1  1189 139 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2  1512  43 DNA METHYLATION AND PROTEIN MARKERS OF CHRONIC INFLAMMATION AND THEIR ASSOCIATIONS WITH BRAIN AND COGNITIVE AGING. BACKGROUND AND OBJECTIVES: TO INVESTIGATE CHRONIC INFLAMMATION IN RELATION TO COGNITIVE AGING BY COMPARISON OF AN EPIGENETIC AND SERUM BIOMARKER OF C-REACTIVE PROTEIN AND THEIR ASSOCIATIONS WITH NEUROIMAGING AND COGNITIVE OUTCOMES. METHODS: AT BASELINE, PARTICIPANTS (N = 521) WERE COGNITIVELY NORMAL, AROUND 73 YEARS OF AGE (MEAN 72.4, SD 0.716), AND HAD INFLAMMATION, VASCULAR RISK (CARDIOVASCULAR DISEASE HISTORY, HYPERTENSION, DIABETES, SMOKING, ALCOHOL CONSUMPTION, BODY MASS INDEX), AND NEUROIMAGING (STRUCTURAL AND DIFFUSION MRI) DATA AVAILABLE. BASELINE INFLAMMATORY STATUS WAS QUANTIFIED BY A TRADITIONAL MEASURE OF PERIPHERAL INFLAMMATION-SERUM C-REACTIVE PROTEIN (CRP)-AND AN EPIGENETIC MEASURE (DNA METHYLATION [DNAM] SIGNATURE OF CRP). LINEAR MODELS WERE USED TO EXAMINE THE INFLAMMATION-BRAIN HEALTH ASSOCIATIONS; MEDIATION ANALYSES WERE PERFORMED TO INTERROGATE THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION, BRAIN STRUCTURE, AND COGNITIVE FUNCTIONING. RESULTS: WE DEMONSTRATE THAT DNAM CRP SHOWS SIGNIFICANTLY (ON AVERAGE 6.4-FOLD) STRONGER ASSOCIATIONS WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP. DNAM CRP IS ASSOCIATED WITH TOTAL BRAIN VOLUME (BETA = -0.197, 95% CONFIDENCE INTERVAL [CI] -0.28 TO -0.12, P (FDR) = 8.42 X 10(-6)), GRAY MATTER VOLUME (BETA = -0.200, 95% CI -0.28 TO -0.12, P (FDR) = 1.66 X 10(-5)), AND WHITE MATTER VOLUME (BETA = -0.150, 95% CI -0.23 TO -0.07, P (FDR) = 0.001) AND REGIONAL BRAIN ATROPHY. WE ALSO FIND THAT DNAM CRP HAS AN INVERSE ASSOCIATION WITH GLOBAL AND DOMAIN-SPECIFIC (SPEED, VISUOSPATIAL, AND MEMORY) COGNITIVE FUNCTIONING AND THAT BRAIN STRUCTURE PARTIALLY MEDIATES THIS CRP-COGNITIVE ASSOCIATION (UP TO 29.7%), DEPENDENT ON LIFESTYLE AND HEALTH FACTORS. DISCUSSION: THESE RESULTS SUPPORT THE HYPOTHESIS THAT CHRONIC INFLAMMATION MAY CONTRIBUTE TO NEURODEGENERATIVE BRAIN CHANGES THAT UNDERLIE DIFFERENCES IN COGNITIVE ABILITY IN LATER LIFE AND HIGHLIGHT THE POTENTIAL OF DNAM PROXIES FOR INDEXING CHRONIC INFLAMMATORY STATUS. CLASSIFICATION OF EVIDENCE: THIS STUDY PROVIDES CLASS II EVIDENCE THAT A DNAM SIGNATURE OF CRP LEVELS IS MORE STRONGLY ASSOCIATED WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP LEVELS.	2021	

3   816  45 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	
                                                                                                                                                                                                                                                                                                                                                                                 
