1  667 241 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	

2 1537  50 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3 2411  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4 2622  61 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5 6112  63 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  497  41 ASSOCIATION BETWEEN BMI AND DNA METHYLATION IN BLOOD OR NORMAL ADULT BREAST TISSUE: A SYSTEMATIC REVIEW. BACKGROUND/AIM: SEVERAL STUDIES HAVE INVESTIGATED THE INFLUENCE OF OBESITY ON DNA METHYLATION (DNAM) TO FIND BIOMARKERS ASSOCIATED WITH THE DETECTION OF CHRONIC DISEASES, INCLUDING BREAST CANCER. THE AIM OF THE STUDY WAS TO SYSTEMATICALLY REVIEW STUDIES EXAMINING THE ASSOCIATION OF BODY MASS INDEX (BMI) AND DNAM IN BLOOD OR NORMAL BREAST TISSUE. MATERIALS AND METHODS: THREE SCIENTIFIC LITERATURE DATABASES (PUBMED, EMBASE AND WEB OF SCIENCE) WERE SCREENED UNTIL MAY 2018. RESULTS: TWENTY-FOUR STUDIES WERE INCLUDED ALONG WITH OURS IN WHICH WE INVESTIGATED THIS RELATION IN THE NORMAL BREAST TISSUE OF 40 BREAST CANCER PATIENTS. CONCLUSION: BMI-ASSOCIATED CPG SITES WERE HIGHLY VARIABLE WITH FEW IDENTIFIED IN LESS THAN HALF OF THE STUDIES. NEVERTHELESS, A FEW GENES POTENTIALLY ASSOCIATED WITH BMI WERE HIGHLIGHTED IN BLOOD (CPT1A, ABCG1, SREBF1 AND LGALS3BP) AND IN NORMAL BREAST TISSUE (PTPRN2 AND ABLIM2). THE VARIABILITY OF THE RESULTS COULD BE EXPLAINED BY THE TISSUE AND CELL-SPECIFICITY OF METHYLATION AND DIFFERENCES IN METHODOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7 3652  45 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8 6311  38 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 1519  38 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10 5882  58 SYSTEMATIC REVIEW OF LUNG FUNCTION AND COPD WITH PERIPHERAL BLOOD DNA METHYLATION IN POPULATION BASED STUDIES. BACKGROUND: EPIGENETIC VARIATIONS IN PERIPHERAL BLOOD HAVE POTENTIAL AS BIOMARKERS FOR DISEASE. THIS SYSTEMATIC REVIEW ASSESSES THE ASSOCIATION OF LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WITH DNA METHYLATION PROFILES IN PERIPHERAL BLOOD FROM POPULATION-BASED STUDIES. METHODS: ONLINE DATABASES MEDLINE, EMBASE, AND WEB OF SCIENCE WERE SEARCHED. GOOGLE SCHOLAR WAS SEARCHED TO IDENTIFY GREY LITERATURE. AFTER REMOVING DUPLICATE ARTICLES, 1155 ARTICLES WERE INDEPENDENTLY SCREENED BY TWO INVESTIGATORS. PEER REVIEWED REPORTS ON POPULATION-BASED STUDIES THAT EXAMINED PERIPHERAL BLOOD DNA METHYLATION IN PARTICIPANTS WITH MEASURED LUNG FUNCTION (FEV1, FEV1/FVC RATIO) OR KNOWN COPD STATUS WERE SELECTED FOR FULL-TEXT REVIEW. SIX ARTICLES WERE SUITABLE FOR INCLUSION. INFORMATION REGARDING STUDY CHARACTERISTICS, DESIGNS, METHODOLOGIES AND CONCLUSIONS WAS EXTRACTED. A NARRATIVE