES (P < 10(-8)). BIOINFORMATIC APPROACHES TO IDENTIFY HISTONE MARKS AND TRANSCRIPTION FACTOR (TF) BINDING EVENTS UNDERLYING DMPS, SHOWED THEIR LOCATION IN ACTIVE REGULATORY REGIONS IN PAIN PATHWAY RELEVANT BRAIN CELLS. USING ENRICHR/PINET ENRICHMENT AND LIBRARY OF INTEGRATED NETWORK-BASED CELLULAR SIGNATURES KNOCKDOWN SIGNATURES, WE IDENTIFIED TFS REGULATING GENES WITH DMPS IN ASSOCIATION WITH CPSP AND CASI. IN CONCLUSION, WE IDENTIFIED EPIGENETICALLY ENRICHED PATHWAYS ASSOCIATED WITH CPSP AND ANXIETY SENSITIVITY IN CHILDREN UNDERGOING SURGERY. OUR FINDINGS SUPPORT GABA HYPOFUNCTION AND THE ROLES OF THE DOPAMINE-DARPP32 PATHWAY IN EMOTION/REWARD AND PAIN. THIS PILOT STUDY PROVIDES NEW EPIGENETIC INSIGHTS INTO THE PATHOPHYSIOLOGY OF CPSP AND A BASIS FOR FUTURE STUDIES IN BIOMARKER DEVELOPMENT AND TARGETABLE INTERVENTIONS. PERSPECTIVE: DIFFERENTIAL DNA METHYLATION IN REGULATORY GENOMIC REGIONS ENRICHING SHARED NEURAL PATHWAYS WERE ASSOCIATED WITH CPSP AND CASI IN ADOLESCENTS UNDERGOING SPINE SURGERY. OUR FINDINGS SUPPORT GABA HYPOFUNCTION AND THE ROLES OF THE DOPAMINE-DARPP32 PATHWAY IN EMOTION/REWARD CONTRIBUTING TO BEHAVIORAL MAINTENANCE OF PAIN 10 TO 12 MONTHS AFTER SURGERY.	2019	
                                                                                                                                                                                                                                                                                                                           
2   876  21 CHRONIC ARSENIC INTOXICATION DIAGNOSTIC SCORE (CASIDS). ARSENIC AND ITS COMPOUNDS ARE WELL-ESTABLISHED, POTENT, ENVIRONMENTALLY WIDESPREAD AND PERSISTENT TOXICANTS WITH METABOLIC, GENOTOXIC, MUTAGENIC, TERATOGENIC, EPIGENETIC AND CARCINOGENIC EFFECTS. ARSENIC OCCURS NATURALLY IN THE EARTH'S CRUST, BUT ANTHROPOGENIC ARSENIC EMISSIONS HAVE SURMOUNTED THE EMISSIONS FROM IMPORTANT NATURAL SOURCES SUCH AS VOLCANISM. INORGANIC ARSENICALS EXHIBIT ACUTE AND CHRONIC TOXICITIES IN VIRTUALLY ALL CELL TYPES AND TISSUES, AND HENCE ARSENIC INTOXICATION AFFECTS MULTIPLE SYSTEMS. WHEREAS ACUTE ARSENIC INTOXICATION IS RARE AND RELATIVELY EASY TO DIAGNOSE, CHRONIC ARSENIC INTOXICATION (CASI) IS COMMON BUT GOES OFTEN MISDIAGNOSED. BASED ON A REVIEW OF THE LITERATURE AS WELL AS OUR OWN CLINICAL EXPERIENCE, WE PROPOSE A CHRONIC ARSENIC INTOXICATION DIAGNOSTIC SCORE (CASIDS). A DISTINCTIVE FEATURE OF CASIDS IS THE USE OF BONE ARSENIC LOAD AS AN ESSENTIAL CRITERION FOR THE INDIVIDUAL RISK ASSESSMENT OF CHRONIC ARSENIC INTOXICATION, COMBINED WITH A SYSTEMIC CLINICAL ASSESSMENT. WE PRESENT CLINICAL EXAMPLES WHERE CASIDS IS APPLIED FOR THE DIAGNOSIS OF CASI, REVIEW THE MAIN TOPICS OF THE TOXICITY OF ARSENIC IN DIFFERENT CELL