1  639 208 BIOMARKERS FOR MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS): A SYSTEMATIC REVIEW. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A MULTIFACETED CONDITION THAT AFFECTS MOST BODY SYSTEMS. THERE IS CURRENTLY NO KNOWN DIAGNOSTIC BIOMARKER; INSTEAD, DIAGNOSIS IS DEPENDENT ON APPLICATION OF SYMPTOM-BASED CASE CRITERIA FOLLOWING EXCLUSION OF ANY OTHER POTENTIAL MEDICAL CONDITIONS. WHILE THERE ARE SOME STUDIES THAT REPORT POTENTIAL BIOMARKERS FOR ME/CFS, THEIR EFFICACY HAS NOT BEEN VALIDATED. THE AIM OF THIS SYSTEMATIC REVIEW IS TO COLLATE AND APPRAISE LITERATURE PERTAINING TO A POTENTIAL BIOMARKER(S) WHICH MAY EFFECTIVELY DIFFERENTIATE ME/CFS PATIENTS FROM HEALTHY CONTROLS. METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED ACCORDING TO THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES AND COCHRANE REVIEW GUIDELINES. PUBMED, EMBASE AND SCOPUS WERE SYSTEMATICALLY SEARCHED FOR ARTICLES CONTAINING "BIOMARKER" AND "ME/CFS" KEYWORDS IN THE ABSTRACT OR TITLE AND IF THEY INCLUDED THE FOLLOWING CRITERIA: (1) WERE OBSERVATIONAL STUDIES PUBLISHED BETWEEN DECEMBER 1994 AND APRIL 2022; (2) INVOLVED ADULT HUMAN PARTICIPANTS; (3) FULL TEXT IS AVAILABLE IN ENGLISH (4) ORIGINAL RESEARCH; (5) DIAGNOSIS OF ME/CFS PATIENTS MADE ACCORDING TO THE FUKUDA CRITERIA (1994), CANADIAN CONSENSUS CRITERIA (2003), INTERNATIONAL CONSENSUS CRITERIA (2011) OR INSTITUTE OF MEDICINE CRITERIA (2015); (6) STUDY INVESTIGATED POTENTIAL BIOMARKERS OF ME/CFS COMPARED TO HEALTHY CONTROLS. QUALITY AND BIAS WERE ASSESSED USING THE JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLIST FOR CASE CONTROL STUDIES. RESULTS: A TOTAL OF 101 PUBLICATIONS WERE INCLUDED IN THIS SYSTEMATIC REVIEW. POTENTIAL BIOMARKERS RANGED FROM GENETIC/EPIGENETIC (19.8%), IMMUNOLOGICAL (29.7%), METABOLOMICS/MITOCHONDRIAL/MICROBIOME (14.85%), ENDOVASCULAR/CIRCULATORY (17.82%), NEUROLOGICAL (7.92%), ION CHANNEL (8.91%) AND PHYSICAL DYSFUNCTION BIOMARKERS (8.91%). MOST OF THE POTENTIAL BIOMARKERS REPORTED WERE BLOOD-BASED (79.2%). USE OF LYMPHOCYTES AS A MODEL TO INVESTIGATE ME/CFS PATHOLOGY WAS PROMINENT AMONG IMMUNE-BASED BIOMARKERS. MOST BIOMARKERS HAD SECONDARY (43.56%) OR TERTIARY (54.47%) SELECTIVITY, WHICH IS THE ABILITY FOR THE BIOMARKER TO IDENTIFY A DISEASE-CAUSING AGENT, AND A MODERATE (59.40%) TO COMPLEX (39.60%) EASE-OF-DETECTION, INCLUDING THE REQUIREMENT OF SPECIALISED EQUIPMENT. CONCLUSIONS: ALL POTENTIAL ME/CFS BIOMARKERS DIFFERED IN EFFICIENCY, QUALITY, AND TRANSLATABILITY AS A DIAGNOSTIC MARKER. REPRODUCIBILITY OF FINDINGS BETWEEN THE INCLUDED PUBLICATIONS WERE LIMITED, HOWEVER, SEVERAL STUDIES VALIDATED THE INVOLVEMENT OF IMMUNE DYSFUNCTION IN THE PATHOLOGY OF ME/CFS AND THE USE OF LYMPHOCYTES AS A MODEL TO INVESTIGATE THE PATHOMECHANISM OF ILLNESS. THE HETEROGENEITY SHOWN ACROSS MANY OF THE INCLUDED STUDIES HIGHLIGHTS THE NEED FOR MULTIDISCIPLINARY RESEARCH AND UNIFORM PROTOCOLS IN ME/CFS BIOMARKER RESEARCH.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 6112  65 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  488  39 ASSESSING DIAGNOSTIC VALUE OF MICRORNAS FROM PERIPHERAL BLOOD MONONUCLEAR CELLS AND EXTRACELLULAR VESICLES IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A DEBILITATING MULTISYSTEMIC DISEASE OF UNKNOWN ETIOLOGY, AFFECTING THOUSANDS OF INDIVIDUALS WORLDWIDE. ITS DIAGNOSIS STILL RELIES ON RULING OUT MEDICAL PROBLEMS LEADING TO UNEXPLAINED FATIGUE DUE TO A COMPLETE LACK OF DISEASE-SPECIFIC BIOMARKERS. OUR GROUP AND OTHERS HAVE EXPLORED THE POTENTIAL VALUE OF MICRORNA PROFILES (MIRNOMES) AS DIAGNOSTIC TOOLS FOR THIS DISEASE. HOWEVER, HETEROGENEITY OF PARTICIPANTS, LOW NUMBERS, THE VARIETY OF SAMPLES ASSAYED, AND OTHER PRE-ANALYTICAL VARIABLES, HAVE HAMPERED THE IDENTIFICATION OF DISEASE-ASSOCIATED MIRNOMES. IN THIS STUDY, OUR TEAM HAS EVALUATED, FOR THE FIRST TIME, ME/CFS MIRNOMES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND EXTRACELLULAR VESICLES (EVS) FROM SEVERELY ILL PATIENTS RECRUITED AT THE MONOGRAPHIC UK ME BIOBANK TO ASSESS, USING STANDARD OPERATING PROCEDURES (SOPS), BLOOD FRACTIONS WITH OPTIMAL DIAGNOSTIC POWER FOR A RAPID TRANSLATION OF A MIR-BASED DIAGNOSTIC METHOD INTO THE