SYNTHESIS WAS PERFORMED BASED ON PUBLISHED RESULTS. RESULTS: THREE OF THE SIX ARTICLES ASSESSED THE ASSOCIATION OF COPD WITH DNA METHYLATION, AND TWO OF THESE ALSO INCLUDED ASSOCIATIONS WITH LUNG FUNCTION. OVERALL, FIVE REPORTS EXAMINED THE ASSOCIATION OF LUNG FUNCTION WITH DNA METHYLATION PROFILES. FIVE OF THE SIX ARTICLES REPORTED 'SIGNIFICANT' RESULTS. HOWEVER, NO CONSISTENT CPG SITES WERE IDENTIFIED ACROSS STUDIES FOR COPD STATUS OR LUNG FUNCTION VALUES. CONCLUSIONS: DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD FROM INDIVIDUALS WITH REDUCED LUNG FUNCTION OR COPD MAY BE DIFFERENT TO THOSE IN PEOPLE WITH NORMAL LUNG FUNCTION. HOWEVER, THIS SYSTEMATIC REVIEW DID NOT FIND ANY CONSISTENT ASSOCIATIONS OF LUNG FUNCTION OR COPD WITH DIFFERENTIALLY METHYLATED CPG SITES. LARGE STUDIES WITH A LONGITUDINAL DESIGN TO ADDRESS REVERSE CAUSALITY MAY PROVE A MORE FRUITFUL AREA OF RESEARCH. TRIAL REGISTRATION: PROSPERO 2016: CRD42016037352 .	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11 1345  37 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12 2079  43 EPIGENETIC DNA METHYLATION CHANGES ASSOCIATED WITH HEADACHE CHRONIFICATION: A RETROSPECTIVE CASE-CONTROL STUDY. BACKGROUND THE BIOLOGICAL MECHANISMS OF HEADACHE CHRONIFICATION ARE POORLY UNDERSTOOD. WE AIMED TO IDENTIFY CHANGES IN DNA METHYLATION ASSOCIATED WITH THE TRANSFORMATION FROM EPISODIC TO CHRONIC HEADACHE. METHODS PARTICIPANTS WERE RECRUITED FROM THE POPULATION-BASED NORWEGIAN HUNT STUDY. THIRTY-SIX FEMALE HEADACHE PATIENTS WHO TRANSFORMED FROM EPISODIC TO CHRONIC HEADACHE BETWEEN BASELINE AND FOLLOW-UP 11 YEARS LATER WERE MATCHED AGAINST 35 CONTROLS WITH EPISODIC HEADACHE. DNA METHYLATION WAS QUANTIFIED AT 485,000 CPG SITES, AND CHANGES IN METHYLATION LEVEL AT THESE SITES WERE COMPARED BETWEEN CASES AND CONTROLS BY LINEAR REGRESSION ANALYSIS. DATA WERE ANALYZED IN TWO STAGES (STAGES 1 AND 2) AND IN A COMBINED META-ANALYSIS. RESULTS NONE OF THE TOP 20 CPG SITES IDENTIFIED IN STAGE 1 REPLICATED IN STAGE 2 AFTER MULTIPLE TESTING CORRECTION. IN THE COMBINED META-ANALYSIS THE STRONGEST ASSOCIATED CPG SITES WERE RELATED TO SH2D5 AND NPTX2, TWO BRAIN-EXPRESSED GENES INVOLVED IN THE REGULATION OF SYNAPTIC PLASTICITY. FUNCTIONAL ENRICHMENT ANALYSIS POINTED TO PROCESSES INCLUDING CALCIUM ION BINDING AND ESTROGEN RECEPTOR PATHWAYS. CONCLUSION IN THIS FIRST GENOME-WIDE STUDY OF DNA METHYLATION IN HEADACHE CHRONIFICATION SEVERAL POTENTIALLY IMPLICATED LOCI AND PROCESSES WERE IDENTIFIED. THE STUDY EXEMPLIFIES THE USE OF PROSPECTIVELY COLLECTED POPULATION COHORTS TO SEARCH FOR EPIGENETIC MECHANISMS OF DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  381  46 AN EPIGENOME-WIDE ASSOCIATION STUDY OF EARLY-ONSET MAJOR