AND ORGAN SYSTEMS AND DISCUSS THE THERAPY AND PREVENTION OF DISEASE CAUSED OR AGGRAVATED BY CHRONIC ARSENIC INTOXICATION. CASIDS CAN HELP PHYSICIANS ESTABLISH THE DIAGNOSIS OF CASI AND ASSOCIATED CONDITIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  4240  36 METHYLATION QUANTITATIVE TRAIT LOCUS ANALYSIS OF CHRONIC POSTSURGICAL PAIN UNCOVERS EPIGENETIC MEDIATORS OF GENETIC RISK. BACKGROUND: OVERLAP OF PATHWAYS ENRICHED BY SINGLE NUCLEOTIDE POLYMORPHISMS AND DNA-METHYLATION UNDERLYING CHRONIC POSTSURGICAL PAIN (CPSP), PROMPTED PILOT STUDY OF CPSP-ASSOCIATED METHYLATION QUANTITATIVE TRAIT LOCI (MEQTL). MATERIALS & METHODS: CHILDREN UNDERGOING SPINE-FUSION WERE RECRUITED PROSPECTIVELY. LOGISTIC-REGRESSION FOR GENOME- AND EPIGENOME-WIDE CPSP ASSOCIATION AND DNA-METHYLATION-SINGLE NUCLEOTIDE POLYMORPHISM ASSOCIATION/MEDIATION ANALYSES TO IDENTIFY MEQTLS WERE FOLLOWED BY FUNCTIONAL GENOMICS ANALYSES. RESULTS: CPSP (N = 20/58) AND NON-CPSP GROUPS DIFFERED IN PAIN-MEASURES. OF 2753 MEQTLS, DNA-METHYLATION AT 127 CYTOSINE-GUANINE DINUCLEOTIDES MEDIATED ASSOCIATION OF 470 MEQTLS WITH CPSP (P < 0.05). AT PARK16 LOCUS, CPSP RISK MEQTLS WERE ASSOCIATED WITH DECREASED DNA-METHYLATION AT RAB7L1 AND INCREASED DNA-METHYLATION AT PM20D1. CORRESPONDING RAB7L1/PM20D1 BLOOD EQTLS (GTEX) AND CYTOSINE-GUANINE DINUCLEOTIDE-LOCI ENRICHMENT FOR HISTONE MARKS, TRANSCRIPTION FACTOR BINDING SITES AND ATAC-SEQ PEAKS SUGGEST ALTERED TRANSCRIPTION FACTOR-BINDING. CONCLUSION: CPSP-ASSOCIATED MEQTLS INDICATE EPIGENETIC MECHANISMS MEDIATE GENETIC RISK. CLINICAL TRIAL REGISTRATION: NCT01839461, NCT01731873 (CLINICALTRIALS.GOV).	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  3063  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  3056  38 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  1910  59 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH KNEE OSTEOARTHRITIS PAIN. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (I.E., GENOMIC REGION WHERE MULTIPLE ADJACENT CPG SITES SHOW DIFFERENTIAL METHYLATION) AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH KNEE OSTEOARTHRITIS PAIN (KOA). WE RECRUITED COGNITIVELY HEALTHY MIDDLE TO OLDER AGED (AGE 45-85) ADULTS WITH (N = 182) AND WITHOUT (N = 31) SELF-REPORTED KOA PAIN. WE ALSO EXTRACTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. THE R PACKAGE MINFI (ARYEE ET AL., 2014) WAS USED TO PERFORM METHYLATION DATA PREPROCESSING AND QUALITY CONTROL. TO INVESTIGATE BIOLOGICAL PATHWAYS IMPACTED BY DIFFERENTIAL METHYLATION, WE PERFORMED PATHWAY ENRICHMENT ANALYSIS USING INGENUITY PATHWAY ANALYSIS (IPA) TO IDENTIFY CANONICAL PATHWAYS AND UPSTREAM REGULATORS. ANNOTATED GENES WITHIN +/- 5 KB OF THE PUTATIVE DIFFERENTIALLY METHYLATED REGIONS (DMRS, P < 