1  1574 186 DNA METHYLATION PATTERNS OF CHRONIC EXPLOSIVE BREACHING IN U.S. MILITARY WARFIGHTERS. BACKGROUND: INJURIES FROM EXPOSURE TO EXPLOSIONS ROSE DRAMATICALLY DURING THE IRAQ AND AFGHANISTAN WARS, WHICH MOTIVATED INVESTIGATION OF BLAST-RELATED NEUROTRAUMA. WE HAVE UNDERTAKEN HUMAN STUDIES INVOLVING MILITARY "BREACHERS" -EXPOSED TO CONTROLLED, LOW-LEVEL BLAST DURING A 3-DAYS EXPLOSIVE BREACHING COURSE. METHODS: WE SCREENED EPIGENETIC PROFILES IN PERIPHERAL BLOOD SAMPLES FROM 59 SUBJECTS (IN TWO SEPARATE U.S. MILITARY TRAINING SESSIONS) USING INFINIUM METHYLATIONEPIC BEADCHIPS. PARTICIPANTS HAD VARYING NUMBERS OF EXPOSURES TO BLAST OVER THEIR MILITARY CAREERS (EMPIRICALLY DEFINED AS HIGH >/= 40, AND CONVERSELY, LOW < 39 BREACHING EXPOSURES). DAILY SELF-REPORTED PHYSIOLOGICAL SYMPTOMS WERE RECORDED. TINNITUS, MEMORY PROBLEMS, HEADACHES, AND SLEEP DISTURBANCES ARE MOST FREQUENTLY REPORTED. RESULTS: WE IDENTIFIED 14 SIGNIFICANTLY DIFFERENTIALLY METHYLATED REGIONS (DMRS) WITHIN GENES ASSOCIATED WITH CUMULATIVE BLAST EXPOSURE IN PARTICIPANTS WITH HIGH RELATIVE TO LOW CUMULATIVE BLAST EXPOSURE. NOTABLY, NTSR1 AND SPON1 WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED IN HIGH RELATIVE TO LOW BLAST EXPOSED GROUPS, SUGGESTING THAT SLEEP DYSREGULATION MAY BE ALTERED IN RESPONSE TO CHRONIC CUMULATIVE BLAST EXPOSURE. IN COMPARING LIFETIME BLAST EXPOSURE AT BASELINE (PRIOR TO EXPOSURE IN CURRENT TRAINING), AND TOP ASSOCIATED SYMPTOMS, WE IDENTIFIED SIGNIFICANT DMRS ASSOCIATED WITH TINNITUS, SLEEP DIFFICULTIES, AND HEADACHE. NOTABLY, WE IDENTIFIED KCNN3, SOD3, MUC4, GALR1, AND WDR45B, WHICH ARE IMPLICATED IN AUDITORY FUNCTION, AS DIFFERENTIALLY METHYLATED ASSOCIATED WITH SELF-REPORTED TINNITUS. THESE FINDINGS SUGGEST NEUROBIOLOGICAL MECHANISMS BEHIND AUDITORY INJURIES IN OUR MILITARY WARFIGHTERS AND ARE PARTICULARLY RELEVANT GIVEN TINNITUS IS NOT ONLY A PRIMARY DISABILITY AMONG VETERANS, BUT HAS ALSO BEEN DEMONSTRATED IN ACTIVE DUTY MEDICAL RECORDS FOR POPULATIONS EXPOSED TO BLAST IN TRAINING. ADDITIONALLY, WE FOUND THAT DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH THE GENES CCDC68 AND COMT TRACK WITH SLEEP DIFFICULTIES, AND THOSE WITHIN FMOD AND TNXB TRACK WITH PAIN AND HEADACHE. CONCLUSION: SLEEP DISTURBANCES, AS WELL AS TINNITUS AND CHRONIC PAIN, ARE WIDELY REPORTED IN U.S. MILITARY SERVICE MEMBERS AND VETERANS. AS WE HAVE PREVIOUSLY DEMONSTRATED, DNA METHYLATION ENCAPSULATES LIFETIME EXPOSURE TO BLAST. THE CURRENT DATA SUPPORT PREVIOUS FINDINGS AND RECAPITULATE TRANSCRIPTIONAL REGULATORY ALTERATIONS IN GENES INVOLVED IN SLEEP, AUDITORY FUNCTION, AND PAIN. THESE DATA UNCOVERED NOVEL EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISM UNDERLYING THE ETIOLOGICAL BASIS OF THESE SYMPTOMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                     
2   214  78 ACUTE AND CHRONIC MOLECULAR SIGNATURES AND ASSOCIATED SYMPTOMS OF BLAST EXPOSURE IN MILITARY BREACHERS. INJURIES FROM EXPOSURE TO EXPLOSIONS ROSE DRAMATICALLY DURING THE IRAQ AND AFGHANISTAN WARS, WHICH MOTIVATED INVESTIGATIONS OF BLAST-RELATED NEUROTRAUMA AND OPERATIONAL BREACHING. IN THIS STUDY, MILITARY "BREACHERS" WERE EXPOSED TO CONTROLLED, LOW-LEVEL BLAST DURING A 10-DAY EXPLOSIVE BREACHING COURSE. USING AN OMICS APPROACH, WE ASSESSED EPIGENETIC, TRANSCRIPTIONAL, AND INFLAMMATORY PROFILE CHANGES IN BLOOD FROM OPERATIONAL BREACHING TRAINEES, WITH VARYING LEVELS OF LIFETIME BLAST EXPOSURE, ALONG WITH DAILY SELF-REPORTED SYMPTOMS (WITH TINNITUS, HEADACHES, AND SLEEP DISTURBANCES AS THE MOST FREQUENTLY REPORTED). ALTHOUGH ACUTE EXPOSURE TO BLAST DID NOT CONFER EPIGENETIC CHANGES, SPECIFICALLY IN DNA METHYLATION, DIFFERENTIALLY METHYLATED REGIONS (DMRS) WITH COORDINATED GENE EXPRESSION CHANGES ASSOCIATED WITH LIFETIME CUMULATIVE BLAST EXPOSURES WERE IDENTIFIED. THE ACCUMULATIVE EFFECT OF BLAST SHOWED INCREASED METHYLATION OF