DEPRESSION IN MONOZYGOTIC TWINS. MAJOR DEPRESSION (MD) IS A DEBILITATING MENTAL HEALTH CONDITION WITH PEAK PREVALENCE OCCURRING EARLY IN LIFE. GENOME-WIDE EXAMINATION OF DNA METHYLATION (DNAM) OFFERS AN ATTRACTIVE COMPLEMENT TO STUDIES OF ALLELIC RISK GIVEN IT CAN REFLECT THE COMBINED INFLUENCE OF GENES AND ENVIRONMENT. THE CURRENT STUDY USED MONOZYGOTIC TWINS TO IDENTIFY DIFFERENTIALLY AND VARIABLY METHYLATED REGIONS OF THE GENOME THAT DISTINGUISH TWINS WITH AND WITHOUT A LIFETIME HISTORY OF EARLY-ONSET MD. THE SAMPLE INCLUDED 150 CAUCASIAN MONOZYGOTIC TWINS BETWEEN THE AGES OF 15 AND 20 (73% FEMALE; MAGE = 17.52 SD = 1.28) WHO WERE ASSESSED DURING A DEVELOPMENTAL STAGE CHARACTERIZED BY RELATIVELY DISTINCT NEUROPHYSIOLOGICAL CHANGES. ALL TWINS WERE GENERALLY HEALTHY AND CURRENTLY FREE OF MEDICATIONS WITH PSYCHOTROPIC EFFECTS. DNAM WAS MEASURED IN PERIPHERAL BLOOD CELLS USING THE INFINIUM HUMAN BEADCHIP 450 K ARRAY. MD ASSOCIATIONS WITH EARLY-ONSET MD WERE DETECTED AT 760 DIFFERENTIALLY AND VARIABLY METHYLATED PROBES/REGIONS THAT MAPPED TO 428 GENES. GENES AND GENOMIC REGIONS INVOLVED NEURAL CIRCUITRY FORMATION, PROJECTION, FUNCTIONING, AND PLASTICITY. GENE ENRICHMENT ANALYSES IMPLICATED GENES RELATED TO NEURON STRUCTURES AND NEURODEVELOPMENTAL PROCESSES INCLUDING CELL-CELL ADHESION GENES (E.G., PCDHA GENES). GENES PREVIOUSLY IMPLICATED IN MOOD AND PSYCHIATRIC DISORDERS AS WELL AS CHRONIC STRESS (E.G., NRG3) ALSO WERE IDENTIFIED. DNAM REGIONS ASSOCIATED WITH EARLY-ONSET MD WERE FOUND TO OVERLAP GENETIC LOCI IDENTIFIED IN THE LATEST PSYCHIATRIC GENOMICS CONSORTIUM META-ANALYSIS OF DEPRESSION. UNDERSTANDING THE TIME COURSE OF EPIGENETIC INFLUENCES DURING EMERGING ADULTHOOD MAY CLARIFY DEVELOPMENTAL PHASES WHERE CHANGES IN THE DNA METHYLOME MAY MODULATE INDIVIDUAL DIFFERENCES IN MD RISK.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14 6761  48 X CHROMOSOME-WIDE ANALYSIS IDENTIFIES DNA METHYLATION SITES INFLUENCED BY CIGARETTE SMOKING. BACKGROUND: TOBACCO SMOKING IS A MAJOR CAUSE OF CHRONIC DISEASE WORLDWIDE. SMOKING MAY INDUCE CELLULAR AND MOLECULAR CHANGES INCLUDING EPIGENETIC MODIFICATION, WITH BOTH SHORT-TERM AND LONG-TERM MODIFICATION PATTERNS THAT MAY CONTRIBUTE TO PHENOTYPIC EXPRESSION OF DISEASES. RECENT EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED DOZENS OF SMOKING-RELATED DNA METHYLATION (DNAM) SITES. HOWEVER, THE X CHROMOSOMAL DNAM SITES HAVE BEEN LARGELY OVERLOOKED DUE TO A LACK OF AN ANALYTICAL FRAMEWORK FOR DEALING WITH THE SEX-DIMORPHIC DISTRIBUTION. TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES ON THE X CHROMOSOME, WE EXAMINED THE MODALITY OF EACH X CHROMOSOMAL DNAM SITE AND CONDUCTED A SEX-SPECIFIC ASSOCIATION STUDY OF CIGARETTE