0.05) WERE SUBJECTED TO THE IPA ANALYSIS. THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE, SEX, STUDY SITE BETWEEN NO PAIN AND PAIN GROUP (P > 0.05). NON-HISPANIC BLACK INDIVIDUALS WERE OVERREPRESENTED IN THE PAIN GROUP (P = 0.003). AT RAW P < 0.05 CUTOFF, WE IDENTIFIED A TOTAL OF 19,710 CPG PROBES, INCLUDING 13,951 HYPERMETHYLATED CPG PROBES, FOR WHICH DNA METHYLATION LEVEL WAS HIGHER IN THE GROUPS WITH HIGHEST PAIN GRADES. WE ALSO IDENTIFIED 5,759 HYPOMETHYLATED CPG PROBES FOR WHICH DNA METHYLATION LEVEL WAS LOWER IN THE PAIN GROUPS WITH HIGHER PAIN GRADES. IPA REVEALED THAT PAIN-RELATED DMRS WERE ENRICHED ACROSS MULTIPLE PATHWAYS AND UPSTREAM REGULATORS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E., ANTIGEN PRESENTATION, PD-1, PD-L1 CANCER IMMUNOTHERAPY, B CELL DEVELOPMENT, IL-4 SIGNALING, TH1 AND TH2 ACTIVATION PATHWAY, AND PHAGOSOME MATURATION). MOREOVER, IN TERMS OF UPSTREAM REGULATORS, NDUFAF3 WAS THE MOST SIGNIFICANT (P = 8.6E-04) UPSTREAM REGULATOR. OUR FINDINGS SUPPORT PREVIOUS PRELIMINARY WORK SUGGESTING THE IMPORTANCE OF EPIGENETIC REGULATION OF THE IMMUNE SYSTEM IN KNEE PAIN AND THE NEED FOR FUTURE WORK TO UNDERSTAND THE EPIGENETIC CONTRIBUTIONS TO CHRONIC PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7  6679  42 USING MACHINE LEARNING TO PREDICT OBESITY BASED ON GENOME-WIDE AND EPIGENOME-WIDE GENE-GENE AND GENE-DIET INTERACTIONS. OBESITY IS ASSOCIATED WITH MANY CHRONIC DISEASES THAT IMPAIR HEALTHY AGING AND IS GOVERNED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AND THEIR COMPLEX INTERACTIONS. THIS STUDY AIMED TO DEVELOP A MODEL THAT PREDICTS AN INDIVIDUAL'S RISK OF OBESITY BY BETTER CHARACTERIZING THESE COMPLEX RELATIONS AND INTERACTIONS FOCUSING ON DIETARY FACTORS. FOR THIS PURPOSE, WE CONDUCTED A COMBINED GENOME-WIDE AND EPIGENOME-WIDE SCAN FOR BODY MASS INDEX (BMI) AND UP TO THREE-WAY INTERACTIONS AMONG 402,793 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), 415,202 DNA METHYLATION SITES (DMSS), AND 397 DIETARY AND LIFESTYLE FACTORS USING THE GENERALIZED MULTIFACTOR DIMENSIONALITY REDUCTION (GMDR) METHOD. THE TRAINING SET CONSISTED OF 1,573 PARTICIPANTS IN EXAM 8 OF THE FRAMINGHAM OFFSPRING STUDY (FOS) COHORT. AFTER IDENTIFYING GENETIC, EPIGENETIC, AND DIETARY FACTORS THAT PASSED STATISTICAL SIGNIFICANCE, WE APPLIED MACHINE LEARNING (ML) ALGORITHMS TO PREDICT PARTICIPANTS' OBESITY STATUS IN THE TEST SET, TAKEN AS A SUBSET OF INDEPENDENT SAMPLES (N = 394) FROM THE SAME COHORT. THE QUALITY AND ACCURACY OF PREDICTION MODELS WERE EVALUATED USING THE AREA UNDER THE RECEIVER OPERATING CHARACTERISTIC CURVE (ROC-AUC). GMDR IDENTIFIED 213 SNPS, 530 DMSS, AND 49 DIETARY AND LIFESTYLE FACTORS AS SIGNIFICANT PREDICTORS OF OBESITY. COMPARING SEVERAL ML