CLINIC. OUR RESULTS SHOW THAT ROUTINE CREATINE KINASE (CK) BLOOD VALUES, PLASMA EVS PHYSICAL CHARACTERISTICS (INCLUDING COUNTS, SIZE AND ZETA-POTENTIAL), AND A LIMITED NUMBER OF DIFFERENTIALLY EXPRESSED PBMC AND EV MIRNAS APPEAR SIGNIFICANTLY ASSOCIATED WITH SEVERE ME/CFS (P < 0.05). GENE ENRICHMENT ANALYSIS POINTS TO EPIGENETIC AND NEUROIMMUNE DYSREGULATED PATHWAYS, IN AGREEMENT WITH PREVIOUS REPORTS. POPULATION VALIDATION BY A COST-EFFECTIVE APPROACH LIMITED TO THESE FEW POTENTIALLY DISCRIMINATING VARIABLES IS GRANTED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4 2093  41 EPIGENETIC EFFECTS FOLLOWING ACUTE AND CHRONIC EXERCISE IN CARDIOVASCULAR DISEASE: A SYSTEMATIC REVIEW. INTRODUCTION: ACUTE EXERCISE AND EXERCISE TRAINING MAY CONFER EPIGENETIC MODIFICATIONS IN HEALTHY SUBJECTS. EPIGENETIC EFFECTS AFTER EXERCISE HAVE BEEN SHOWED IN PATIENTS WITH CARDIOVASCULAR DISEASE. THE AIM OF THIS SYSTEMATIC REVIEW WAS TO SUMMARIZE THE EVIDENCE FROM AVAILABLE CLINICAL TRIALS THAT STUDY EPIGENETIC ADAPTATIONS AFTER EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. METHODS: THE SEARCH STRATEGY WAS PERFORMED IN PUBMED AND CENTRAL DATABASES ON ARTICLES PUBLISHED UNTIL SEPTEMBER 2020. STUDIES WITH TITLES AND ABSTRACTS RELEVANT TO EXERCISE EPIGENETIC MODIFICATION APPLIED TO CARDIOVASCULAR PATIENTS WERE FULLY EXAMINED. INCLUSION AND EXCLUSION CRITERIA WERE UTILIZED FOR STUDIES SCREENING. QUALITY ASSESSMENT WITH PEDRO SCALE AND EVALUATION BY TWO INDEPENDENT REVIEWERS WAS PERFORMED. RESULTS: OF THE 1714 ARTICLES RETRIEVED, 88 ARTICLES WERE ASSESSED FOR ELIGIBILITY CRITERIA AND 8 ARTICLES MATCHED OUR SEARCH CRITERIA AND FINALLY INCLUDED IN THE SYSTEMATIC ANALYSIS. THE ACUTE EXERCISE EPIGENETIC (MIRNAS) EFFECTS WERE ASSESSED IN THREE STUDIES AND THE CHRONIC EXERCISE TRAINING EFFECTS (MIRNAS AND DNA METHYLATION) IN SIX STUDIES. THE RESULTS HAVE SHOWN THAT THERE IS POSSIBLY AN ACUTE SIGNIFICANT EXERCISE EFFECT ON EPIGENETIC TARGETS WHICH IS MORE EVIDENT AFTER CHRONIC EXERCISE TRAINING. CONCLUSIONS: BY THE PRESENT SYSTEMATIC REVIEW, WE PROVIDE PRELIMINARY EVIDENCE OF BENEFICIAL EPIGENETIC ADAPTATIONS FOLLOWING ACUTE AND CHRONIC EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. MORE CONTROLLED STUDIES ARE NEEDED TO CONFIRM SUCH EVIDENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5 6524  51 TRANSCRIPTIONAL AND EPIGENETIC RESPONSE TO SEDENTARY BEHAVIOR AND PHYSICAL ACTIVITY IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW. BACKGROUND: THE LINKS OF SEDENTARY BEHAVIOR AND PHYSICAL ACTIVITY WITH HEALTH OUTCOMES IN CHILDREN AND ADOLESCENTS IS WELL KNOWN. HOWEVER, THE MOLECULAR MECHANISMS INVOLVED ARE POORLY UNDERSTOOD. WE AIMED TO SYNTHESIZE THE CURRENT KNOWLEDGE OF THE ASSOCIATION OF SEDENTARY BEHAVIOR AND PHYSICAL ACTIVITY (ACUTE AND CHRONIC EFFECTS) WITH GENE EXPRESSION AND EPIGENETIC MODIFICATIONS IN CHILDREN AND ADOLESCENTS. METHODS: PUBMED, WEB OF SCIENCE, AND SCOPUS DATABASES WERE SYSTEMATICALLY SEARCHED UNTIL APRIL 2022. A TOTAL OF 15 ARTICLES WERE ELIGIBLE FOR THIS REVIEW. THE RISK OF BIAS ASSESSMENT WAS PERFORMED USING THE JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL TOOL FOR SYSTEMATIC REVIEWS AND/OR A MODIFIED VERSION OF THE DOWNS AND BLACK CHECKLIST. RESULTS: THIRTEEN STUDIES USED CANDIDATE GENE APPROACH, WHILE ONLY 2 STUDIES PERFORMED HIGH-THROUGHPUT ANALYSES. THE CANDIDATE GENES SIGNIFICANTLY LINKED TO SEDENTARY BEHAVIOR OR PHYSICAL ACTIVITY WERE: FOXP3, HSD11B2, IL-10, TNF-ALPHA, ADRB2, VEGF, HSP70, SOX, AND GPX. NON-CODING RIBONUCLEIC ACIDS (RNAS) REGULATED BY SEDENTARY BEHAVIOR OR PHYSICAL ACTIVITY WERE: MIRNA-222, MIRNA-146(A), MIRNA-16, MIRNA-126, MIR-320(A), AND LONG NON-CODING RNA MALAT1. THESE MOLECULES ARE INVOLVED IN INFLAMMATION, IMMUNE FUNCTION, ANGIOGENIC PROCESS, AND CARDIOVASCULAR DISEASE. TRANSCRIPTOMICS ANALYSES DETECTED THOUSANDS OF GENES THAT WERE ALTERED FOLLOWING AN ACUTE BOUT OF PHYSICAL ACTIVITY AND ARE LINKED TO GENE PATHWAYS RELATED TO IMMUNE FUNCTION, APOPTOSIS, AND METABOLIC DISEASES. CONCLUSION: THE EVIDENCE FOUND TO DATE IS RATHER LIMITED. MULTIDISCIPLINARY STUDIES ARE ESSENTIAL TO CHARACTERIZE THE MOLECULAR MECHANISMS IN RESPONSE TO SEDENTARY BEHAVIOR AND PHYSICAL ACTIVITY IN THE PEDIATRIC POPULATION. LARGER COHORTS AND RANDOMIZED CONTROLLED TRIALS, IN COMBINATION WITH MULTI-OMICS ANALYSES, MAY PROVIDE THE NECESSARY DATA TO BRING THE FIELD FORWARD. SYSTEMATIC REVIEW REGISTRATION: [WWW.CLINICALTRIALS.GOV], IDENTIFIER [CRD42021235431].	