SMOKING. RESULTS: WE USED A DISCOVERY SAMPLE OF 139 MIDDLE-AGE TWINS, AND THREE REPLICATION SAMPLES OF 78 TWINS, 464 AND 333 UNRELATED INDIVIDUALS INCLUDING 47, 17, 22, AND 89 CURRENT SMOKERS, RESPECTIVELY. AFTER CORRECTION FOR MULTIPLE TESTING, THE TOP SMOKING-RELATED DNAM SITES IN BCOR AND TSC22D3 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, AMONG CURRENT SMOKERS. THESE SMOKING-ASSOCIATED SITES WERE REPLICATED WITH META-ANALYSIS P-VALUES OF 9.17 X 10(-12) AND 1.61 X 10(-9). FOR BOTH SITES, THE SMOKING EFFECTS ON METHYLATION LEVELS WERE LARGER IN MALES THAN THAT IN FEMALES. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING X CHROMOSOME METHYLATION PATTERNS AND THEIR ASSOCIATIONS WITH ENVIRONMENTAL EXPOSURES AND DISEASE PHENOTYPES AND DEMONSTRATE A ROBUST STATISTICAL METHODOLOGY FOR SUCH STUDY. EXISTING EWAS OF HUMAN DISEASES SHOULD INCORPORATE THE X CHROMOSOMAL SITES TO COMPLETE A COMPREHENSIVE EPIGENOME-WIDE SCAN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 5748  50 SOCIAL AND PHYSICAL ENVIRONMENTS EARLY IN DEVELOPMENT PREDICT DNA METHYLATION OF INFLAMMATORY GENES IN YOUNG ADULTHOOD. CHRONIC INFLAMMATION CONTRIBUTES TO A WIDE RANGE OF HUMAN DISEASES, AND ENVIRONMENTS IN INFANCY AND CHILDHOOD ARE IMPORTANT DETERMINANTS OF INFLAMMATORY PHENOTYPES. THE UNDERLYING BIOLOGICAL MECHANISMS CONNECTING EARLY ENVIRONMENTS WITH THE REGULATION OF INFLAMMATION IN ADULTHOOD ARE NOT KNOWN, BUT EPIGENETIC PROCESSES ARE PLAUSIBLE CANDIDATES. WE TESTED THE HYPOTHESIS THAT PATTERNS OF DNA METHYLATION (DNAM) IN INFLAMMATORY GENES IN YOUNG ADULTHOOD WOULD BE PREDICTED BY EARLY LIFE NUTRITIONAL, MICROBIAL, AND PSYCHOSOCIAL EXPOSURES PREVIOUSLY ASSOCIATED WITH LEVELS OF INFLAMMATION. DATA COME FROM A POPULATION-BASED LONGITUDINAL BIRTH COHORT STUDY IN METROPOLITAN CEBU, THE PHILIPPINES, AND DNAM WAS CHARACTERIZED IN WHOLE BLOOD SAMPLES FROM 494 PARTICIPANTS (AGE 20-22 Y). ANALYSES FOCUSED ON PROBES IN 114 TARGET GENES INVOLVED IN THE REGULATION OF INFLAMMATION, AND WE IDENTIFIED 10 SITES ACROSS NINE GENES WHERE THE LEVEL OF DNAM WAS SIGNIFICANTLY PREDICTED BY THE FOLLOWING VARIABLES: HOUSEHOLD SOCIOECONOMIC STATUS IN CHILDHOOD, EXTENDED ABSENCE OF A PARENT IN CHILDHOOD, EXPOSURE TO ANIMAL FECES IN INFANCY, BIRTH IN THE DRY SEASON, OR DURATION OF EXCLUSIVE BREASTFEEDING. TO EVALUATE THE BIOLOGICAL SIGNIFICANCE OF THESE SITES, WE TESTED FOR ASSOCIATIONS WITH A PANEL OF INFLAMMATORY BIOMARKERS MEASURED IN PLASMA OBTAINED AT THE SAME AGE AS DNAM ASSESSMENT. THREE SITES PREDICTED ELEVATED INFLAMMATION, AND ONE SITE PREDICTED LOWER INFLAMMATION, CONSISTENT WITH THE INTERPRETATION THAT LEVELS OF DNAM AT THESE SITES ARE FUNCTIONALLY RELEVANT. THIS PATTERN OF RESULTS POINTS TOWARD DNAM AS A