ALGORITHMS, WE FOUND THAT THE STOCHASTIC GRADIENT BOOSTING MODEL PROVIDED THE BEST PREDICTION ACCURACY FOR OBESITY WITH AN OVERALL ACCURACY OF 70%, WITH ROC-AUC OF 0.72 IN TEST SET SAMPLES. TOP PREDICTORS OF THE BEST-FIT MODEL WERE 21 SNPS, 230 DMSS IN GENES SUCH AS CPT1A, ABCG1, SLC7A11, RNF145, AND SREBF1, AND 26 DIETARY FACTORS, INCLUDING PROCESSED MEAT, DIET SODA, FRENCH FRIES, HIGH-FAT DAIRY, ARTIFICIAL SWEETENERS, ALCOHOL INTAKE, AND SPECIFIC NUTRIENTS AND FOOD COMPONENTS, SUCH AS CALCIUM AND FLAVONOLS. IN CONCLUSION, WE DEVELOPED AN INTEGRATED APPROACH WITH ML TO PREDICT OBESITY USING OMICS AND DIETARY DATA. THIS EXTENDS OUR KNOWLEDGE OF THE DRIVERS OF OBESITY, WHICH CAN INFORM PRECISION NUTRITION STRATEGIES FOR THE PREVENTION AND TREATMENT OF OBESITY. CLINICAL TRIAL REGISTRATION: [WWW.CLINICALTRIALS.GOV], THE FRAMINGHAM HEART STUDY (FHS), [NCT00005121].	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8   972  45 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  2962  39 GENETIC AND EPIGENETIC MECHANISMS INFLUENCING ACUTE TO CHRONIC POSTSURGICAL PAIN TRANSITIONS IN PEDIATRICS: PRECLINICAL TO CLINICAL EVIDENCE. BACKGROUND: CHRONIC POSTSURGICAL PAIN (CPSP) IN CHILDREN REMAINS AN IMPORTANT PROBLEM WITH NO EFFECTIVE PREVENTIVE OR THERAPEUTIC STRATEGIES. RECENTLY, GENOMIC UNDERPINNINGS EXPLAINING ADDITIONAL INTERINDIVIDUAL RISK BEYOND PSYCHOLOGICAL FACTORS HAVE BEEN PROPOSED. AIMS: WE PRESENT A COMPREHENSIVE REVIEW OF CURRENT PRECLINICAL AND CLINICAL EVIDENCE FOR GENETIC AND EPIGENETIC MECHANISMS RELEVANT TO PEDIATRIC CPSP. METHODS: NARRATIVE REVIEW. RESULTS: ANIMAL MODELS ARE RELEVANT TO TRANSLATIONAL RESEARCH FOR UNRAVELING GENOMIC MECHANISMS. FOR EXAMPLE, CACNG2, P2RX7, AND BDNF MUTANT MICE SHOW ALTERED MECHANICAL HYPERSENSITIVITY TO INJURY, AND VARIANTS OF THE SAME GENES HAVE BEEN ASSOCIATED WITH CPSP SUSCEPTIBILITY IN HUMANS; SIMILARLY, DIFFERENTIAL DNA METHYLATION (H1SP) AND MIRNAS (MIR-96/7A) HAVE SHOWN TRANSLATIONAL IMPLICATIONS. ANIMAL STUDIES ALSO SUGGEST THAT CROSSTALK BETWEEN NEURONS AND IMMUNE CELLS MAY BE INVOLVED IN NOCICEPTIVE PRIMING OBSERVED IN NEONATES. IN CHILDREN, DIFFERENTIAL DNA METHYLATION IN REGULATORY GENOMIC REGIONS ENRICHING GABAERGIC, DOPAMINERGIC, AND IMMUNE PATHWAYS, AS WELL AS POLYGENIC RISK SCORES FOR ENHANCED PREDICTION OF CPSP, HAVE BEEN DESCRIBED. GENOME-WIDE STUDIES IN PEDIATRIC CPSP ARE SCARCE, BUT PATHWAYS IDENTIFIED BY ADULT GENE ASSOCIATION STUDIES POINT TO POTENTIAL COMMON MECHANISMS. CONCLUSIONS: BENCH-TO-BEDSIDE GENOMICS RESEARCH IN PEDIATRIC CPSP IS CURRENTLY LIMITED. REVERSE TRANSLATIONAL APPROACHES, USE OF OTHER -OMICS, AND INCLUSION OF PEDIATRIC/CPSP ENDOPHENOTYPES IN LARGE-SCALE BIOBANKS MAY BE POTENTIAL SOLUTIONS. TIME OF DEVELOPMENTAL