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6 2050  45 EPIGENETIC COMPONENTS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME UNCOVER POTENTIAL TRANSPOSABLE ELEMENT ACTIVATION. PURPOSE: STUDIES TO DETERMINE EPIGENETIC CHANGES ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) REMAIN SCARCE; HOWEVER, CURRENT EVIDENCE CLEARLY SHOWS THAT METHYLATION PATTERNS OF GENOMIC DNA AND NONCODING RNA PROFILES OF IMMUNE CELLS DIFFER BETWEEN PATIENTS AND HEALTHY SUBJECTS, SUGGESTING AN ACTIVE ROLE OF THESE EPIGENETIC MECHANISMS IN THE DISEASE. THE PRESENT STUDY COMPARES AND CONTRASTS THE AVAILABLE ME/CFS EPIGENETIC DATA IN AN EFFORT TO EVIDENCE OVERLAPPING PATHWAYS CAPABLE OF EXPLAINING AT LEAST SOME OF THE DYSFUNCTIONAL IMMUNE PARAMETERS LINKED TO THIS DISEASE. METHODS: A SYSTEMATIC SEARCH OF THE LITERATURE EVALUATING THE ME/CFS EPIGENOME LANDSCAPE WAS PERFORMED FOLLOWING THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES CRITERIA. DIFFERENTIAL DNA METHYLATION AND NONCODING RNA DIFFERENTIAL EXPRESSION PATTERNS ASSOCIATED WITH ME/CFS WERE USED TO SCREEN FOR THE PRESENCE OF TRANSPOSABLE ELEMENTS USING THE DFAM BROWSER, A SEARCH PROGRAM NURTURED WITH THE REPBASE REPETITIVE SEQUENCE DATABASE AND THE REPEATMASKER ANNOTATION TOOL. FINDINGS: UNEXPECTEDLY, PARTICULAR ASSOCIATIONS OF TRANSPOSABLE ELEMENTS AND ME/CFS EPIGENETIC HALLMARKS WERE UNCOVERED. A MODEL FOR THE DISEASE EMERGED INVOLVING TRANSCRIPTIONAL INDUCTION OF ENDOGENOUS DORMANT TRANSPOSONS AND STRUCTURED CELLULAR RNA INTERACTIONS, TRIGGERING THE ACTIVATION OF THE INNATE IMMUNE SYSTEM WITHOUT A CONCOMITANT ACTIVE INFECTION. IMPLICATIONS: REPETITIVE SEQUENCE FILTERS (IE, REPEATMASKER) SHOULD BE AVOIDED WHEN ANALYZING TRANSCRIPTOMIC DATA TO ASSESS THE POTENTIAL PARTICIPATION OF REPETITIVE SEQUENCES ("JUNK REPETITIVE DNA"), REPRESENTING >45% OF THE HUMAN GENOME, IN THE ONSET AND EVOLUTION OF ME/CFS. IN ADDITION, TRANSPOSABLE ELEMENT SCREENINGS AIMED AT DESIGNING COST-EFFECTIVE, FOCUSED EMPIRICAL ASSAYS THAT CAN CONFIRM OR DISPROVE THE SUSPECTED INVOLVEMENT OF TRANSPOSON TRANSCRIPTIONAL ACTIVATION IN THIS DISEASE, FOLLOWING THE PILOT STRATEGY PRESENTED HERE, WILL REQUIRE DATABASES GATHERING LARGE ME/CFS EPIGENETIC DATASETS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 6127  39 THE EPIGENETIC OVERLAP BETWEEN OBESITY AND MOOD DISORDERS: A SYSTEMATIC REVIEW. (1) BACKGROUND: OBESITY AND MOOD DISORDERS ARE CONSIDERED AS THE MOST PREVALENT MORBIDITIES IN MANY COUNTRIES. WE SUPPOSE THAT EPIGENETIC MECHANISMS MAY INDUCE HIGHER RATES OF OBESITY IN SUBJECTS WHO SUFFER FROM MOOD DISORDERS. IN THIS SYSTEMATIC REVIEW, WE FOCUSED ON THE POTENTIAL ROLES OF DNA METHYLATION ON MOOD DISORDERS AND OBESITY DEVELOPMENT. (2) METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED IN ACCORDANCE WITH THE PRISMA STATEMENT AND REGISTERED IN PROSPERO. A SYSTEMATIC SEARCH WAS CONDUCTED IN MEDLINE, SCOPUS, WEB OF SCIENCE, COCHRANE CENTRAL DATABASE, EMBASE, AND CINHAL. WE ALSO CONDUCTED A GREY LITERATURE SEARCH, SUCH AS GOOGLE SCHOLAR. (3) RESULTS: AFTER DEDUPLICATION, WE IDENTIFIED 198 POTENTIALLY RELATED CITATIONS. FINALLY, TEN UNIQUE STUDIES MET OUR INCLUSION CRITERIA. WE HAVE FOUND THREE OVERLAP GENES THAT SHOW SIGNIFICANT DNA METHYLATION CHANGES, BOTH IN OBESITY AND DEPRESSION. PATHWAY ANALYSIS INTERACTION FOR TAPBP, BDNF, AND SORBS2 CONFIRMED THE RELATION OF THESE GENES IN BOTH OBESITY AND MOOD DISORDERS. (4) CONCLUSIONS: WHILE MECHANISMS LINKING BOTH OBESITY AND MOOD DISORDERS TO EPIGENETIC RESPONSE ARE STILL UNKNOWN, WE HAVE ALREADY KNOWN CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM. AS THE RESULTS OF GENE ENRICHMENT, PATHWAYS ANALYSIS SHOWED THAT TAPBP, BDNF, AND SORBS2 LINKED TOGETHER BY INFLAMMATORY PATHWAYS. HYPERMETHYLATION IN THESE GENES MIGHT PLAY A CRUCIAL RULE IN THE CO-OCCURRENCE OF OBESITY AND MOOD DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 1517  40 DNA