POTENTIALLY IMPORTANT BIOLOGICAL MECHANISM THROUGH WHICH DEVELOPMENTAL ENVIRONMENTS SHAPE INFLAMMATORY PHENOTYPES ACROSS THE LIFE COURSE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16 1585  42 DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC DIFFERENCES BETWEEN DIABETES PATIENTS WITH ESRD AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED POTENTIAL EPIGENETIC BIOMARKERS FOR CHRONIC KIDNEY DISEASE PROGRESSION BY COMPARING SITE-SPECIFIC DNA METHYLATION LEVELS IN MORE THAN 14,000 GENES BETWEEN AFRICAN AMERICAN AND HISPANIC DIABETES PATIENTS WITH END STAGE RENAL DISEASE (ESRD) AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED 187 GENES THAT ARE DIFFERENTIALLY METHYLATED BETWEEN THE TWO GROUPS ON AT LEAST TWO CPG SITES IN EACH GENE IN DNA EXTRACTED FROM SALIVA. OF THE 187 GENES WHOSE MEAN METHYLATION LEVELS DIFFERED BETWEEN THE TWO GROUPS, 39 GENES, OR CLOSELY RELATED GENE FAMILY MEMBERS, HAVE BEEN REPORTED TO BE INVOLVED IN KIDNEY DEVELOPMENT OR DIABETIC NEPHROPATHY, PER SE, OR HAVE BEEN ASSOCIATED WITH DIALYSIS-INDUCED CHANGES IN GENE EXPRESSION IN PERIPHERAL BLOOD CELLS. THE FACT THAT SUCH A SUBSTANTIAL FRACTION (21%) OF THE 187 CANDIDATE GENES HAVE BEEN IMPLICATED PREVIOUSLY THROUGH GENOME ASSOCIATION OR TRANSCRIPTION PROFILING STUDIES SUGGESTS STRONGLY THAT THE DNA METHYLATION DIFFERENCES WE OBSERVE ARE ASSOCIATED WITH DISEASE PREDISPOSITION AND/OR TREATMENT. THE FACT THAT THESE NEPHROPATHY AND/OR DIALYSIS-ASSOCIATED DIFFERENCES BETWEEN PATIENTS WERE IDENTIFIED IN DNA EXTRACTED FROM SALIVA OFFERS PROOF-OF-PRINCIPLE THAT INTER-INDIVIDUAL EPIGENETIC DIFFERENCES MAY PROVE USEFUL AS PREDICTIVE BIOMARKERS OF DISEASE SUSCEPTIBILITY.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17 3914  47 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  816  42 CHARACTERISATION OF AN INFLAMMATION-RELATED EPIGENETIC SCORE AND ITS ASSOCIATION WITH COGNITIVE ABILITY. BACKGROUND: CHRONIC SYSTEMIC INFLAMMATION HAS BEEN ASSOCIATED WITH INCIDENT DEMENTIA, BUT ITS ASSOCIATION WITH AGE-RELATED COGNITIVE DECLINE IS LESS CLEAR. THE ACUTE RESPONSES OF MANY INFLAMMATORY BIOMARKERS MEAN THEY MAY PROVIDE AN UNRELIABLE PICTURE OF THE CHRONICITY OF INFLAMMATION. RECENTLY, A LARGE-SCALE EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIED DNA METHYLATION CORRELATES OF C-REACTIVE PROTEIN (CRP)-A WIDELY USED ACUTE-PHASE INFLAMMATORY BIOMARKER. DNA METHYLATION IS THOUGHT TO BE RELATIVELY STABLE IN THE SHORT TERM, MARKING IT AS A POTENTIALLY USEFUL SIGNATURE OF EXPOSURE. METHODS: WE UTILISE A DNA METHYLATION-BASED SCORE FOR CRP AND INVESTIGATE ITS TRAJECTORIES WITH AGE, AND ASSOCIATIONS WITH COGNITIVE ABILITY IN COMPARISON WITH SERUM CRP AND A GENETIC CRP SCORE IN A LONGITUDINAL