PAX8 ANTISENSE TRANSCRIPT WITH COORDINATED REPRESSION OF GENE EXPRESSION, WHICH HAS BEEN ASSOCIATED WITH SLEEP DISTURBANCE. DNA METHYLATION ANALYSES CONDUCTED IN CONJUNCTION WITH REPORTED SYMPTOMS OF TINNITUS IN THE LOW VERSUS HIGH BLAST INCIDENTS GROUPS IDENTIFIED DMRS IN KCNE1 AND CYP2E1 GENES. KCNE1 AND CYP2E1 SHOWED THE EXPECTED INVERSE CORRELATION BETWEEN DNA METHYLATION AND GENE EXPRESSION, WHICH HAVE BEEN PREVIOUSLY IMPLICATED IN NOISE-RELATED HEARING LOSS. ALTHOUGH NO SIGNIFICANT TRANSCRIPTIONAL CHANGES WERE OBSERVED IN SAMPLES OBTAINED AT THE ONSET OF THE TRAINING COURSE RELATIVE TO CHRONIC CUMULATIVE BLAST, WE IDENTIFIED A LARGE NUMBER OF TRANSCRIPTIONAL PERTURBATIONS ACUTELY PRE- VERSUS POST-BLAST EXPOSURE. ACUTELY, 67 ROBUSTLY DIFFERENTIALLY EXPRESSED GENES (FOLD CHANGE >/=1.5), INCLUDING UFC1 AND YOD1 UBIQUITIN-RELATED PROTEINS, WERE IDENTIFIED. INFLAMMATORY ANALYSES OF CYTOKINES AND CHEMOKINES REVEALED DYSREGULATION OF MCP-1, GCSF, HGF, MCSF, AND RANTES ACUTELY AFTER BLAST EXPOSURE. THESE DATA SHOW THE IMPORTANCE OF AN OMICS APPROACH, REVEALING THAT TRANSCRIPTIONAL AND INFLAMMATORY BIOMARKERS CAPTURE ACUTE LOW-LEVEL BLAST OVERPRESSURE EXPOSURE, WHEREAS DNA METHYLATION MARKS ENCAPSULATE CHRONIC LONG-TERM SYMPTOMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3  5655  30 SEX-BASED MEDICINE MEETS PSORIATIC ARTHRITIS: LESSONS LEARNED AND TO LEARN. HUMORALLY ASSOCIATED AUTOIMMUNE DISEASES GENERALLY SHOW A FEMALE PREDOMINANCE WHEREAS ANKYLOSING SPONDYLITIS, A DISEASE THAT OVERLAPS WITH PSORIATIC ARTHRITIS (PSA), SHOWS A MALE PREDOMINANCE. THE PRESENT REVIEW ASCERTAINS THE CURRENT KNOWLEDGE OF SEX-SPECIFIC DIFFERENCES RELATED TO PSORIATIC ARTHRITIS (PSA), A CHRONIC, INFLAMMATORY CONDITION ASSOCIATED WITH PSORIASIS. SEX DIFFERENCES MAY HAVE IMPORTANT IMPLICATIONS FOR CLINICAL RESEARCH IN PSA AND IN TERMS OF EPIDEMIOLOGY (INCIDENCE, PREVALENCE, LIFETIME RISK, SURVIVAL, AND MORTALITY), CLINICAL, RADIOLOGICAL, AND LABORATORY FEATURES, AND RESPONSE TO TREATMENT. WHILE NATIONWIDE SURVEYS AND LARGE-SCALE DATABASES AND REGISTRIES SHOW NO SEX-SPECIFIC DIFFERENCES, VARYING MALE/FEMALE RATIOS HAVE BEEN REPORTED, RANGING FROM 0.42 TO 2.75 (COMPARABLE WITH THOSE REPORTED FOR PSORIASIS VULGARIS: RANGING FROM 0.28 TO 2.38). THIS MAY REFLECT SUBTLE, COMPLEX, NONLINEAR INTERACTIONS BETWEEN THE BIOLOGICAL MAKE-UP OF THE INDIVIDUAL (GENETIC AND EPIGENETIC DIFFERENCES), HORMONAL COMPONENTS INCLUDING MENOPAUSAL STATUS, ENVIRONMENTAL EXPOSURES INCLUDING SKELETAL PHYSICAL STRESSING, AND PSYCHOLOGICAL VARIABLES. THERE EXISTS METHODOLOGICAL HETEROGENEITY AND PAUCITY OF DATA CONCERNING SEX-SPECIFIC DIFFERENCES, IN TERMS OF THE SPECIFIC POPULATION STUDIED, STUDY DESIGN, AND THE DIAGNOSTIC CRITERIA UTILIZED. HARMONIZING AND RECONCILING THESE DISCREPANCIES WOULD BE OF CRUCIAL IMPORTANCE IN ACHIEVING THE AMBITIOUS GOALS OF PERSONALIZED/INDIVIDUALIZED MEDICINE AND FURTHER STANDARDIZED META-DATA AND BIG DATA COULD HELP DISENTANGLE AND ELUCIDATE THE PRECISE MECHANISMS OF UNDERLYING POTENTIAL PSA SEX-SPECIFIC DIFFERENCES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  3502  47 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277.	2020	

5  3487  44 IDENTIFICATION OF DIFFERENTIALLY METHYLATED SITES WITH WEAK METHYLATION EFFECTS. DEOXYRIBONUCLEIC ACID (DNA) METHYLATION IS AN EPIGENETIC ALTERATION CRUCIAL FOR REGULATING STRESS RESPONSES. IDENTIFYING LARGE-SCALE DNA METHYLATION AT SINGLE NUCLEOTIDE RESOLUTION IS MADE POSSIBLE BY WHOLE GENOME BISULFITE SEQUENCING. AN ESSENTIAL TASK FOLLOWING THE GENERATION OF BISULFITE SEQUENCING DATA IS TO DETECT DIFFERENTIALLY METHYLATED CYTOSINES (DMCS) AMONG TREATMENTS. MOST STATISTICAL METHODS FOR DMC DETECTION DO NOT CONSIDER THE DEPENDENCY OF METHYLATION PATTERNS ACROSS THE GENOME, THUS POSSIBLY INFLATING TYPE I ERROR. FURTHERMORE, SMALL SAMPLE SIZES AND WEAK METHYLATION EFFECTS AMONG