1 5882 137 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2 2622  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3 6112  52 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  497  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5 2093  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  642  45 BIOMARKERS OF PARTICULATE MATTER EXPOSURE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A SYSTEMATIC REVIEW. BACKGROUND: IN RECENT YEARS, AMBIENT PARTICULATE MATTER (PM) EXPOSURE HAS BEEN STRONGLY LINKED WITH HEALTH EFFECTS. ELEVATED LEVELS OF PM IN POLLUTED AIR HAVE BEEN CORRELATED WITH THE ONSET AND DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS SYSTEMATIC REVIEW WAS CONDUCTED TO EVALUATE BIOMARKERS THAT COULD REFLECT THE EFFECTS OF PM EXPOSURE IN PATIENTS WITH COPD. METHODS: WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES PUBLISHED ON BIOMARKERS ASSOCIATED WITH PM EXPOSURE IN PATIENTS WITH COPD BETWEEN JANUARY 01, 2012 AND JUNE 30, 2022 IN PUBMED/MEDLINE, EMBASE, AND COCHRANE DATABASES. STUDIES THAT INCLUDED DATA ON BIOMARKERS WITH COPD EXPOSED PM WERE ELIGIBLE FOR INCLUSION. BIOMARKERS WERE CLASSIFIED INTO 4 GROUPS ACCORDING TO THEIR MECHANISMS. RESULTS: OF THE 105 STUDIES IDENTIFIED, 22 WERE INCLUDED IN THIS STUDY. NEARLY 50 BIOMARKERS HAVE BEEN PROPOSED IN THE STUDIES INCLUDED IN THIS REVIEW, AND THE MOST STUDIED IN RELATION TO PM ARE SEVERAL INTERLEUKINS. VARIOUS MECHANISMS HAVE BEEN REPORTED BY WHICH PM INDUCES AND AGGRAVATES COPD. SIX STUDIES RELATED TO OXIDATIVE STRESS, ONE RELATED TO DIRECT EFFECT OF INNATE AND ADAPTIVE IMMUNE SYSTEMS, 16 ASSOCIATED WITH GENETIC REGULATION OF INFLAMMATION, AND TWO RELATED TO EPIGENETIC REGULATION OF PHYSIOLOGY AND SUSCEPTIBILITY WERE FOUND. BIOMARKERS RELATED TO THESE MECHANISMS WERE DETECTED IN SERUM, SPUTUM, URINE, EXHALED BREATH CONCENTRATION (EBC), AND SHOWED VARIOUS CORRELATIONS WITH PM IN COPD. CONCLUSIONS: VARIOUS BIOMARKERS HAVE SHOWN POTENTIAL IN PREDICTING THE EXTENT OF PM EXPOSURE IN COPD PATIENTS. FUTURE STUDIES ARE NEEDED TO ESTABLISH RECOMMENDATIONS FOR REGULATION TO REDUCE AIRBORNE PM, WHICH COULD BE USED TO DEVELOP STRATEGIES FOR PREVENTION AND MANAGEMENT OF ENVIRONMENTAL RESPIRATORY DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7 6311  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8   70  32 A METHOD TO DETECT DIFFERENTIALLY METHYLATED LOCI WITH NEXT-GENERATION SEQUENCING. EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION AT CPG LOCI HAVE IMPORTANT IMPLICATIONS IN CANCER AND OTHER COMPLEX DISEASES. WITH THE DEVELOPMENT OF NEXT-GENERATION SEQUENCING (NGS), IT IS FEASIBLE TO GENERATE DATA TO INTERROGATE THE DIFFERENCE IN METHYLATION STATUS FOR GENOME-WIDE LOCI USING CASE-CONTROL DESIGN. HOWEVER, A PROPER AND EFFICIENT STATISTICAL TEST IS LACKING. THERE ARE SEVERAL CHALLENGES. FIRST, UNLIKE METHYLATION EXPERIMENTS USING MICROARRAYS, WHERE THERE IS ONE MEASURE OF METHYLATION FOR ONE INDIVIDUAL AT A PARTICULAR CPG SITE, HERE WE HAVE THE COUNTS OF METHYLATION ALLELE AND UNMETHYLATION ALLELE FOR EACH INDIVIDUAL. SECOND, DUE TO THE