METHYLATION AS A MEDIATOR OF ASSOCIATIONS BETWEEN THE ENVIRONMENT AND CHRONIC DISEASES: A SCOPING REVIEW ON APPLICATION OF MEDIATION ANALYSIS. DNA METHYLATION (DNAM) IS ONE OF THE MOST STUDIED EPIGENETIC MODIFICATIONS. DNAM HAS EMERGED AS A KEY BIOLOGICAL MECHANISM AND BIOMARKERS TO TEST ASSOCIATIONS BETWEEN ENVIRONMENTAL EXPOSURE AND OUTCOMES IN EPIDEMIOLOGICAL STUDIES. ALTHOUGH PREVIOUS STUDIES HAVE FOCUSED ON ASSOCIATIONS BETWEEN DNAM AND EITHER EXPOSURE/OUTCOMES, IT IS USEFUL TO TEST FOR MEDIATION OF THE ASSOCIATION BETWEEN EXPOSURE AND OUTCOME BY DNAM. THE PURPOSE OF THIS SCOPING REVIEW IS TO INTRODUCE THE METHODOLOGICAL ESSENCE OF STATISTICAL MEDIATION ANALYSIS AND TO EXAMINE EMERGING EPIDEMIOLOGICAL RESEARCH APPLYING MEDIATION ANALYSES. WE CONDUCTED THIS SCOPING REVIEW FOR PUBLISHED PEER-REVIEWED JOURNALS ON THIS TOPIC USING ONLINE DATABASES (PUBMED, SCOPUS, COCHRANE, AND CINAHL) ENDING IN DECEMBER 2020. WE EXTRACTED A TOTAL OF 219 ARTICLES BY INITIAL SCREENING. AFTER REVIEWING TITLES, ABSTRACTS, AND FULL TEXTS, A TOTAL OF 69 ARTICLES WERE ELIGIBLE FOR THIS REVIEW. THE BREAKDOWN OF STUDIES ASSIGNED TO EACH CATEGORY WAS 13 FOR SMOKING (18.8%), 8 FOR DIETARY INTAKE AND FAMINE (11.6%), 6 FOR OTHER LIFESTYLE FACTORS (8.7%), 8 FOR CLINICAL ENDPOINTS (11.6%), 22 FOR ENVIRONMENTAL CHEMICAL EXPOSURES (31.9%), 2 FOR SOCIOECONOMIC STATUS (SES) (2.9%), AND 10 FOR GENETIC FACTORS AND RACE (14.5%). IN THIS REVIEW, WE PROVIDE AN EXPOSURE-WIDE SUMMARY FOR THE MEDIATION ANALYSIS USING DNAM LEVELS. HOWEVER, WE FOUND HETEROGENOUS METHODS AND INTERPRETATIONS IN MEDIATION ANALYSIS WITH TYPICAL ISSUES SUCH AS DIFFERENT CELL COMPOSITIONS AND TISSUE-SPECIFICITY. FURTHER ACCUMULATION OF EVIDENCE WITH DIVERSE EXPOSURES, POPULATIONS AND WITH RIGOROUS METHODOLOGY WILL BE EXPECTED TO PROVIDE FURTHER INSIGHT IN THE ROLE OF DNAM IN DISEASE SUSCEPTIBILITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 1601  50 DNA METHYLATION SIGNATURES OF FUNCTIONAL SOMATIC SYNDROMES: SYSTEMATIC REVIEW. OBJECTIVE: FUNCTIONAL SOMATIC SYNDROMES (FSS) ARE HIGHLY PREVALENT ACROSS ALL LEVELS OF HEALTHCARE. THE FACT THAT THEY ARE CHARACTERISED BY MEDICALLY UNEXPLAINED SYMPTOMS, SUCH AS FATIGUE AND PAIN, RAISES THE IMPORTANT QUESTION OF THEIR UNDERLYING PATHOPHYSIOLOGY. PSYCHOSOCIAL STRESS REPRESENTS A SIGNIFICANT FACTOR IN THE DEVELOPMENT OF FSS AND CAN INDUCE LONG-TERM MODIFICATIONS AT THE EPIGENETIC LEVEL. THE AIM OF THIS REVIEW WAS TO SYSTEMATICALLY REVIEW, FOR THE FIRST TIME, WHETHER INDIVIDUALS WITH FSS ARE CHARACTERISED BY SPECIFIC ALTERATIONS IN DNA METHYLATION. METHODS: MEDLINE AND PSYCINFO WERE SEARCHED FROM THE FIRST AVAILABLE DATE UNTIL SEPTEMBER 2022. THE INCLUSION CRITERIA WERE: 1) ADULTS FULFILLING RESEARCH DIAGNOSTIC CRITERIA FOR CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, AND/OR IRRITABLE BOWEL SYNDROME, 2) HEALTHY CONTROL GROUP, AND 3) CANDIDATE-GENE OR GENOME-WIDE STUDY OF DNA METHYLATION. RESULTS: SIXTEEN STUDIES (N = 957) WERE INCLUDED. IN CANDIDATE-GENE STUDIES, SPECIFIC SITES WITHIN NR3C1 WERE IDENTIFIED, WHICH WERE HYPOMETHYLATED IN INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME COMPARED TO HEALTHY CONTROLS. IN GENOME-WIDE STUDIES IN CHRONIC FATIGUE SYNDROME, A HYPOMETHYLATED SITE LOCATED TO LY86 AND HYPERMETHYLATED SITES WITHIN HLA-DQB1 WERE FOUND. IN GENOME-WIDE STUDIES IN FIBROMYALGIA SYNDROME, DIFFERENTIAL METHYLATION IN SITES RELATED TO HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , AND LY6G5C WAS FOUND. CONCLUSIONS: INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA SYNDROME APPEAR TO BE CHARACTERISED BY ALTERED DNA METHYLATION OF GENES REGULATING CELLULAR SIGNALLING AND IMMUNE FUNCTIONING. IN CHRONIC FATIGUE SYNDROME, THERE IS PRELIMINARY EVIDENCE FOR THESE TO BE IMPLICATED IN KEY PATHOPHYSIOLOGICAL ALTERATIONS, SUCH AS HYPOCORTISOLISM AND LOW-GRADE INFLAMMATION, AND TO CONTRIBUTE TO THE DEBILITATING SYMPTOMS THESE INDIVIDUALS EXPERIENCE.PREREGISTRATION PROSPERO IDENTIFIER: CRD42022364720.