DIFFERENT PHENOTYPE CATEGORIES MAKE IT DIFFICULT FOR THESE STATISTICAL METHODS TO ACCURATELY DETECT DMCS. TO ADDRESS THESE ISSUES, THE WAVELET-BASED FUNCTIONAL MIXED MODEL (WFMM) WAS INTRODUCED TO DETECT DMCS. TO FURTHER EXAMINE THE PERFORMANCE OF WFMM IN DETECTING WEAK DIFFERENTIAL METHYLATION EVENTS, WE USED BOTH SIMULATED AND EMPIRICAL DATA AND COMPARE WFMM PERFORMANCE TO A POPULAR DMC DETECTION TOOL METHYLKIT. ANALYSES OF SIMULATED DATA THAT REPLICATED THE EFFECTS OF THE HERBICIDE GLYPHOSATE ON DNA METHYLATION IN ARABIDOPSIS THALIANA SHOW THAT WFMM RESULTS IN HIGHER SENSITIVITY AND SPECIFICITY IN DETECTING DMCS COMPARED TO METHYLKIT, ESPECIALLY WHEN THE METHYLATION DIFFERENCES AMONG PHENOTYPE GROUPS ARE SMALL. MOREOVER, THE PERFORMANCE OF WFMM IS ROBUST WITH RESPECT TO SMALL SAMPLE SIZES, MAKING IT PARTICULARLY ATTRACTIVE CONSIDERING THE CURRENT HIGH COSTS OF BISULFITE SEQUENCING. ANALYSIS OF EMPIRICAL ARABIDOPSIS THALIANA DATA UNDER VARYING GLYPHOSATE DOSAGES, AND THE ANALYSIS OF MONOZYGOTIC (MZ) TWINS WHO HAVE DIFFERENT PAIN SENSITIVITIES-BOTH DATASETS HAVE WEAK METHYLATION EFFECTS OF <1%-SHOW THAT WFMM CAN IDENTIFY MORE RELEVANT DMCS RELATED TO THE PHENOTYPE OF INTEREST THAN METHYLKIT. DIFFERENTIALLY METHYLATED REGIONS (DMRS) ARE GENOMIC REGIONS WITH DIFFERENT DNA METHYLATION STATUS ACROSS BIOLOGICAL SAMPLES. DMRS AND DMCS ARE ESSENTIALLY THE SAME CONCEPTS, WITH THE ONLY DIFFERENCE BEING HOW METHYLATION INFORMATION ACROSS THE GENOME IS SUMMARIZED. IF METHYLATION LEVELS ARE DETERMINED BY GROUPING NEIGHBORING CYTOSINE SITES, THEN THEY ARE DMRS; IF METHYLATION LEVELS ARE CALCULATED BASED ON SINGLE CYTOSINES, THEY ARE DMCS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  2622  40 EPIGENOME-WIDE ASSOCIATION STUDIES IN ASTHMA: A SYSTEMATIC REVIEW. OBJECTIVE: ASTHMA IS A COMMON CHRONIC RESPIRATORY AIRWAY DISEASE INFLUENCED BY ENVIRONMENTAL FACTORS AND POSSIBLY THEIR INTERACTION WITH THE HUMAN GENOME CAUSING EPIGENETIC CHANGES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE MAINLY INVESTIGATED DNA METHYLATION AND ITS ASSOCIATION WITH DISEASE OR TRAITS, EXPOSURE FACTORS OR GENE EXPRESSION. THIS SYSTEMATIC REVIEW AIMED TO IDENTIFY ALL EWAS ASSESSING DIFFERENTIALLY METHYLATED SITES ASSOCIATED WITH ASTHMA IN HUMANS. DESIGN: STRUCTURED SYSTEMATIC LITERATURE SEARCH FOLLOWING PRISMA GUIDELINES, NEWCASTLE-OTTAWA SCALE (NOS) FOR COHORT STUDIES WAS USED FOR BIAS ASSESSMENT. DATA SOURCES: WE SEARCHED PUBMED AND EMBASE DATABASES FROM 2005 TO 2019. ELIGIBILITY CRITERIA: EPIGENOME-WIDE ASSOCIATION STUDIES TESTING ASSOCIATION BETWEEN DIFFERENTIAL METHYLATION AND ASTHMA IN HUMANS. RESULTS: OVERALL, WE IDENTIFIED 16 EWAS STUDIES COMPLYING WITH OUR SEARCH CRITERIA. TWELVE STUDIES WERE CONDUCTED ON CHILDREN, AND 10 WERE CONDUCTED ON SAMPLE SIZES <150 SUBJECTS. FOUR HUNDRED AND NINETEEN CPGS WERE REPORTED IN CHILDREN STUDIES AFTER CORRECTION FOR MULTIPLE TESTING. IN THE ADULT STUDIES, THOUSANDS OF DIFFERENTIALLY METHYLATED SITES WERE IDENTIFIED. DIFFERENTIAL METHYLATION IN INFLAMMATORY-RELATED GENES CORRELATED WITH HIGHER LEVELS OF GENE EXPRESSIONS OF INFLAMMATORY MODULATORS IN ASTHMA. DIFFERENTIALLY METHYLATED GENES ASSOCIATED WITH ASTHMA INCLUDED SMAD3, SERPINC1, PROK1, IL13, RUNX3 AND TIGIT. FORTY-ONE CPGS WERE REPLICATED AT LEAST ONCE IN BLOOD SAMPLES, AND 28 CPGS WERE REPLICATED IN NASAL SAMPLES. CONCLUSION: ALTHOUGH MANY DIFFERENTIALLY METHYLATED CPGS IN GENES KNOWN TO BE INVOLVED IN ASTHMA HAVE BEEN IDENTIFIED IN EWAS TO DATE, WE CONCLUDE THAT FURTHER STUDIES OF LARGER SAMPLE SIZES AND ANALYSES OF DIFFERENTIAL METHYLATION BETWEEN DIFFERENT PHENOTYPES ARE NEEDED IN ORDER TO COMPREHENSIVELY EVALUATE THE ROLE OF EPIGENETIC FACTORS IN THE PATHOPHYSIOLOGY AND HETEROGENEITY OF ASTHMA, AND THE POTENTIAL CLINICAL UTILITY TO PREDICT OR CLASSIFY PATIENTS WITH ASTHMA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  