NATURE OF SAMPLE PREPARATION, THE MEASURED METHYLATION REFLECTS THE METHYLATION STATUS OF A MIXTURE OF CELLS INVOLVED IN SAMPLE PREPARATION. THEREFORE, THE UNDERLYING DISTRIBUTION OF THE MEASURED METHYLATION LEVEL IS UNKNOWN, AND A ROBUST TEST IS MORE DESIRABLE THAN PARAMETRIC APPROACH. THIRD, CURRENTLY NGS MEASURES METHYLATION AT OVER 2 MILLION CPG SITES. ANY STATISTICAL TESTS HAVE TO BE COMPUTATIONALLY EFFICIENT IN ORDER TO BE APPLIED TO THE NGS DATA. TAKING THESE CHALLENGES INTO ACCOUNT, WE PROPOSE A TEST FOR DIFFERENTIAL METHYLATION BASED ON CLUSTERED DATA ANALYSIS BY MODELING THE METHYLATION COUNTS. WE PERFORMED SIMULATIONS TO SHOW THAT IT IS ROBUST UNDER SEVERAL DISTRIBUTIONS FOR THE MEASURED METHYLATION LEVELS. IT HAS GOOD POWER AND IS COMPUTATIONALLY EFFICIENT. FINALLY, WE APPLY THE TEST TO OUR NGS DATA ON CHRONIC LYMPHOCYTIC LEUKEMIA. THE RESULTS INDICATE THAT IT IS A PROMISING AND PRACTICAL TEST.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 1705  41 DYNAMICS OF SMOKING-INDUCED GENOME-WIDE METHYLATION CHANGES WITH TIME SINCE SMOKING CESSATION. SEVERAL STUDIES HAVE RECENTLY IDENTIFIED STRONG EPIGENETIC SIGNALS RELATED TO TOBACCO SMOKING. HOWEVER, AN ASPECT THAT DID NOT RECEIVE MUCH ATTENTION IS THE EVOLUTION OF EPIGENETIC CHANGES WITH TIME SINCE SMOKING CESSATION. WE CONDUCTED A SERIES OF EPIGENOME-WIDE ASSOCIATION STUDIES TO CAPTURE THE DYNAMICS OF SMOKING-INDUCED EPIGENETIC CHANGES AFTER SMOKING CESSATION, USING GENOME-WIDE METHYLATION PROFILES OBTAINED FROM BLOOD SAMPLES IN 745 WOMEN FROM 2 EUROPEAN POPULATIONS. TWO DISTINCT CLASSES OF CPG SITES WERE IDENTIFIED: SITES WHOSE METHYLATION REVERTS TO LEVELS TYPICAL OF NEVER SMOKERS WITHIN DECADES AFTER SMOKING CESSATION, AND SITES REMAINING DIFFERENTIALLY METHYLATED, EVEN MORE THAN 35 YEARS AFTER SMOKING CESSATION. OUR RESULTS SUGGEST THAT THE DYNAMICS OF METHYLATION CHANGES FOLLOWING SMOKING CESSATION ARE DRIVEN BY A DIFFERENTIAL AND SITE-SPECIFIC MAGNITUDE OF THE SMOKING-INDUCED ALTERATIONS (WITH PERSISTENT SITES BEING MOST AFFECTED) IRRESPECTIVE OF THE INTENSITY AND DURATION OF SMOKING. ANALYSES OF THE LINK BETWEEN METHYLATION AND EXPRESSION LEVELS REVEALED THAT METHYLATION PREDOMINANTLY AND REMOTELY DOWN-REGULATES GENE EXPRESSION. AMONG GENES WHOSE EXPRESSION WAS ASSOCIATED WITH OUR CANDIDATE CPG SITES, LRRN3 APPEARED TO BE PARTICULARLY INTERESTING AS IT WAS ONE OF THE FEW GENES WHOSE METHYLATION AND EXPRESSION WERE DIRECTLY ASSOCIATED, AND THE ONLY GENE IN WHICH BOTH METHYLATION AND GENE EXPRESSION WERE FOUND ASSOCIATED WITH SMOKING. OUR STUDY HIGHLIGHTS PERSISTENT EPIGENETIC MARKERS OF SMOKING, WHICH CAN POTENTIALLY BE DETECTED DECADES AFTER CESSATION. SUCH HISTORICAL SIGNATURES ARE PROMISING BIOMARKERS TO REFINE INDIVIDUAL RISK PROFILING OF SMOKING-INDUCED CHRONIC DISEASE SUCH AS LUNG CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  667  58 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	