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10 6159  53 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 2108  37 EPIGENETIC FACTORS RELATED TO LOW BACK PAIN: A SYSTEMATIC REVIEW OF THE CURRENT LITERATURE. LOW BACK PAIN (LBP) IS ONE OF THE MOST COMMON CAUSES OF PAIN AND DISABILITY. AT PRESENT, TREATMENT AND INTERVENTIONS FOR ACUTE AND CHRONIC LOW BACK PAIN OFTEN FAIL TO PROVIDE SUFFICIENT LEVELS OF PAIN RELIEF, AND FULL FUNCTIONAL RESTORATION CAN BE CHALLENGING. CONSIDERING THE SIGNIFICANT SOCIO-ECONOMIC BURDEN AND RISK-TO-BENEFIT RATIO OF MEDICAL AND SURGICAL INTERVENTION IN LOW BACK PAIN PATIENTS, THE IDENTIFICATION OF RELIABLE BIOMARKERS SUCH AS EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN COULD BE USEFUL IN CLINICAL PRACTICE. THE AIM OF THIS STUDY WAS TO REVIEW THE AVAILABLE LITERATURE REGARDING THE EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN. THIS REVIEW WAS CARRIED OUT IN ACCORDANCE WITH PREFERENTIAL REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. THE SEARCH WAS CARRIED OUT IN OCTOBER 2022. ONLY PEER-REVIEWED ARTICLES WERE CONSIDERED FOR INCLUSION. FOURTEEN STUDIES WERE INCLUDED AND SHOWED PROMISING RESULTS IN TERMS OF RELIABLE MARKERS. EPIGENETIC MARKERS FOR LBP HAVE THE POTENTIAL TO SIGNIFICANTLY MODIFY DISEASE MANAGEMENT. MOST RECENT EVIDENCE SUGGESTS THAT EPIGENETICS IS A MORE PROMISING FIELD FOR THE IDENTIFICATION OF FACTORS ASSOCIATED WITH LBP, OFFERING A RATIONALE FOR FURTHER INVESTIGATION IN THIS FIELD WITH THE LONG-TERM GOAL OF FINDING EPIGENETIC BIOMARKERS THAT COULD CONSTITUTE BIOLOGICAL TARGETS FOR DISEASE MANAGEMENT AND TREATMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 4869  36 OSTEOARTHRITIS YEAR IN REVIEW: GENETICS, GENOMICS, EPIGENETICS. OBJECTIVE: IN THIS REVIEW, WE HAVE HIGHLIGHTED ADVANCES IN GENETICS, GENOMICS AND EPIGENETICS IN THE FIELD OF OSTEOARTHRITIS (OA) OVER THE PAST YEAR. METHODS: A LITERATURE SEARCH WAS PERFORMED USING PUBMED AND THE CRITERIA: "OSTEOARTHRITIS" AND ONE OF THE FOLLOWING TERMS "GENETIC(S), GENOMIC(S), EPIGENETIC(S), EPIGENOMIC(S), NONCODING RNA, MICRORNA, LONG NONCODING RNA, LNCRNA, CIRCULAR RNA, RNA SEQUENCING, SINGLE CELL SEQUENCING, OR DNA METHYLATION BETWEEN APRIL 1, 2019 AND APRIL 30, 2020. RESULTS: WE IDENTIFIED 653 UNIQUE PUBLICATIONS, MANY STUDIES SPANNED MULTIPLE SEARCH TERMS. WE SUMMARIZED ADVANCES RELATING TO EVOLUTIONARY GENETICS, PAIN, ETHNICITY SPECIFIC RISK FACTORS, FUNCTIONAL STUDIES OF GENE VARIANTS, AND INTERACTIONS BETWEEN CODING AND NON-CODING RNAS IN OA PATHOGENESIS. CONCLUSIONS: STUDIES HAVE IDENTIFIED VARIANTS CONTRIBUTING TO OA SUSCEPTIBILITY, CANDIDATE BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS, AS WELL AS PROMISING THERAPEUTIC CANDIDATES. VALIDATION IN MULTIPLE COHORTS, MULTI-OMICS STRATEGIES, AND MACHINE LEARNING AIDED COMPUTATIONAL ANALYSES HAVE ALL CONTRIBUTED TO THE STRENGTH OF PUBLISHED LITERATURE. OPEN ACCESS DATA-SETS, GREATER SAMPLE SIZES TO CAPTURE BROADER POPULATIONS AND UNDERSTANDING DISEASE MECHANISMS BY INVESTIGATING THE INTERACTIONS BETWEEN MULTIPLE TISSUE TYPES WILL FURTHER AID IN PROGRESS TOWARDS UNDERSTANDING AND CURING OA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 3041  37 GENOME-EPIGENOME INTERACTIONS ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE OF UNKNOWN ETIOLOGY. MULTIPLE STUDIES POINT TO DISRUPTIONS IN IMMUNE FUNCTIONING IN ME/CFS PATIENTS AS WELL AS SPECIFIC GENETIC POLYMORPHISMS AND ALTERATIONS OF THE DNA METHYLOME IN LYMPHOCYTES. HOWEVER, POTENTIAL INTERACTIONS BETWEEN DNA METHYLATION AND GENETIC BACKGROUND IN RELATION TO ME/CFS HAVE NOT BEEN EXAMINED. IN THIS STUDY WE EXPLORED THIS ASSOCIATION BY CHARACTERIZING THE EPIGENETIC (~480 THOUSAND CPG LOCI) AND GENETIC (~4.3 MILLION SNPS) VARIATION BETWEEN COHORTS OF ME/CFS PATIENTS AND HEALTHY CONTROLS. WE FOUND SIGNIFICANT ASSOCIATIONS OF DNA METHYLATION STATES IN T-LYMPHOCYTES AT SEVERAL CPG LOCI AND REGIONS WITH ME/CFS PHENOTYPE. THESE METHYLATION ANOMALIES ARE IN CLOSE PROXIMITY TO GENES INVOLVED WITH IMMUNE FUNCTION AND CELLULAR METABOLISM. FINALLY, WE FOUND SIGNIFICANT CORRELATIONS OF GENOTYPES WITH METHYLATION MODIFICATIONS ASSOCIATED WITH ME/CFS. THE FINDINGS FROM THIS STUDY HIGHLIGHT THE ROLE OF EPIGENETIC AND GENETIC INTERACTIONS IN COMPLEX DISEASES, AND SUGGEST SEVERAL GENETIC AND EPIGENETIC ELEMENTS POTENTIALLY INVOLVED IN THE MECHANISMS OF DISEASE IN