2411  32 EPIGENETIC SCORES FOR THE CIRCULATING PROTEOME AS TOOLS FOR DISEASE PREDICTION. PROTEIN BIOMARKERS HAVE BEEN IDENTIFIED ACROSS MANY AGE-RELATED MORBIDITIES. HOWEVER, CHARACTERISING EPIGENETIC INFLUENCES COULD FURTHER INFORM DISEASE PREDICTIONS. HERE, WE LEVERAGE EPIGENOME-WIDE DATA TO STUDY LINKS BETWEEN THE DNA METHYLATION (DNAM) SIGNATURES OF THE CIRCULATING PROTEOME AND INCIDENT DISEASES. USING DATA FROM FOUR COHORTS, WE TRAINED AND TESTED EPIGENETIC SCORES (EPISCORES) FOR 953 PLASMA PROTEINS, IDENTIFYING 109 SCORES THAT EXPLAINED BETWEEN 1% AND 58% OF THE VARIANCE IN PROTEIN LEVELS AFTER ADJUSTING FOR KNOWN PROTEIN QUANTITATIVE TRAIT LOCI (PQTL) GENETIC EFFECTS. BY PROJECTING THESE EPISCORES INTO AN INDEPENDENT SAMPLE (GENERATION SCOTLAND; N = 9537) AND RELATING THEM TO INCIDENT MORBIDITIES OVER A FOLLOW-UP OF 14 YEARS, WE UNCOVERED 137 EPISCORE-DISEASE ASSOCIATIONS. THESE ASSOCIATIONS WERE LARGELY INDEPENDENT OF IMMUNE CELL PROPORTIONS, COMMON LIFESTYLE AND HEALTH FACTORS, AND BIOLOGICAL AGING. NOTABLY, WE FOUND THAT OUR DIABETES-ASSOCIATED EPISCORES HIGHLIGHTED PREVIOUS TOP BIOMARKER ASSOCIATIONS FROM PROTEOME-WIDE ASSESSMENTS OF DIABETES. THESE EPISCORES FOR PROTEIN LEVELS CAN THEREFORE BE A VALUABLE RESOURCE FOR DISEASE PREDICTION AND RISK STRATIFICATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
8  1516  41 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  1776  40 ECONOMIC HARDSHIP AND BIOLOGICAL WEATHERING: THE EPIGENETICS OF AGING IN A U.S. SAMPLE OF BLACK WOMEN. BACKGROUND: PAST RESEARCH HAS LINKED LOW SOCIO-ECONOMIC STATUS (SES) TO INFLAMMATION, METABOLIC DYSREGULATION, AND VARIOUS CHRONIC AND AGE-RELATED DISEASES SUCH AS TYPE 2 DIABETES, CORONARY HEART DISEASE, STROKE, AND DEMENTIA. THESE STUDIES SUGGEST THAT THE CHALLENGES AND ADVERSITIES ASSOCIATED WITH LOW SES MAY RESULT IN PREMATURE AGING AND INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: BUILDING UPON THIS RESEARCH, THE PRESENT STUDY INVESTIGATES VARIOUS AVENUES WHEREBY LOW INCOME MIGHT ACCELERATE BIOLOGICAL AGING. METHODS: STRUCTURAL EQUATION MODELING AND LONGITUDINAL DATA FROM A SAMPLE OF 100 BLACK, MIDDLE-AGED WOMEN RESIDING IN THE UNITED STATES WAS USED TO INVESTIGATE THE EFFECT OF INCOME ON A RECENTLY DEVELOPED EPIGENETIC MEASURE OF BIOLOGICAL AGING. THIS MEASURE CAN BE USED AS A "BIOLOGICAL CLOCK" TO ASSESS, AT ANY POINT DURING ADULTHOOD, THE EXTENT TO WHICH AN INDIVIDUAL IS EXPERIENCING ACCELERATED OR DECELERATED BIOLOGICAL AGING. RESULTS: LOW INCOME DISPLAYED A ROBUST ASSOCIATION WITH ACCELERATED AGING THAT WAS UNAFFECTED AFTER CONTROLLING FOR OTHER SES-RELATED FACTORS SUCH AS EDUCATION, MARITAL STATUS, AND CHILDHOOD ADVERSITY. FURTHER, OUR ANALYSES INDICATED THAT THE ASSOCIATION BETWEEN INCOME AND BIOLOGICAL AGING WAS NOT EXPLAINED BY HEALTH-RELATED BEHAVIORS SUCH AS DIET, EXERCISE, SMOKING, ALCOHOL CONSUMPTION, OR HAVING HEALTH INSURANCE. RATHER, IN LARGE MEASURE, IT WAS FINANCIAL PRESSURE (DIFFICULTY PAYING BILLS, BUYING NECESSITIES, OR MEETING DAILY EXPENSES) THAT ACCOUNTED FOR THE ASSOCIATION BETWEEN LOW INCOME AND ACCELERATED AGING. CONCLUSIONS: THESE FINDINGS SUPPORT THE VIEW THAT CHRONIC FINANCIAL PRESSURES ASSOCIATED WITH LOW INCOME EXERT A WEATHERING EFFECT THAT RESULTS IN PREMATURE AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  2643  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11  1957  42 EPIGENETIC AGE PREDICTORS IN COMMUNITY-DWELLING ADULTS WITH HIGH IMPACT KNEE PAIN. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, AND EMERGING EVIDENCE SUGGESTS THAT HIGH IMPACT CHRONIC PAIN MAY BE ASSOCIATED WITH VARIOUS ACCELERATED BIOLOGICAL AGING PROCESSES. IN PARTICULAR, EPIGENETIC AGING IS A ROBUST PREDICTOR OF HEALTH-SPAN AND DISABILITY COMPARED TO CHRONOLOGICAL AGE ALONE. THE CURRENT STUDY AIMED TO DETERMINE WHETHER SEVERAL EPIGENETIC AGING BIOMARKERS WERE ASSOCIATED WITH HIGH IMPACT CHRONIC PAIN IN MIDDLE TO OLDER AGE ADULTS (44-78 YEARS OLD). PARTICIPANTS (N = 213) UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOSOCIAL, PAIN AND FUNCTIONAL ASSESSMENTS. WE ESTIMATED FIVE EPIGENETIC CLOCKS AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, WHICH HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK, AS WELL AS INCLUDED ADDITIONAL DERIVED VARIABLES OF EPIGENETIC AGE PREVIOUSLY ASSOCIATED WITH PAIN. THERE WERE SIGNIFICANT DIFFERENCES ACROSS PAIN IMPACT GROUPS IN THREE OUT OF THE FIVE EPIGENETIC CLOCKS EXAMINED (DNAMAGE, DNAMPHENOAGE AND DNAMGRIMAGE), INDICATING THAT PAIN-RELATED DISABILITY DURING THE PAST 6 MONTHS WAS ASSOCIATED WITH MARKERS OF EPIGENETIC AGING. ONLY DNAMPHENOAGE AND DNAMGRIMAGE WERE ASSOCIATED WITH HIGHER KNEE PAIN INTENSITY DURING THE PAST 48 H. FINALLY, PAIN CATASTROPHIZING, DEPRESSIVE SYMPTOMATOLOGY AND MORE NEUROPATHIC PAIN SYMPTOMS WERE SIGNIFICANTLY ASSOCIATED WITH AN OLDER EPIGENOME IN ONLY ONE OF THE FIVE EPIGENETIC CLOCKS (I.E. DNAMGRIMAGE) AFTER CORRECTING FOR MULTIPLE COMPARISONS (CORRECTED P'S < 0.05). GIVEN THE SCANT LITERATURE IN RELATION TO EPIGENETIC AGING AND THE COMPLEX EXPERIENCE OF PAIN, ADDITIONAL RESEARCH IS NEEDED TO UNDERSTAND WHETHER EPIGENETIC AGING MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  1343  42 DETECTING CORD BLOOD CELL TYPE-SPECIFIC EPIGENETIC ASSOCIATIONS WITH GESTATIONAL DIABETES MELLITUS AND EARLY CHILDHOOD GROWTH. BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE PROVIDED OPPORTUNITIES TO UNDERSTAND THE ROLE OF EPIGENETIC MECHANISMS IN DEVELOPMENT AND PATHOPHYSIOLOGY OF MANY CHRONIC DISEASES. HOWEVER, AN IMPORTANT LIMITATION OF CONVENTIONAL EWAS IS THAT PROFILES OF EPIGENETIC VARIABILITY ARE OFTEN OBTAINED IN SAMPLES OF MIXED CELL TYPES. HERE, WE AIM TO ASSESS WHETHER CHANGES IN CORD BLOOD DNA METHYLATION (DNAM) ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) EXPOSURE AND EARLY CHILDHOOD GROWTH MARKERS OCCUR IN A CELL TYPE-SPECIFIC MANNER. RESULTS: WE ANALYZED 275 CORD BLOOD SAMPLES COLLECTED AT DELIVERY FROM A PROSPECTIVE PRE-BIRTH COHORT WITH GENOME-WIDE DNAM PROFILED BY THE ILLUMINA METHYLATIONEPIC ARRAY. WE ESTIMATED PROPORTIONS OF SEVEN COMMON CELL TYPES IN EACH SAMPLE USING A CORD BLOOD-SPECIFIC DNAM REFERENCE PANEL. LEVERAGING A RECENTLY DEVELOPED APPROACH NAMED CELLDMC, WE PERFORMED CELL TYPE-SPECIFIC EWAS TO IDENTIFY CPG LOCI SIGNIFICANTLY ASSOCIATED WITH GDM, OR 3-YEAR-OLD BODY MASS INDEX (BMI) Z-SCORE. A TOTAL OF 1410 CPG LOCI DISPLAYED SIGNIFICANT CELL TYPE-SPECIFIC DIFFERENCES IN METHYLATION LEVEL BETWEEN 23 GDM CASES AND 252 CONTROLS WITH A FALSE DISCOVERY RATE < 0.05. GENE ONTOLOGY ENRICHMENT ANALYSIS INDICATED THAT LDL TRANSPORTATION EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM B-CELLS DNAM ANALYSES AND THE MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM NATURAL KILLER CELLS DNAM ANALYSES. IN ADDITION, WE IDENTIFIED FOUR AND SIX LOCI ASSOCIATED WITH 3-YEAR-OLD BMI Z-SCORE THAT WERE SPECIFIC TO CD8+ T-CELLS AND MONOCYTES, RESPECTIVELY. BY PERFORMING GENOME-WIDE PERMUTATION TESTS, WE VALIDATED THAT MOST OF OUR DETECTED SIGNALS HAD LOW FALSE POSITIVE RATES. CONCLUSION: COMPARED TO CONVENTIONAL EWAS ADJUSTING FOR THE EFFECTS OF CELL TYPE HETEROGENEITY, THE PROPOSED APPROACH BASED ON CELL TYPE-SPECIFIC EWAS COULD PROVIDE ADDITIONAL BIOLOGICALLY MEANINGFUL ASSOCIATIONS BETWEEN CPG METHYLATION, PRENATAL MATERNAL GDM OR 3-YEAR-OLD BMI. WITH CAREFUL VALIDATION, THESE FINDINGS MAY PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS, PROGRAMMING, AND CONSEQUENCES OF RELATED CHILDHOOD METABOLIC DYSREGULATION. THEREFORE, WE PROPOSE THAT CELL TYPE-SPECIFIC ANALYSES ARE WORTH CAUTIOUS EXPLORATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13    54  31 A DRY IMMERSION MODEL OF MICROGRAVITY MODULATES PLATELET PHENOTYPE, MIRNA SIGNATURE, AND CIRCULATING