11 2920  40 GENE-SET ANALYSIS IS SEVERELY BIASED WHEN APPLIED TO GENOME-WIDE METHYLATION DATA. MOTIVATION: DNA METHYLATION IS AN EPIGENETIC MARK THAT CAN STABLY REPRESS GENE EXPRESSION. BECAUSE OF ITS BIOLOGICAL AND CLINICAL SIGNIFICANCE, SEVERAL METHODS HAVE BEEN DEVELOPED TO COMPARE GENOME-WIDE PATTERNS OF METHYLATION BETWEEN GROUPS OF SAMPLES. THE APPLICATION OF GENE SET ANALYSIS TO IDENTIFY RELEVANT GROUPS OF GENES THAT ARE ENRICHED FOR DIFFERENTIALLY METHYLATED GENES IS OFTEN A MAJOR COMPONENT OF THE ANALYSIS OF THESE DATA. THIS CAN BE USED, FOR EXAMPLE, TO IDENTIFY PROCESSES OR PATHWAYS THAT ARE PERTURBED IN DISEASE DEVELOPMENT. WE SHOW THAT GENE-SET ANALYSIS, AS IT IS TYPICALLY APPLIED TO GENOME-WIDE METHYLATION ASSAYS, IS SEVERELY BIASED AS A RESULT OF DIFFERENCES IN THE NUMBERS OF CPG SITES ASSOCIATED WITH DIFFERENT CLASSES OF GENES AND GENE PROMOTERS. RESULTS: WE DEMONSTRATE THIS BIAS USING PUBLISHED DATA FROM A STUDY OF DIFFERENTIAL CPG ISLAND METHYLATION IN LUNG CANCER AND A DATASET WE GENERATED TO STUDY METHYLATION CHANGES IN PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS. WE SHOW THAT SEVERAL OF THE GENE SETS THAT SEEM ENRICHED WOULD ALSO BE IDENTIFIED WITH RANDOMIZED DATA. WE SUGGEST TWO EXISTING APPROACHES THAT CAN BE ADAPTED TO CORRECT THE BIAS. ACCOUNTING FOR THE BIAS IN THE LUNG CANCER AND ULCERATIVE COLITIS DATASETS PROVIDES NOVEL BIOLOGICAL INSIGHTS INTO THE ROLE OF METHYLATION IN CANCER DEVELOPMENT AND CHRONIC INFLAMMATION, RESPECTIVELY. OUR RESULTS HAVE SIGNIFICANT IMPLICATIONS FOR MANY PREVIOUS GENOME-WIDE METHYLATION STUDIES THAT HAVE DRAWN CONCLUSIONS ON THE BASIS OF SUCH STRONGLY BIASED ANALYSIS. CONTACT: CATHAL.SEOIGHE@NUIGALWAY.IE SUPPLEMENTARY INFORMATION: SUPPLEMENTARY DATA ARE AVAILABLE AT BIOINFORMATICS ONLINE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12 1599  37 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  287  29 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14 1585  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15  178  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 4607  40 NEIGHBORHOOD ENVIRONMENT AND DNA METHYLATION: IMPLICATIONS FOR CARDIOVASCULAR DISEASE RISK. EXPOSURE TO CHRONIC STRESS SUCH AS LIVING IN DISADVANTAGED NEIGHBORHOODS HAS BEEN RELATED TO CARDIOVASCULAR DISEASE (CVD). CHRONIC STRESS MAY INCREASE THE RISK FOR CVD BY INCREASING LEVELS OF SYSTEMIC INFLAMMATION (E.G., HIGHER LEVELS OF PRO-INFLAMMATORY CYTOKINES). DIFFERENTIAL DNA METHYLATION OF INFLAMMATION-RELATED CANDIDATE GENES IS ALSO RELATED TO HIGHER RISK FOR CVD. THUS, THE PURPOSE OF THIS REVIEW WAS TO EXAMINE THE ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH DNA METHYLATION. A SEARCH OF LITERATURE WAS CONDUCTED USING SCOPUS, CINAHL, PUBMED, MEDLINE, AND EMBASE DATABASES. THE KEYWORDS NEIGHBORHOOD, NEIGHBORHOOD DISORDER, NEIGHBORHOOD CRIME, NEIGHBORHOOD VIOLENCE, NEIGHBORHOOD SAFETY, BUILT ENVIRONMENT, AND HOUSING VACANCY WERE COMBINED WITH THE KEYWORDS DNA METHYLATION AND EPIGENETICS. FIVE STUDIES WERE INCLUDED IN THIS REVIEW (N = 3 ADULT BLOOD SAMPLES AND N = 2 FETAL BLOOD SAMPLES). FOUR OF THE FIVE STUDIES REPORTED AN ASSOCIATION OF NEIGHBORHOOD SOCIOECONOMIC STATUS, SOCIAL ENVIRONMENT, AND CRIME WITH EITHER GLOBAL OR GENE-SPECIFIC DNA METHYLATION. ONLY