VULNERABILITY AND LONGITUDINAL GENOMIC CHANGES AFTER SURGERY WARRANT FURTHER INVESTIGATION. EMERGENCE OF PROMISING PRECISION PAIN MANAGEMENT STRATEGIES BASED ON GENE EDITING AND EPIGENETIC PROGRAMING EMPHASIZE NEED FOR FURTHER RESEARCH IN PEDIATRIC CPSP-RELATED GENOMICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  3637  26 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  2564  53 EPIGENETICS INSIGHTS INTO CHRONIC PAIN: DNA HYPOMETHYLATION IN FIBROMYALGIA-A CONTROLLED PILOT-STUDY. TO EVALUATE CHANGES IN DNA METHYLATION PROFILES IN PATIENTS WITH FIBROMYALGIA (FM) COMPARED TO MATCHED HEALTHY CONTROLS (HCS). ALL INDIVIDUALS UNDERWENT FULL CLINICAL AND NEUROPHYSIOLOGICAL ASSESSMENT BY CORTICAL EXCITABILITY (CE) PARAMETERS MEASURED BY TRANSCRANIAL MAGNETIC STIMULATION. DNA FROM THE PERIPHERAL BLOOD OF PATIENTS WITH FM (N = 24) AND HC (N = 24) WERE ASSESSED USING THE ILLUMINA-HUMANMETHYLATION450 BEADCHIPS. WE IDENTIFIED 1610 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) IN PATIENTS WITH FM DISPLAYING A NONRANDOM DISTRIBUTION IN REGIONS OF THE GENOME. SIXTY-NINE PERCENT OF DMP IN FM WERE HYPOMETHYLATED COMPARED TO HC. DIFFERENTIALLY METHYLATED POSITIONS WERE ENRICHED IN 5 GENOMIC REGIONS (1P34; 6P21; 10Q26; 17Q25; 19Q13). THE FUNCTIONAL CHARACTERIZATION OF 960 GENES RELATED TO DMPS REVEALED AN ENRICHMENT FOR MAPK SIGNALING PATHWAY (N = 18 GENES), REGULATION OF ACTIN CYTOSKELETON (N = 15 GENES), AND FOCAL ADHESION (N = 13 GENES). A GENE-GENE INTERACTION NETWORK ENRICHMENT ANALYSIS REVEALED THE PARTICIPATION OF DNA REPAIR PATHWAYS, MITOCHONDRIA-RELATED PROCESSES, AND SYNAPTIC SIGNALING. EVEN THOUGH DNA WAS EXTRACTED FROM PERIPHERAL BLOOD, THIS SET OF GENES WAS ENRICHED FOR DISORDERS SUCH AS SCHIZOPHRENIA, MOOD DISORDERS, BULIMIA, HYPERPHAGIA, AND OBESITY. REMARKABLY, THE HIERARCHICAL CLUSTERIZATION BASED ON THE METHYLATION LEVELS OF THE 1610 DMPS SHOWED AN ASSOCIATION WITH NEUROPHYSIOLOGICAL MEASUREMENTS OF CE IN FM AND HC. FIBROMYALGIA HAS A HYPOMETHYLATION DNA PATTERN, WHICH IS ENRICHED IN GENES IMPLICATED IN STRESS RESPONSE AND DNA REPAIR/FREE RADICAL CLEARANCE. THESE CHANGES OCCURRED PARALLEL TO CHANGES IN CE PARAMETERS. NEW EPIGENETIC INSIGHTS INTO THE PATHOPHYSIOLOGY OF FM MAY PROVIDE THE BASIS FOR THE DEVELOPMENT OF BIOMARKERS OF THIS DISORDER.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  2643  31 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13  1571  50 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT.	2021	