PLASMA PROTEIN BIOMARKER PROFILE. GROUND BASED RESEARCH MODALITIES OF MICROGRAVITY HAVE BEEN PROPOSED AS INNOVATIVE METHODS TO INVESTIGATE THE AETIOLOGY OF CHRONIC AGE-RELATED CONDITIONS SUCH AS CARDIOVASCULAR DISEASE. DRY IMMERSION (DI), HAS BEEN EFFECTIVELY USED TO INTERROGATE THE SEQUELAE OF PHYSICAL INACTIVITY (PI) AND MICROGRAVITY ON MULTIPLE PHYSIOLOGICAL SYSTEMS. HEREIN WE LOOK AT THE CAUSA ET EFFECTUS OF 3-DAY DI ON PLATELET PHENOTYPE, AND CORRELATE WITH BOTH MIROMIC AND CIRCULATING BIOMARKER EXPRESSION. THE MIROMIC PROFILE OF PLATELETS IS REFLECTIVE OF PHENOTYPE, WHICH ITSELF IS SENSITIVE AND MALLEABLE TO THE EXPOSOME, UNDERGOING RESPONSIVE TRANSITIONS IN ORDER TO FULFIL PLATELETS ROLE IN THROMBOSIS AND HAEMOSTASIS. HETEROGENEOUS PLATELET SUBPOPULATIONS CIRCULATE AT ANY GIVEN TIME, WITH VARYING DEGREES OF SENSITIVITY TO ACTIVATION. EMPLOYING A DI MODEL, WE INVESTIGATE THE EFFECT OF ACUTE PI ON PLATELET FUNCTION IN 12 HEALTHY MALES. 3-DAY DI RESULTED IN A SIGNIFICANT INCREASE IN PLATELET COUNT, PLATELETCRIT, PLATELET ADHESION, AGGREGATION, AND A MODEST ELEVATION OF PLATELET REACTIVITY INDEX (PRI). WE IDENTIFIED 15 PROTEIN BIOMARKERS AND 22 MIRNA WHOSE EXPRESSION LEVELS WERE ALTERED AFTER DI. A 3-DAY DI MODEL OF MICROGRAVITY/PHYSICAL INACTIVITY INDUCED A PROTHROMBOTIC PLATELET PHENOTYPE WITH AN UNIQUE PLATELET MIRNA SIGNATURE, INCREASED PLATELET COUNT AND PLATELETCRIT. THIS CORRELATED WITH A UNIQUE CIRCULATING PROTEIN BIOMARKER SIGNATURE. TAKEN TOGETHER, THESE FINDINGS HIGHLIGHT PLATELETS AS SENSITIVE ADAPTIVE SENTINELS AND FUNCTIONAL BIOMARKERS OF EPIGENETIC DRIFT WITHIN THE CARDIOVASCULAR COMPARTMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  6711  44 VIRTUES AND WEAKNESSES OF DNA METHYLATION AS A TEST FOR CERVICAL CANCER PREVENTION. EPIGENETICS IS THE STUDY OF HERITABLE AND NON-HERITABLE GENETIC CODING THAT IS ADDITIVE TO INFORMATION CONTAINED WITHIN CLASSICAL DNA BASE PAIR SEQUENCES. DIFFERENTIAL METHYLATION HAS A FUNDAMENTAL ROLE IN THE DEVELOPMENT AND OUTCOME OF MALIGNANCIES, CHRONIC AND DEGENERATIVE DISEASES AND AGING. DNA METHYLATION CAN BE MEASURED ACCURATELY AND EASILY VIA VARIOUS MOLECULAR METHODS AND HAS BECOME A KEY TECHNOLOGY FOR RESEARCH AND HEALTHCARE DELIVERY, WITH IMMEDIATE ROLES IN THE ELUCIDATION OF DISEASE NATURAL HISTORY, DIAGNOSTICS AND DRUG DISCOVERY. THIS REVIEW FOCUSES ON CANCERS OF THE LOWER GENITAL TRACT, FOR WHICH THE MOST EPIGENETIC INFORMATION EXISTS. DNA METHYLATION HAS BEEN PROPOSED AS A TRIAGE FOR WOMEN INFECTED WITH HUMAN PAPILLOMAVIRUS (HPV) AND MAY EVENTUALLY DIRECTLY COMPLEMENT OR REPLACE HPV SCREENING AS A ONE-STEP MOLECULAR DIAGNOSTIC AND PROGNOSTIC TEST. METHYLATION OF HUMAN GENES IS STRONGLY ASSOCIATED WITH CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) AND CANCER. OF THE MORE THAN 100 HUMAN METHYLATION BIOMARKER GENES TESTED SO FAR IN CERVICAL TISSUE, CLOSE TO 20 HAVE BEEN REPORTED IN DIFFERENT STUDIES, AND APPROXIMATELY 10 HAVE BEEN REPEATEDLY SHOWN TO HAVE ELEVATED METHYLATION IN CERVICAL CANCERS AND HIGH-GRADE CIN (CIN2 AND CIN3), MOST PROMINENTLY CADM1, EPB41L3, FAM19A4, MAL, MIR-124, PAX1 AND SOX1. OBTAINING CONSISTENT PERFORMANCE DATA FROM THE LITERATURE IS QUITE DIFFICULT BECAUSE MOST METHYLATION STUDIES USED A VARIETY OF DIFFERENT ASSAY METHODOLOGIES AND HAD INCOMPLETE AND/OR BIASED CLINICAL SPECIMEN SETS, VARYING ASSAY THRESHOLDS AND DISPARATE TARGET GENE REGIONS. THERE HAVE BEEN RELATIVELY FEW VALIDATION STUDIES OF DNA METHYLATION BIOMARKERS IN LARGE POPULATION-BASED SCREENING STUDIES, BUT AN ENCOURAGING DEVELOPMENT MORE RECENTLY IS THE EXECUTION OF WELL-DESIGNED STUDIES TO TEST THE TRUE PERFORMANCE OF THE MARKERS IN REAL-WORLD SETTINGS. METHYLATION OF HPV GENES, ESPECIALLY HPV16, HPV18, HPV31, HPV33 AND HPV45, IN DISEASE PROGRESSION HAS BEEN A MAJOR FOCUS OF RESEARCH. ELEVATED METHYLATION OF THE HPV16 L1 AND L2 OPEN READING FRAMES, IN