ME/CFS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 2585  55 EPIGENETICS OF OBSTRUCTIVE SLEEP APNEA SYNDROME: A SYSTEMATIC REVIEW. STUDY OBJECTIVES: OBSTRUCTIVE SLEEP APNEA (OSA) IS A CHRONIC AND WIDELY PREVALENT DISEASE ASSOCIATED WITH MULTIPLE HEALTH DISORDERS. CURRENT DIAGNOSTIC STRATEGIES FOR OSA ARE LIMITED BECAUSE OF COST, TIME, AND ACCESS. EPIGENETIC SIGNATURES OFFER INSIGHT INTO THE RELATIONSHIPS BETWEEN DISEASE AND ENVIRONMENT AND COULD PLAY A SIGNIFICANT ROLE IN DEVELOPING BOTH DIAGNOSTIC AND THERAPEUTIC TOOLS FOR OSA. IN THE CURRENT STUDY, A SYSTEMATIC LITERATURE SEARCH WAS CONDUCTED TO INVESTIGATE THE EXISTING EVIDENCE OF OSA-ASSOCIATED EPIGENETIC MODIFICATIONS. METHODS: A SYSTEMATIC LITERATURE SEARCH WAS PERFORMED USING ELECTRONIC ACADEMIC DATABASES INCLUDING PUBMED, CINAHL, SCOPUS, EMBASE, EBM REVIEWS, AND WEB OF SCIENCE. HOWEVER, THE CURRENT STUDY FOCUSED ON SCREENING FOR ORIGINAL, ENGLISH-LANGUAGE ARTICLES PERTAINING TO OSA AND ASSOCIATED EPIGENETIC MECHANISMS. TO PRODUCE UNBIASED RESULTS, SCREENING WAS PERFORMED INDEPENDENTLY BY AUTHORS. RESULTS: WE IDENTIFIED 2,944 PUBLICATIONS IN OUR SYSTEMATIC SEARCH. AMONG THEM, 65 RESEARCH ARTICLES WERE RELATED TO OS A-ASSOCIATED DIFFERENTIAL GENE EXPRESSION, GENETIC VARIATION, AND EPIGENETIC MODIFICATIONS. ALTHOUGH THESE 65 ARTICLES WERE CONSIDERED FOR FULL MANUSCRIPT REVIEW, ONLY 12 ARTICLES MET THE CRITERIA OF OSA-ASSOCIATED EPIGENETIC MODIFICATIONS IN HUMAN AND ANIMAL MODELS. HUMAN PATIENTS WITH OSA HAD UNIQUE EPIGENETIC CHANGES COMPARED TO HEALTHY CONTROL PATIENTS AND, INTERESTINGLY, EPIGENETIC SIGNATURES WERE COMMONLY IDENTIFIED IN GENES ASSOCIATED WITH METABOLIC AND INFLAMMATORY PATHWAYS. CONCLUSIONS: ALTHOUGH THE AVAILABLE STUDIES ARE LIMITED, THIS RESEARCH PROVIDES NOVEL INSIGHTS FOR THE DEVELOPMENT OF EPIGENETIC MARKERS FOR THE DIAGNOSIS AND TREATMENT OF OSA. THOROUGH GENOME-WIDE INVESTIGATIONS WILL BE REQUIRED TO DEVELOP COST-EFFECTIVE, ROBUST BIOMARKERS FOR THE IDENTIFICATION OF OSA AMONG CHILDREN AND ADULTS. HERE, WE OFFER A STUDY DESIGN FOR SUCH EFFORTS. CITATION: LEADER BA, KORITALA BSC, MOORE CA, DEAN EG, KOTTYAN LC, SMITH DF. EPIGENETICS OF OBSTRUCTIVE SLEEP APNEA SYNDROME: A SYSTEMATIC REVIEW. J CLIN SLEEP MED. 2021;17(12):2533-2541.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15 4865  34 ORO-FACIAL PAIN AND TEMPOROMANDIBULAR DISORDERS CLASSIFICATION SYSTEMS: A CRITICAL APPRAISAL AND FUTURE DIRECTIONS. IT IS A DIFFICULT UNDERTAKING TO DESIGN A CLASSIFICATION SYSTEM FOR ANY DISEASE ENTITY, LET ALONE FOR ORO-FACIAL PAIN (OFP) AND MORE SPECIFICALLY FOR TEMPOROMANDIBULAR DISORDERS (TMD). A FURTHER COMPLICATION OF THIS TASK IS THAT BOTH PHYSICAL AND PSYCHOSOCIAL VARIABLES MUST BE INCLUDED. TO AUGMENT THIS PROCESS, A TWO-STEP SYSTEMATIC REVIEW, ADHERING TO PRISMA GUIDELINES, OF THE CLASSIFICATION SYSTEMS PUBLISHED DURING THE LAST 20 YEARS FOR OFP AND TMD WAS PERFORMED. THE FIRST SEARCH STEP IDENTIFIED 190 POTENTIAL CITATIONS WHICH ULTIMATELY RESULTED IN ONLY 17 ARTICLES BEING INCLUDED FOR IN-DEPTH ANALYSIS AND REVIEW. THE SECOND STEP RESULTED IN ONLY 5 ARTICLES BEING SELECTED FOR INCLUSION IN THIS REVIEW. FIVE ADDITIONAL ARTICLES AND FOUR CLASSIFICATION GUIDELINES/CRITERIA WERE ALSO INCLUDED DUE TO EXPANSION OF THE SEARCH CRITERIA. THUS, IN TOTAL, 14 DOCUMENTS COMPRISING ARTICLES AND GUIDELINES/CRITERIA (8 PROPOSALS OF CLASSIFICATION SYSTEMS FOR OFP; 6 FOR TMD) WERE SELECTED FOR INCLUSION IN THE SYSTEMATIC REVIEW. FOR EACH, A DISCUSSION AS TO THEIR ADVANTAGES, STRENGTHS AND LIMITATIONS WAS PROVIDED. SUGGESTIONS REGARDING THE FUTURE DIRECTION FOR IMPROVING THE CLASSIFICATION PROCESS WITH THE USE OF ONTOLOGICAL PRINCIPLES RATHER THAN TAXONOMY ARE DISCUSSED. FURTHERMORE, THE POTENTIAL FOR EXPANDING THE SCOPE OF AXES INCLUDED IN EXISTING CLASSIFICATION SYSTEMS, TO INCLUDE GENETIC, EPIGENETIC AND NEUROBIOLOGICAL VARIABLES, IS EXPLORED. IT IS THEREFORE RECOMMENDED THAT FUTURE CLASSIFICATION SYSTEM PROPOSALS BE BASED ON COMBINED APPROACHES AIMING TO PROVIDE ARCHETYPAL TREATMENT-ORIENTED CLASSIFICATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16 6678  42 USING GENETIC BURDEN SCORES FOR GENE-BY-METHYLATION INTERACTION ANALYSIS ON METABOLIC SYNDROME IN