14    93  36 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  1909  67 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16   404  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  5005  38 PERIPHERAL BLOOD DNA METHYLATION-BASED MACHINE LEARNING MODELS FOR PREDICTION OF KNEE OSTEOARTHRITIS PROGRESSION: BIOLOGIC SPECIMENS AND DATA FROM THE OSTEOARTHRITIS INITIATIVE AND JOHNSTON COUNTY OSTEOARTHRITIS PROJECT. OBJECTIVE: THE LACK OF ACCURATE BIOMARKERS TO PREDICT KNEE OSTEOARTHRITIS (OA) PROGRESSION IS A KEY UNMET NEED IN OA CLINICAL RESEARCH. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP BASELINE PERIPHERAL BLOOD EPIGENETIC BIOMARKER MODELS TO PREDICT KNEE OA PROGRESSION. METHODS: GENOME-WIDE BUFFY COAT DNA METHYLATION PATTERNS FROM 554 INDIVIDUALS FROM THE OSTEOARTHRITIS BIOMARKERS CONSORTIUM (OABC) WERE DETERMINED USING ILLUMINA INFINIUM METHYLATIONEPIC 850K ARRAYS. DATA WERE DIVIDED INTO MODEL DEVELOPMENT AND VALIDATION SETS, AND MACHINE LEARNING MODELS WERE TRAINED TO CLASSIFY FUTURE OA PROGRESSION BY KNEE PAIN, RADIOGRAPHIC IMAGING, KNEE PAIN PLUS RADIOGRAPHIC IMAGING, AND ANY PROGRESSION (PAIN, RADIOGRAPHIC, OR BOTH). PARSIMONIOUS MODELS USING THE TOP 13 CPG SITES MOST FREQUENTLY SELECTED DURING DEVELOPMENT WERE TESTED ON INDEPENDENT SAMPLES FROM PARTICIPANTS IN THE JOHNSTON COUNTY OSTEOARTHRITIS (JOCO OA) PROJECT (N = 128) AND A PREVIOUSLY PUBLISHED OSTEOARTHRITIS INITIATIVE (OAI) DATA SET (N = 55). RESULTS: FULL MODELS ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC-ONLY PROGRESSION (MEAN +/- SEM ACCURACY 87 +/- 0.8%, AREA UNDER THE CURVE [AUC] 0.94 +/- 0.004), PAIN-ONLY PROGRESSION (ACCURACY 89 +/- 0.9%, AUC 0.97 +/- 0.004), PAIN PLUS RADIOGRAPHIC PROGRESSION (ACCURACY 72 +/- 0.7%, AUC 0.79 +/- 0.006), AND ANY PROGRESSION (ACCURACY 78 +/- 0.4%, AUC 0.86 +/- 0.004). PAIN-ONLY AND RADIOGRAPHIC-ONLY PROGRESSORS WERE NOT DISTINGUISHABLE (MEAN +/- SEM ACCURACY 58 +/- 1%, AUC 0.62 +/- 0.001). PARSIMONIOUS MODELS SHOWED SIMILAR PERFORMANCE AND ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC PROGRESSORS IN THE OABC COHORT AND IN BOTH VALIDATION COHORTS (MEAN +/- SEM ACCURACY 80 +/- 0.3%, AUC 0.88 +/- 0.003 [USING JOCO OA PROJECT DATA], ACCURACY 80 +/- 0.8%, AUC 0.89 +/- 0.002 [USING PREVIOUS OAI DATA]). CONCLUSION: OUR DATA SUGGEST THAT PAIN AND STRUCTURAL PROGRESSION SHARE SIMILAR EARLY SYSTEMIC IMMUNE EPIGENOTYPES. FURTHER STUDIES SHOULD FOCUS ON EVALUATING THE PATHOPHYSIOLOGIC CONSEQUENCES OF DIFFERENTIAL DNA METHYLATION AND PERIPHERAL BLOOD CELL EPIGENOTYPES IN INDIVIDUALS WITH KNEE OA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  1550  36 DNA METHYLATION IS ASSOCIATED WITH AIRFLOW OBSTRUCTION IN PATIENTS LIVING WITH HIV. INTRODUCTION: PEOPLE LIVING WITH HIV (PLWH) SUFFER FROM AGE-RELATED COMORBIDITIES SUCH AS COPD. THE PROCESSES RESPONSIBLE FOR REDUCED LUNG FUNCTION IN PLWH ARE LARGELY UNKNOWN. WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY TO INVESTIGATE WHETHER BLOOD DNA METHYLATION