PARTICULAR, IS ASSOCIATED WITH CIN2, CIN3 AND INVASIVE CANCER. ESSENTIALLY ALL CANCERS HAVE HIGH LEVELS OF METHYLATION FOR HUMAN GENES AND FOR DRIVER HPV TYPES, WHICH SUGGESTS THAT QUANTITATIVE METHYLATION TESTS MAY HAVE UTILITY IN PREDICTING CIN2 AND CIN3 THAT ARE LIKELY TO PROGRESS. IT IS STILL EARLY IN THE PROCESS OF DEVELOPMENT OF METHYLATION BIOMARKERS, BUT ALREADY THEY ARE SHOWING STRONG PROMISE AS A UNIVERSAL AND SYSTEMATIC APPROACH TO MOLECULAR TRIAGE, APPLICABLE TO ALL CANCERS, NOT JUST CANCER OF THE CERVIX. DNA METHYLATION TESTING IS BETTER THAN HPV GENOTYPING TRIAGE AND IS COMPETITIVE WITH OR COMPLEMENTARY TO OTHER APPROACHES SUCH AS CYTOLOGY AND P16 STAINING. GENOME-WIDE STUDIES ARE UNDERWAY TO SYSTEMATICALLY EXPAND METHYLATION CLASSIFIER PANELS AND FIND THE BEST COMBINATIONS OF BIOMARKERS. METHYLATION TESTING IS LIKELY TO SHOW BIG IMPROVEMENTS IN PERFORMANCE IN THE NEXT 5 YEARS.	2016	
                            
15  6027  24 THE BLOOD DNA METHYLATION CLOCK GRIMAGE IS A ROBUST SURROGATE FOR AIRWAY EPITHELIA AGING. ONE KEY FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS THAT ITS PREVALENCE INCREASES EXPONENTIALLY WITH AGE. DNA METHYLATION CLOCKS HAVE BECOME POWERFUL BIOMARKERS TO DETECT ACCELERATED AGING IN A VARIETY OF DISEASES AND CAN HELP PROGNOSE OUTCOMES IN SEVERE COPD. THIS STUDY INVESTIGATED WHICH DNA METHYLATION CLOCK COULD BEST REFLECT AIRWAY EPIGENETIC AGE WHEN USED IN MORE ACCESSIBLE BLOOD SAMPLES. OUR ANALYSES SHOWED THAT OUT OF SIX DNA METHYLATION CLOCKS INVESTIGATED, DNAMGRIMAGE DEMONSTRATED THE STRONGEST CORRELATION AND THE SMALLEST DIFFERENCE BETWEEN THE AIRWAY EPITHELIUM AND BLOOD. OUR FINDINGS SUGGESTS THAT BLOOD DNAMGRIMAGE ACCURATELY REFLECTS AIRWAY EPIGENETIC AGE OF INDIVIDUALS AND THAT ITS ELEVATION IS HIGHLY ASSOCIATED WITH COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  2734  45 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  3032  31 GENETICS OF TINNITUS: AN EMERGING AREA FOR MOLECULAR DIAGNOSIS AND DRUG DEVELOPMENT. SUBJECTIVE TINNITUS IS THE PERCEPTION OF SOUND IN THE ABSENCE OF EXTERNAL OR BODILY-GENERATED SOUNDS. CHRONIC TINNITUS IS A HIGHLY PREVALENT CONDITION AFFECTING OVER 70 MILLION PEOPLE IN EUROPE. A WIDE VARIETY OF COMORBIDITIES, INCLUDING HEARING LOSS, PSYCHIATRIC DISORDERS, NEURODEGENERATIVE DISORDERS, AND TEMPOROMANDIBULAR JOINT (TMJ) DYSFUNCTION, HAVE BEEN SUGGESTED TO CONTRIBUTE TO THE ONSET OR PROGRESSION OF TINNITUS; HOWEVER, THE PRECISE MOLECULAR MECHANISMS OF TINNITUS ARE NOT WELL UNDERSTOOD AND THE CONTRIBUTION OF GENETIC AND EPIGENETIC FACTORS REMAINS UNKNOWN. HUMAN GENETIC STUDIES COULD ENABLE THE IDENTIFICATION OF NOVEL MOLECULAR THERAPEUTIC TARGETS, POSSIBLY LEADING TO THE DEVELOPMENT OF NOVEL PHARMACEUTICAL THERAPEUTICS. IN THIS ARTICLE, WE BRIEFLY DISCUSS THE AVAILABLE EVIDENCE FOR A ROLE OF GENETICS IN TINNITUS AND CONSIDER POTENTIAL HURDLES IN DESIGNING GENETIC STUDIES FOR TINNITUS. SINCE MULTIPLE DISEASES HAVE TINNITUS AS A SYMPTOM AND THE SUPPORTING GENETIC EVIDENCE IS SPARSE, WE PROPOSE VARIOUS STRATEGIES TO INVESTIGATE THE GENETIC UNDERPINNINGS OF TINNITUS, FIRST BY SHOWING EVIDENCE OF HERITABILITY USING CONCORDANCE STUDIES IN TWINS, AND SECOND BY IMPROVING PATIENT SELECTION ACCORDING TO PHENOTYPE AND/OR ETIOLOGY IN ORDER TO CONTROL POTENTIAL BIASES AND OPTIMIZE GENETIC DATA OUTPUT. THE INCREASED KNOWLEDGE RESULTING FROM THIS ENDEAVOR COULD ULTIMATELY IMPROVE THE DRUG DEVELOPMENT PROCESS AND LEAD TO THE PREVENTIVE OR CURATIVE TREATMENT OF TINNITUS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18  6112  39 THE EPIGENETIC CLOCK AS A PREDICTOR OF DISEASE AND MORTALITY RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: AGEING IS ONE OF THE PRINCIPAL RISK FACTORS FOR MANY CHRONIC DISEASES. HOWEVER, THERE IS CONSIDERABLE BETWEEN-PERSON VARIATION IN THE RATE OF AGEING AND INDIVIDUAL DIFFERENCES IN THEIR