AFRICAN AMERICANS. WITH THE RAPID ADVANCEMENT OF OMICS-BASED RESEARCH, PARTICULARLY BIG DATA SUCH AS GENOME- AND EPIGENOME-WIDE ASSOCIATION STUDIES THAT INCLUDE EXTENSIVE ENVIRONMENTAL AND CLINICAL VARIABLES, DATA ANALYTICS HAVE BECOME INCREASINGLY COMPLEX. RESEARCHERS FACE SIGNIFICANT CHALLENGES REGARDING HOW TO ANALYZE MULTIFACTORIAL DATA AND MAKE USE OF THE FINDINGS FOR CLINICAL TRANSLATION. THE PURPOSE OF THIS ARTICLE IS TO PROVIDE A SCIENTIFIC EXEMPLAR FOR USE OF GENETIC BURDEN SCORES AS A DATA ANALYSIS METHOD FOR STUDIES WITH BOTH GENOTYPE AND DNA METHYLATION DATA IN WHICH THE GOAL IS TO EVALUATE ASSOCIATIONS WITH CHRONIC CONDITIONS SUCH AS METABOLIC SYNDROME (METS). THIS STUDY INCLUDED 739 AFRICAN AMERICAN MEN AND WOMEN FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY STUDY WHO MET DIAGNOSTIC CRITERIA FOR METS AND HAD AVAILABLE GENETIC AND EPIGENETIC DATA. GENETIC BURDEN SCORES FOR EVALUATED GENES WERE NOT SIGNIFICANT AFTER MULTIPLE TESTING CORRECTIONS, BUT DNA METHYLATION AT 2 CPG SITES (DIHYDROOROTATE DEHYDROGENASE CG22381196 PFDR = .014; CTNNA3 CG00132141 PFDR = .043) WAS SIGNIFICANTLY ASSOCIATED WITH METS AFTER CONTROLLING FOR MULTIPLE COMPARISONS. INTERACTIONS BETWEEN THE MARGINALLY SIGNIFICANT CPG SITES AND BURDEN SCORES, HOWEVER, WERE NOT SIGNIFICANT. MORE WORK IS REQUIRED IN THIS AREA TO IDENTIFY INTERMEDIATE BIOLOGICAL PATHWAYS INFLUENCED BY ENVIRONMENTAL, GENETIC, AND EPIGENETIC VARIATION THAT MAY EXPLAIN THE HIGH PREVALENCE OF METS AMONG AFRICAN AMERICANS. THIS STUDY DOES SERVE, HOWEVER, AS AN EXAMPLE OF THE USE OF THE GENETIC BURDEN SCORE AS AN ALTERNATIVE DATA ANALYSIS APPROACH FOR COMPLEX STUDIES INVOLVING THE ANALYSIS OF GENETIC AND EPIGENETIC DATA SIMULTANEOUSLY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17 1045  38 CLINICAL CORRELATION AMONG MALE INFERTILITY AND OVERALL MALE HEALTH: A SYSTEMATIC REVIEW OF THE LITERATURE. PURPOSE: ONGOING EVIDENCE HAS SUGGESTED THE ROLE OF MALE FACTOR INFERTILITY AS A POTENTIAL PREDICTOR OF MORTALITY AND GENERAL HEALTH STATUS. THE AIM OF THE PRESENT REVIEW IS TO UPDATE THE CURRENT KNOWLEDGE BASE REGARDING THE ASSOCIATION BETWEEN MALE FACTOR INFERTILITY AND GENERAL HEALTH THROUGH A CRITICAL REVIEW OF THE LITERATURE. MATERIALS AND METHODS: A SYSTEMATIC REVIEW OF THE LITERATURE WAS CARRIED OUT FROM INCEPTION TO NOVEMBER 2019 IN ORDER TO EVALUATE SIGNIFICANT ASSOCIATIONS BETWEEN MALE INFERTILITY AND ADVERSE HEALTH OUTCOMES SUCH AS CARDIOVASCULAR, ONCOLOGIC, METABOLIC AND AUTOIMMUNE DISEASES AS WELL AS OVERALL MORTALITY. RESULTS: IN ALL, 27 STUDIES MET INCLUSION CRITERIA AND WERE CRITICALLY EXAMINED. FIVE STUDIES EXAMINED MALE INFERTILITY AND CARDIOVASCULAR DISEASE RISK, 11 EXAMINED ONCOLOGIC RISK (E.G., OVERALL CANCER RISK, TESTIS AND PROSTATE CANCER), 8 EXAMINED AGGREGATE CHRONIC MEDICAL DISEASES AND 5 INFERTILITY RELATED TO INCIDENCE OF MORTALITY, FOR A TOTAL OF 599,807 MEN DIAGNOSED WITH ANY MALE FACTOR INFERTILITY COVERING A PERIOD FROM 1916 TO 2016. CONCLUSIONS: A MAN'S FERTILITY AND OVERALL HEALTH APPEAR TO BE INTERCONNECTED. THEREFORE, A DIAGNOSIS OF MALE INFERTILITY MAY ALLOW A WINDOW INTO FUTURE COMORBIDITY AND/OR MORTALITY WHICH MAY HELP GUIDE CLINICAL DECISIONS AND COUNSELING. SEVERAL POSSIBLE ETIOLOGIES SUCH AS GENETIC, EPIGENETIC, DEVELOPMENTAL, AND LIFESTYLE-BASED FACTORS NEED TO BE FURTHER EVALUATED IN ORDER TO ESTABLISH THE UNDERLYING MECHANISMS BETWEEN MALE INFERTILITY AND HEALTH.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18 3496  50 IDENTIFICATION OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME-ASSOCIATED DNA METHYLATION PATTERNS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX CONDITION INVOLVING MULTIPLE ORGAN SYSTEMS AND CHARACTERIZED BY PERSISTENT/RELAPSING DEBILITATING FATIGUE, IMMUNE DYSFUNCTION, NEUROLOGICAL PROBLEMS, AND OTHER SYMPTOMS NOT CURABLE FOR AT LEAST 6 MONTHS. DISRUPTION OF DNA METHYLATION PATTERNS HAS BEEN TIED TO VARIOUS IMMUNE AND NEUROLOGICAL DISEASES; HOWEVER, ITS STATUS IN ME/CFS REMAINS UNCERTAIN. OUR STUDY AIMED AT IDENTIFYING CHANGES IN THE DNA METHYLATION PATTERNS THAT ASSOCIATE WITH ME/CFS. METHODS: WE EXTRACTED GENOMIC DNA FROM PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 