IS ASSOCIATED WITH IMPAIRED LUNG FUNCTION IN PLWH. METHODS: USING BLOOD DNA METHYLATION PROFILES FROM 161 PLWH, WE TESTED THE EFFECT OF METHYLATION ON FEV(1), FEV(1)/FVC RATIO AND FEV(1) DECLINE OVER A MEDIAN OF 5 YEARS. WE EVALUATED THE GLOBAL METHYLATION OF PLWH WITH AIRFLOW OBSTRUCTION BY TESTING THE DIFFERENTIAL METHYLATION OF TRANSPOSABLE ELEMENTS ALU AND LINE-1, A WELL-DESCRIBED MARKER OF EPIGENETIC AGEING. RESULTS: AIRFLOW OBSTRUCTION AS DEFINED BY A FEV(1)/FVC<0.70 WAS ASSOCIATED WITH 1393 DIFFERENTIALLY METHYLATED POSITIONS (DMPS), WHILE 4676 WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION BASED ON THE FEV(1)/FVC<LOWER LIMIT OF NORMAL. THESE DMPS WERE ENRICHED FOR BIOLOGICAL PATHWAYS ASSOCIATED WITH CHRONIC VIRAL INFECTIONS. THE AIRFLOW OBSTRUCTION GROUP WAS GLOBALLY HYPOMETHYLATED COMPARED WITH THOSE WITHOUT AIRFLOW OBSTRUCTION. 103 AND 7112 DMPS WERE ASSOCIATED WITH FEV(1) AND FEV(1)/FVC, RESPECTIVELY. NO POSITIONS WERE ASSOCIATED WITH FEV(1) DECLINE. CONCLUSION: A LARGE NUMBER OF DMPS WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION AND LUNG FUNCTION IN A UNIQUE COHORT OF PLWH. AIRFLOW OBSTRUCTION IN EVEN RELATIVELY YOUNG PLWH IS ASSOCIATED WITH GLOBAL HYPOMETHYLATION, SUGGESTING ADVANCED EPIGENETIC AGEING COMPARED WITH THOSE WITH NORMAL LUNG FUNCTION. THE DISTURBANCE OF THE EPIGENETIC REGULATION OF KEY GENES NOT PREVIOUSLY IDENTIFIED IN NON-HIV COPD COHORTS COULD EXPLAIN THE UNIQUE RISK OF COPD IN PLWH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  3951  39 LOCUS-SPECIFIC DIFFERENTIAL DNA METHYLATION AND URINARY ARSENIC: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AMONG ADULTS WITH LOW-TO-MODERATE ARSENIC EXPOSURE. BACKGROUND: CHRONIC EXPOSURE TO ARSENIC (AS), A HUMAN TOXICANT AND CARCINOGEN, REMAINS A GLOBAL PUBLIC HEALTH PROBLEM. HEALTH RISKS PERSIST AFTER AS EXPOSURE HAS ENDED, SUGGESTING EPIGENETIC DYSREGULATION AS A MECHANISTIC LINK BETWEEN EXPOSURE AND HEALTH OUTCOMES. OBJECTIVES: WE INVESTIGATED THE ASSOCIATION BETWEEN TOTAL URINARY AS AND LOCUS-SPECIFIC DNA METHYLATION IN THE STRONG HEART STUDY, A COHORT OF AMERICAN INDIAN ADULTS WITH LOW-TO-MODERATE AS EXPOSURE [TOTAL URINARY AS, MEAN (+/-SD) MUG/G CREATININE: 11.7 (10.6)]. METHODS: DNA METHYLATION WAS MEASURED IN 2,325 PARTICIPANTS USING THE ILLUMINA METHYLATIONEPIC ARRAY. WE IMPLEMENTED LINEAR MODELS TO TEST DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND THE DMRCATE METHOD TO IDENTIFY REGIONS (DMRS) AND CONDUCTED GENE ONTOLOGY ENRICHMENT ANALYSIS. MODELS WERE ADJUSTED FOR ESTIMATED CELL TYPE PROPORTIONS, AGE, SEX, BODY MASS INDEX, SMOKING, EDUCATION, ESTIMATED GLOMERULAR FILTRATION RATE, AND STUDY CENTER. ARSENIC WAS MEASURED IN URINE AS THE SUM OF INORGANIC AND METHYLATED