SUSCEPTIBILITY TO DISEASE AND DEATH. EPIGENETIC MECHANISMS MAY PLAY A ROLE IN HUMAN AGEING, AND DNA METHYLATION AGE BIOMARKERS MAY BE GOOD PREDICTORS OF AGE-RELATED DISEASES AND MORTALITY RISK. THE AIMS OF THIS SYSTEMATIC REVIEW WERE TO IDENTIFY AND SYNTHESISE THE EVIDENCE FOR AN ASSOCIATION BETWEEN PERIPHERALLY MEASURED DNA METHYLATION AGE AND LONGEVITY, AGE-RELATED DISEASE, AND MORTALITY RISK. METHODS: A SYSTEMATIC SEARCH WAS CONDUCTED IN LINE WITH THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. USING RELEVANT SEARCH TERMS, MEDLINE, EMBASE, COCHRANE CENTRAL REGISTER OF CONTROLLED TRIALS, AND PSYCHINFO DATABASES WERE SEARCHED TO IDENTIFY ARTICLES MEETING THE INCLUSION CRITERIA. STUDIES WERE ASSESSED FOR BIAS USING JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLISTS. DATA WAS EXTRACTED FROM STUDIES MEASURING AGE ACCELERATION AS A PREDICTOR OF AGE-RELATED DISEASES, MORTALITY OR LONGEVITY, AND THE FINDINGS FOR SIMILAR OUTCOMES COMPARED. USING REVIEW MANAGER 5.3 SOFTWARE, TWO META-ANALYSES (ONE PER EPIGENETIC CLOCK) WERE CONDUCTED ON STUDIES MEASURING ALL-CAUSE MORTALITY. RESULTS: TWENTY-THREE RELEVANT ARTICLES WERE IDENTIFIED, INCLUDING A TOTAL OF 41,607 PARTICIPANTS. FOUR STUDIES FOCUSED ON AGEING AND LONGEVITY, 11 ON AGE-RELATED DISEASE (CANCER, CARDIOVASCULAR DISEASE, AND DEMENTIA), AND 11 ON MORTALITY. THERE WAS SOME, ALTHOUGH INCONSISTENT, EVIDENCE FOR AN ASSOCIATION BETWEEN INCREASED DNA METHYLATION AGE AND RISK OF DISEASE. META-ANALYSES INDICATED THAT EACH 5-YEAR INCREASE IN DNA METHYLATION AGE WAS ASSOCIATED AN 8 TO 15% INCREASED RISK OF MORTALITY. CONCLUSION: DUE TO THE SMALL NUMBER OF STUDIES AND HETEROGENEITY IN STUDY DESIGN AND OUTCOMES, THE ASSOCIATION BETWEEN DNA METHYLATION AGE AND AGE-RELATED DISEASE AND LONGEVITY IS INCONCLUSIVE. INCREASED EPIGENETIC AGE WAS ASSOCIATED WITH MORTALITY RISK, BUT POSITIVE PUBLICATION BIAS NEEDS TO BE CONSIDERED. FURTHER RESEARCH IS NEEDED TO DETERMINE THE EXTENT TO WHICH DNA METHYLATION AGE CAN BE USED AS A CLINICAL BIOMARKER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  5395  30 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  5808  36 STRATIFICATION OF COMPANION ANIMAL LIFE STAGES FROM ELECTRONIC MEDICAL RECORD DIAGNOSIS DATA. AGING IS A COMPLEX, MULTIFACTORIAL PROCESS, WHERE DIFFERENT LIFE STAGES REFLECT CHANGES IN METABOLIC PROCESSES, IMMUNE CAPACITIES, AND GENETIC/EPIGENETIC REPERTOIRES. WITH ACCUMULATING EXPOSURE TO ENVIRONMENTAL STRESSES AND DETERIORATION OF PHYSIOLOGICAL FUNCTIONS, BODY SYSTEMS BECOME MORE PRONE TO LOW-GRADE CHRONIC INFLAMMATION AND AN INCREASING RANGE OF PATHOLOGIES. WE HYPOTHESIZED THAT DIFFERENTIAL SUSCEPTIBILITY TO DISEASES ACROSS LIFE SPAN REFLECTS PHASED CHANGES IN AN ORGANISM'S PHYSIOLOGICAL CAPACITY THAT MAY HIGHLIGHT WHEN INTERVENTIONS MAY BE APPROPRIATELY USED. FURTHERMORE, THE NUMBER OF LIFE STAGES MAY VARY BETWEEN SPECIES AND BE IMPACTED BY SIGNALMENT SUCH AS BREED. WE TESTED THIS HYPOTHESIS USING DISEASE DIAGNOSES DATA FROM VETERINARY ELECTRONIC MEDICAL RECORDS CONTAINING ALMOST 2 MILLION CATS AND OVER 4 MILLION DOGS. BI-CLUSTERING (ON RATES OF DISEASE DIAGNOSES) AND ADAPTIVE BRANCH PRUNING WERE USED TO IDENTIFY AGE CLUSTERS THAT COULD BE USED TO DEFINE ADULT LIFE STAGES. CLUSTERING AMONG DIAGNOSES WERE THEN INTERPRETED WITHIN THE CONTEXT OF EACH DEFINED LIFE STAGE. THE ANALYSES IDENTIFIED 5 AGE CLUSTERS IN CATS AND 4 AGE CLUSTERS WITHIN EACH OF THE 4 CANINE BREED SIZE CATEGORIES USED. THIS STUDY, USING POPULATION SCALE DATA FOR TWO SPECIES, ONE WITH DIFFERENTIAL SIZE AND LIFE EXPECTANCIES, IS THE FIRST TO OUR KNOWLEDGE TO USE DISEASE DIAGNOSIS DATA TO DEFINE ADULT LIFE STAGES. THE LIFE STAGES PRESENTED HERE ARE A RESULT OF A DATA-DRIVEN APPROACH TO AGE AND DISEASE STRATIFICATION AND ARE INTENDED TO SUPPORT CONVERSATIONS BETWEEN CLINICIANS AND CLIENTS ABOUT APPROPRIATE HEALTH CARE RECOMMENDATIONS.	2023