13 ME/CFS STUDY SUBJECTS AND 12 HEALTHY CONTROLS AND MEASURED GLOBAL DNA METHYLATION BY ELISA-LIKE METHOD AND SITE-SPECIFIC METHYLATION STATUS USING ILLUMINA METHYLATIONEPIC MICROARRAYS. PYROSEQUENCING VALIDATION INCLUDED 33 ME/CFS CASES AND 31 CONTROLS FROM TWO GEOGRAPHICALLY DISTANT COHORTS. RESULTS: GLOBAL DNA METHYLATION LEVELS OF ME/CFS CASES WERE SIMILAR TO THOSE OF CONTROLS. HOWEVER, MICROARRAY-BASED APPROACH ALLOWED DETECTION OF 17,296 DIFFERENTIALLY METHYLATED CPG SITES IN 6,368 GENES ACROSS REGULATORY ELEMENTS AND WITHIN CODING REGIONS OF GENES. ANALYSIS OF DNA METHYLATION IN PROMOTER REGIONS REVEALED 307 DIFFERENTIALLY METHYLATED PROMOTERS. INGENUITY PATHWAY ANALYSIS INDICATED THAT GENES ASSOCIATED WITH DIFFERENTIALLY METHYLATED PROMOTERS PARTICIPATED IN AT LEAST 15 DIFFERENT PATHWAYS MOSTLY RELATED TO CELL SIGNALING WITH A STRONG IMMUNE COMPONENT. CONCLUSIONS: THIS IS THE FIRST STUDY THAT HAS EXPLORED GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH ME/CFS USING THE ADVANCED ILLUMINA METHYLATIONEPIC MICROARRAYS COVERING ABOUT 850,000 CPG SITES IN TWO GEOGRAPHICALLY DISTANT COHORTS OF ME/CFS CASES AND MATCHED CONTROLS. OUR RESULTS ARE ALIGNED WITH PREVIOUS STUDIES THAT INDICATE A DYSREGULATION OF THE IMMUNE SYSTEM IN ME/CFS. THEY ALSO SUGGEST A POTENTIAL ROLE OF EPIGENETIC DE-REGULATION IN THE PATHOBIOLOGY OF ME/CFS. WE PROPOSE SCREENING OF LARGER COHORTS OF ME/CFS CASES TO DETERMINE THE EXTERNAL VALIDITY OF THESE EPIGENETIC CHANGES IN ORDER TO IMPLEMENT THEM AS POSSIBLE DIAGNOSTIC MARKERS IN CLINICAL SETTING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 2207  52 EPIGENETIC MODIFICATIONS AND GLUCOCORTICOID SENSITIVITY IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS). BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A DEBILITATING IDIOPATHIC DISEASE CHARACTERIZED BY UNEXPLAINED FATIGUE THAT FAILS TO RESOLVE WITH SUFFICIENT REST. DIAGNOSIS IS BASED ON A LIST OF SYMPTOMS AND EXCLUSION OF OTHER FATIGUE-RELATED HEALTH CONDITIONS. DESPITE A HETEROGENEOUS PATIENT POPULATION, IMMUNE AND HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS FUNCTION DIFFERENCES, SUCH AS ENHANCED NEGATIVE FEEDBACK TO GLUCOCORTICOIDS, ARE RECURRING FINDINGS IN ME/CFS STUDIES. EPIGENETIC MODIFICATIONS, SUCH AS CPG METHYLATION, ARE KNOWN TO REGULATE LONG-TERM PHENOTYPIC DIFFERENCES AND PREVIOUS WORK BY OUR GROUP FOUND DNA METHYLOME DIFFERENCES IN ME/CFS, HOWEVER THE RELATIONSHIP BETWEEN DNA METHYLOME MODIFICATIONS, CLINICAL AND FUNCTIONAL CHARACTERISTICS ASSOCIATED WITH ME/CFS HAS NOT BEEN EXAMINED. METHODS: WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF A LARGER COHORT OF FEMALE ME/CFS PATIENTS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY. IN PARALLEL TO THE DNA METHYLOME ANALYSIS, WE INVESTIGATED IN VITRO GLUCOCORTICOID SENSITIVITY DIFFERENCES BY STIMULATING PBMCS WITH PHYTOHAEMAGGLUTININ AND SUPPRESSED GROWTH WITH DEXAMETHASONE. WE EXPLORED DNA METHYLATION DIFFERENCES USING BISULFITE PYROSEQUENCING AND STATISTICAL PERMUTATION. LINEAR REGRESSION WAS IMPLEMENTED TO DISCOVER EPIGENOMIC REGIONS ASSOCIATED WITH SELF-REPORTED QUALITY OF LIFE AND NETWORK ANALYSIS OF GENE ONTOLOGY TERMS TO BIOLOGICALLY CONTEXTUALIZE RESULTS. RESULTS: WE DETECTED 12,608 DIFFERENTIALLY METHYLATED SITES BETWEEN ME/CFS PATIENTS AND HEALTHY CONTROLS PREDOMINANTLY LOCALIZED TO CELLULAR METABOLISM GENES, SOME OF WHICH WERE ALSO RELATED TO SELF-REPORTED QUALITY OF LIFE HEALTH SCORES. AMONG ME/CFS PATIENTS, GLUCOCORTICOID SENSITIVITY WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION AT 13 LOCI. CONCLUSIONS: OUR RESULTS INDICATE DNA METHYLATION MODIFICATIONS IN CELLULAR METABOLISM IN ME/CFS DESPITE A HETEROGENEOUS PATIENT POPULATION, IMPLICATING THESE PROCESSES IN IMMUNE AND HPA AXIS DYSFUNCTION IN ME/CFS. MODIFICATIONS TO EPIGENETIC LOCI ASSOCIATED WITH DIFFERENCES IN GLUCOCORTICOID SENSITIVITY MAY BE IMPORTANT AS BIOMARKERS FOR FUTURE CLINICAL TESTING. OVERALL, THESE FINDINGS ALIGN WITH RECENT ME/CFS WORK THAT POINT TOWARDS IMPAIRMENT IN CELLULAR ENERGY PRODUCTION IN THIS PATIENT POPULATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  667  61 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023