STUDY OF OLDER ADULTS (N = 889) AND A LARGE, CROSS-SECTIONAL COHORT (N = 7028). RESULTS: WE IDENTIFIED NO HOMOGENEOUS TRAJECTORIES OF SERUM CRP WITH AGE ACROSS THE COHORTS, WHEREAS THE EPIGENETIC CRP SCORE WAS CONSISTENTLY FOUND TO INCREASE WITH AGE (STANDARDISED BETA = 0.07 AND 0.01) AND TO DO SO MORE RAPIDLY IN MALES COMPARED TO FEMALES. ADDITIONALLY, THE EPIGENETIC CRP SCORE HAD HIGHER TEST-RETEST RELIABILITY COMPARED TO SERUM CRP, INDICATING ITS ENHANCED TEMPORAL STABILITY. HIGHER SERUM CRP WAS NOT FOUND TO BE ASSOCIATED WITH POORER COGNITIVE ABILITY (STANDARDISED BETA = - 0.08 AND - 0.05); HOWEVER, A CONSISTENT NEGATIVE ASSOCIATION WAS IDENTIFIED BETWEEN COGNITIVE ABILITY AND THE EPIGENETIC CRP SCORE IN BOTH COHORTS (STANDARDISED BETA = - 0.15 AND - 0.08). CONCLUSIONS: AN EPIGENETIC PROXY OF CRP MAY PROVIDE A MORE RELIABLE SIGNATURE OF CHRONIC INFLAMMATION, ALLOWING FOR MORE ACCURATE STRATIFICATION OF INDIVIDUALS, AND THUS CLEARER INFERENCE OF ASSOCIATIONS WITH INCIDENT HEALTH OUTCOMES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  178  43 ACCELERATED EPIGENETIC AGING AS A RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND DECREASED LUNG FUNCTION IN TWO PROSPECTIVE COHORT STUDIES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A FREQUENT DIAGNOSIS IN OLDER INDIVIDUALS AND CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY. GIVEN THE LINK BETWEEN LUNG DISEASE AND AGING, WE NEED TO UNDERSTAND HOW MOLECULAR INDICATORS OF AGING RELATE TO LUNG FUNCTION AND DISEASE. USING DATA FROM THE POPULATION-BASED KORA (COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG) SURVEYS, WE ASSOCIATED BASELINE EPIGENETIC (DNA METHYLATION) AGE ACCELERATION WITH INCIDENT COPD AND LUNG FUNCTION. MODELS WERE ADJUSTED FOR AGE, SEX, SMOKING, HEIGHT, WEIGHT, AND BASELINE LUNG DISEASE AS APPROPRIATE. ASSOCIATIONS WERE REPLICATED IN THE NORMATIVE AGING STUDY. OF 770 KORA PARTICIPANTS, 131 DEVELOPED INCIDENT COPD OVER 7 YEARS. BASELINE ACCELERATED EPIGENETIC AGING WAS SIGNIFICANTLY ASSOCIATED WITH INCIDENT COPD. THE CHANGE IN AGE ACCELERATION (FOLLOW-UP - BASELINE) WAS MORE STRONGLY ASSOCIATED WITH COPD THAN BASELINE AGING ALONE. THE ASSOCIATION BETWEEN THE CHANGE IN AGE ACCELERATION BETWEEN BASELINE AND FOLLOW-UP AND INCIDENT COPD REPLICATED IN THE NORMATIVE AGING STUDY. ASSOCIATIONS WITH SPIROMETRIC LUNG FUNCTION PARAMETERS WERE WEAKER THAN THOSE WITH COPD, BUT A META-ANALYSIS OF BOTH COHORTS PROVIDE SUGGESTIVE EVIDENCE OF ASSOCIATIONS. ACCELERATED EPIGENETIC AGING, BOTH BASELINE MEASURES AND CHANGES OVER TIME, MAY BE A RISK FACTOR FOR COPD AND REDUCED LUNG FUNCTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20 6083  45 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014