SPECIES. RESULTS: IN ADJUSTED MODELS, METHYLATION AT 20 CPGS WAS ASSOCIATED WITH URINARY AS AFTER FALSE DISCOVERY RATE (FDR) CORRECTION (FDR < 0.05). AFTER BONFERRONI CORRECTION, 5 CPGS REMAINED ASSOCIATED WITH TOTAL URINARY AS (PBONFERRONI < 0.05), LOCATED IN SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. WE IDENTIFIED ONE DMR ON CHROMOSOME 11 (CHR11:2,322,050-2,323,247), ANNOTATED TO C11ORF2; TSPAN32 GENES. DISCUSSION: THIS IS ONE OF THE FIRST EPIGENOME-WIDE ASSOCIATION STUDIES TO INVESTIGATE AS EXPOSURE AND LOCUS-SPECIFIC DNA METHYLATION USING THE ILLUMINA METHYLATIONEPIC ARRAY AND THE LARGEST EPIGENOME-WIDE STUDY OF AS EXPOSURE. THE TOP DMP WAS LOCATED IN SLC7A11A, A GENE INVOLVED IN CYSTINE/GLUTAMATE TRANSPORT AND THE BIOSYNTHESIS OF GLUTATHIONE, AN ANTIOXIDANT THAT MAY PROTECT AGAINST AS-INDUCED OXIDATIVE STRESS. ADDITIONAL DMPS WERE LOCATED IN GENES ASSOCIATED WITH TUMOR DEVELOPMENT AND GLUCOSE METABOLISM. FURTHER RESEARCH IS NEEDED, INCLUDING RESEARCH IN MORE DIVERSE POPULATIONS, TO INVESTIGATE WHETHER AS-RELATED DNA METHYLATION SIGNATURES ARE ASSOCIATED WITH GENE EXPRESSION OR MAY SERVE AS BIOMARKERS OF DISEASE DEVELOPMENT. HTTPS://DOI.ORG/10.1289/EHP6263.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  4818  30 OCCURRENCE OF ACCELERATED EPIGENETIC AGING AND METHYLATION DISRUPTIONS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE ANTIRETROVIRAL THERAPY. BACKGROUND: WHETHER ACCELERATED AGING DEVELOPS OVER THE COURSE OF CHRONIC HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION OR CAN BE OBSERVED BEFORE SIGNIFICANT IMMUNOSUPPRESSION ON IS UNKNOWN. WE STUDIED DNA METHYLATION IN BLOOD TO ESTIMATE CELLULAR AGING IN PERSONS LIVING WITH HIV (PLWH) BEFORE THE INITIATION OF ANTIRETROVIRAL THERAPY (ART). METHODS: A TOTAL OF 378 ART-NAIVE PLWH WHO HAD CD4 T-CELL COUNTS >500/MICROL AND WERE ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL THERAPY TRIAL (PULMONARY SUBSTUDY) WERE COMPARED WITH 34 HIV-NEGATIVE CONTROLS. DNA METHYLATION WAS PERFORMED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN PLWH COMPARED WITH CONTROLS WERE IDENTIFIED USING A ROBUST LINEAR MODEL. METHYLATION AGE WAS CALCULATED USING A PREVIOUSLY DESCRIBED EPIGENETIC CLOCK. RESULTS: THERE WERE A TOTAL OF 56 639 DMPS AND 6103 DMRS AT A FALSE DISCOVERY RATE OF <0.1. THE TOP 5 DMPS CORRESPONDED TO GENES NLRC5, VRK2, B2M, AND GPR6 AND WERE HIGHLY ENRICHED FOR CANCER-RELATED PATHWAYS. PLWH HAD SIGNIFICANTLY HIGHER METHYLATION AGE THAN HIV-NEGATIVE CONTROLS (P = .001), WITH BLACK RACE, LOW CD4 AND HIGH CD8 T-CELL COUNTS, AND DURATION OF HIV BEING RISK FACTORS FOR AGE ACCELERATION. CONCLUSIONS: PLWH BEFORE THE INITIATION OF ART AND WITH PRESERVED IMMUNE STATUS SHOW EVIDENCE OF ADVANCED METHYLATION AGING.	2021