TWO STUDIES EXAMINED THE ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH INFLAMMATION-RELATED CANDIDATE GENES. ONE OF THESE STUDIES FOUND A SIGNIFICANT ASSOCIATION OF NEIGHBORHOOD SOCIOECONOMIC DISADVANTAGE AND SOCIAL ENVIRONMENT WITH DNA METHYLATION IN INFLAMMATION-RELATED CANDIDATE GENES. THUS, DATA ARE LIMITED ON THE ASSOCIATION BETWEEN NEIGHBORHOOD DISADVANTAGE AND DNA METHYLATION OF INFLAMMATION-RELATED CANDIDATE GENES, AS WELL AS GENES IN OTHER POTENTIAL MECHANISTIC PATHWAYS INCLUDING PSYCHOSOCIAL STRESS, TOXIN RESPONSE, AND ADIPOSITY. FUTURE STUDIES SHOULD EXAMINE THESE ASSOCIATIONS AND THE POTENTIAL EPIGENETIC MECHANISMS BY WHICH NEIGHBORHOOD DISADVANTAGE INCREASES THE RISK FOR CVD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17 3652  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  311  41 ALCOHOL AND THE METHYLOME: DESIGN AND ANALYSIS CONSIDERATIONS FOR RESEARCH USING HUMAN SAMPLES. BACKGROUND: A GROWING NUMBER OF STUDIES IN HUMAN SAMPLES HAVE SOUGHT TO DETERMINE WHETHER CHRONIC ALCOHOL USE AND ALCOHOL USE DISORDERS (AUDS) MAY BE ASSOCIATED WITH EPIGENETIC FACTORS, SUCH AS DNA METHYLATION. WE REVIEW THE EXTANT LITERATURE IN LIGHT OF SOME OF THE CHALLENGES THAT CURRENTLY AFFECT THE DESIGN AND INTERPRETATION OF EPIGENETIC RESEARCH IN HUMAN SAMPLES. METHOD: A LITERATURE SEARCH WAS USED TO IDENTIFY STUDIES THAT HAVE EXAMINED DNA METHYLATION IN RELATION TO ALCOHOL USE OR AUDS IN HUMAN SAMPLES (THROUGH JULY 2013). A TOTAL OF 22 STUDIES WERE IDENTIFIED. RESULTS: ASSOCIATIONS WITH QUANTITATIVE OR DIAGNOSTIC PHENOTYPES OF ALCOHOL USE OR AUDS HAVE BEEN REPORTED FOR SEVERAL GENES. HOWEVER, ALL STUDIES TO DATE HAVE RELIED ON RELATIVELY SMALL SAMPLES AND CROSS-SECTIONAL STUDY DESIGNS. ADDITIONALLY, ATTEMPTS TO REPLICATE RESULTS HAVE BEEN RARE. MORE GENERALLY, RESEARCH PROGRESS IS HAMPERED BY SEVERAL ISSUES, INCLUDING LIMITATIONS OF THE TECHNOLOGIES USED TO ASSESS DNA METHYLATION, TISSUE- AND CELL-SPECIFICITY OF METHYLATION PATTERNS, THE DIFFICULTIES OF RELATING OBSERVED METHYLATION DIFFERENCES AT A GIVEN LOCUS TO A FUNCTIONAL EFFECT, AND LIMITED KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF ALCOHOL ON DNA METHYLATION. CONCLUSIONS: ALTHOUGH WE SHARE THE OPTIMISM THAT EPIGENETICS MAY LEAD TO NEW INSIGHTS INTO THE ETIOLOGY AND PATHOPHYSIOLOGY OF AUDS, THE METHODOLOGICAL AND SCIENTIFIC CHALLENGES ASSOCIATED WITH CONDUCTING METHYLOMIC RESEARCH IN HUMAN SAMPLES NEED TO BE CAREFULLY CONSIDERED WHEN DESIGNING AND EVALUATING SUCH STUDIES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  348  48 ALTERED DNA METHYLATION IS ASSOCIATED WITH ABERRANT GENE EXPRESSION IN PARENCHYMAL BUT NOT AIRWAY FIBROBLASTS ISOLATED FROM INDIVIDUALS WITH COPD. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A HETEROGENEOUS DISEASE OF THE LUNGS THAT IS CURRENTLY THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. GENETIC FACTORS ACCOUNT FOR ONLY A SMALL AMOUNT OF COPD RISK, BUT EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HAVE THE POTENTIAL TO MEDIATE THE INTERACTIONS BETWEEN AN INDIVIDUAL'S GENETICS AND ENVIRONMENTAL EXPOSURE. DNA METHYLATION IS HIGHLY CELL TYPE-SPECIFIC, AND INDIVIDUAL CELL TYPE STUDIES OF DNA METHYLATION IN COPD ARE SPARSE. FIBROBLASTS ARE PRESENT WITHIN THE AIRWAY AND PARENCHYMA OF THE LUNG AND CONTRIBUTE TO THE ABERRANT DEPOSITION OF EXTRACELLULAR MATRIX IN COPD. NO ASSESSMENT OR COMPARISON OF GENOME-WIDE DNA METHYLATION PROFILES IN THE AIRWAY AND PARENCHYMAL FIBROBLASTS FROM INDIVIDUALS WITH AND WITHOUT COPD HAS BEEN UNDERTAKEN. THESE DATA PROVIDE VALUABLE INSIGHT INTO THE MOLECULAR MECHANISMS CONTRIBUTING TO COPD AND THE DIFFERING PATHOLOGIES OF SMALL AIRWAYS DISEASE AND EMPHYSEMA IN COPD. METHODS: GENOME-WIDE DNA METHYLATION WAS EVALUATED AT OVER 485,000 CPG SITES USING THE ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY IN THE AIRWAY (NON-COPD N = 8, COPD N = 7) AND PARENCHYMAL FIBROBLASTS (NON-COPD N = 17, COPD N = 29) ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD. TARGETED GENE EXPRESSION WAS ASSESSED BY QPCR IN MATCHED RNA SAMPLES. RESULTS: DIFFERENTIALLY METHYLATED DNA REGIONS WERE IDENTIFIED BETWEEN CELLS ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD IN BOTH AIRWAY AND PARENCHYMAL FIBROBLASTS. ONLY IN PARENCHYMAL FIBROBLASTS WAS DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH DIFFERENTIAL GENE EXPRESSION. A SECOND ANALYSIS OF DIFFERENTIAL DNA METHYLATION VARIABILITY IDENTIFIED 359 INDIVIDUAL DIFFERENTIALLY VARIABLE CPG SITES IN PARENCHYMAL FIBROBLASTS. NO DIFFERENTIALLY VARIABLE CPG SITES WERE IDENTIFIED IN THE AIRWAY FIBROBLASTS. FIVE DIFFERENTIALLY VARIABLE-METHYLATED CPG SITES, ASSOCIATED WITH THREE GENES, WERE SUBSEQUENTLY ASSESSED FOR GENE EXPRESSION DIFFERENCES. TWO GENES (OAT AND GRIK2) DISPLAYED SIGNIFICANTLY INCREASED GENE EXPRESSION IN CELLS ISOLATED FROM INDIVIDUALS WITH COPD. CONCLUSIONS: DIFFERENTIAL AND VARIABLE DNA METHYLATION WAS ASSOCIATED WITH COPD STATUS IN THE PARENCHYMAL FIBROBLASTS BUT NOT AIRWAY FIBROBLASTS. ABERRANT DNA METHYLATION WAS ASSOCIATED WITH ALTERED GENE EXPRESSION IMPARTING BIOLOGICAL FUNCTION TO DNA METHYLATION CHANGES. CHANGES IN DNA METHYLATION ARE THEREFORE IMPLICATED IN THE MOLECULAR MECHANISMS UNDERLYING COPD PATHOGENESIS AND MAY REPRESENT NOVEL THERAPEUTIC TARGETS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20 6027  27 THE BLOOD DNA METHYLATION CLOCK GRIMAGE IS A ROBUST SURROGATE FOR AIRWAY EPITHELIA AGING. ONE KEY FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS THAT ITS PREVALENCE INCREASES EXPONENTIALLY WITH AGE. DNA METHYLATION CLOCKS HAVE BECOME POWERFUL BIOMARKERS TO DETECT ACCELERATED AGING IN A VARIETY OF DISEASES AND CAN HELP PROGNOSE OUTCOMES IN SEVERE COPD. THIS STUDY INVESTIGATED WHICH DNA METHYLATION CLOCK COULD BEST REFLECT AIRWAY EPIGENETIC AGE WHEN USED IN MORE ACCESSIBLE BLOOD SAMPLES. OUR ANALYSES SHOWED THAT OUT OF SIX DNA METHYLATION CLOCKS INVESTIGATED, DNAMGRIMAGE DEMONSTRATED THE STRONGEST CORRELATION AND THE SMALLEST DIFFERENCE BETWEEN THE AIRWAY EPITHELIUM AND BLOOD. OUR FINDINGS SUGGESTS THAT BLOOD DNAMGRIMAGE ACCURATELY REFLECTS AIRWAY EPIGENETIC AGE OF INDIVIDUALS AND THAT ITS ELEVATION IS HIGHLY ASSOCIATED WITH COPD.	2022