4  6508  38 TRAJECTORIES OF INFLAMMATORY BIOMARKERS OVER THE EIGHTH DECADE AND THEIR ASSOCIATIONS WITH IMMUNE CELL PROFILES AND EPIGENETIC AGEING. BACKGROUND: EPIGENETIC AGE ACCELERATION (AN OLDER METHYLATION AGE COMPARED TO CHRONOLOGICAL AGE) CORRELATES STRONGLY WITH VARIOUS AGE-RELATED MORBIDITIES AND MORTALITY. CHRONIC SYSTEMIC INFLAMMATION IS THOUGHT TO BE A HALLMARK OF AGEING, BUT THE RELATIONSHIP BETWEEN AN INCREASED EPIGENETIC AGE AND THIS LIKELY KEY PHENOTYPE OF AGEING HAS NOT YET BEEN EXTENSIVELY INVESTIGATED. METHODS: WE MODELLED THE TRAJECTORIES OF THE INFLAMMATORY BIOMARKERS C-REACTIVE PROTEIN (CRP; MEASURED USING BOTH A HIGH- AND LOW-SENSITIVITY ASSAY) AND INTERLEUKIN-6 (IL-6) OVER THE EIGHTH DECADE IN THE LOTHIAN BIRTH COHORT 1936. USING LINEAR MIXED MODELS, WE INVESTIGATED THE ASSOCIATION BETWEEN CRP AND IMMUNE CELL PROFILES IMPUTED FROM THE METHYLATION DATA AND EXAMINED THE CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATION BETWEEN THE INFLAMMATORY BIOMARKERS AND TWO MEASURES OF EPIGENETIC AGE ACCELERATION, DERIVED FROM THE HORVATH AND HANNUM EPIGENETIC CLOCKS. RESULTS: WE FOUND THAT LOW-SENSITIVITY CRP DECLINED, HIGH-SENSITIVITY CRP DID NOT CHANGE, AND IL-6 INCREASED OVER TIME WITHIN THE COHORT. CRP LEVELS INVERSELY ASSOCIATED WITH CD8+T CELLS AND CD4+T CELLS AND POSITIVELY ASSOCIATED WITH SENESCENT CD8+T CELLS, PLASMABLASTS AND GRANULOCYTES. CROSS-SECTIONALLY, THE HANNUM, BUT NOT THE HORVATH, MEASURE OF AGE ACCELERATION WAS POSITIVELY ASSOCIATED WITH EACH OF THE INFLAMMATORY BIOMARKERS, INCLUDING A RESTRICTED MEASURE OF CRP (</= 10 MG/L) LIKELY REFLECTING LEVELS RELEVANT TO CHRONIC INFLAMMATION. CONCLUSIONS: WE FOUND A DIVERGENT RELATIONSHIP BETWEEN INFLAMMATION AND IMMUNE SYSTEM PARAMETERS IN OLDER AGE. WE ADDITIONALLY REPORT THE HANNUM MEASURE OF EPIGENETIC AGE ACCELERATION ASSOCIATED WITH AN ELEVATED INFLAMMATORY PROFILE CROSS-SECTIONALLY, BUT NOT LONGITUDINALLY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                              
5   504  41 ASSOCIATION OF CIGARETTE SMOKING AND CRP LEVELS WITH DNA METHYLATION IN ALPHA-1 ANTITRYPSIN DEFICIENCY. ALPHA-1 ANTITRYPSIN (AAT) DEFICIENCY AND TOBACCO SMOKING ARE CONFIRMED RISK FACTORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. WE HYPOTHESIZED THAT VARIABLE DNA METHYLATION WOULD BE ASSOCIATED WITH SMOKING AND INFLAMMATION, AS REFLECTED BY THE LEVEL OF C-REACTIVE PROTEIN (CRP) IN AAT-DEFICIENT SUBJECTS. METHYLATION LEVELS OF 1,411 AUTOSOMAL CPG SITES FROM THE ILLUMINA GOLDENGATE METHYLATION CANCER PANEL I WERE ANALYZED IN 316 SUBJECTS. ASSOCIATIONS OF FIVE SMOKING BEHAVIORS AND CRP LEVELS WITH INDIVIDUAL CPG SITES AND AVERAGE METHYLATION LEVELS WERE ASSESSED USING NON-PARAMETRIC TESTING, LINEAR REGRESSION AND LINEAR MIXED EFFECT MODELS, WITH AND WITHOUT ADJUSTMENT FOR AGE AND GENDER. UNIVARIATE LINEAR REGRESSION ANALYSIS REVEALED THAT METHYLATION LEVELS OF 16 CPG SITES SIGNIFICANTLY ASSOCIATED WITH EVER-SMOKING STATUS. A CPG SITE IN THE TGFBI GENE WAS THE ONLY SITE ASSOCIATED WITH EVER-SMOKING AFTER ADJUSTMENT FOR AGE AND GENDER. NO HIGHLY SIGNIFICANT ASSOCIATIONS EXISTED BETWEEN AGE AT SMOKING INITIATION, PACK-YEARS SMOKED, DURATION OF SMOKING, AND TIME SINCE QUITTING SMOKING AS PREDICTORS OF INDIVIDUAL CPG SITE METHYLATION LEVELS. HOWEVER, EVER-SMOKING AND YOUNGER AGE AT SMOKING INITIATION ASSOCIATED WITH LOWER METHYLATION LEVEL AVERAGED ACROSS ALL SITES. DNA METHYLATION AT CPG SITES IN THE RUNX3, JAK3 AND KRT1 GENES ASSOCIATED WITH CRP LEVELS. THE MOST SIGNIFICANTLY ASSOCIATED CPG SITES WITH GENDER AND AGE MAPPED TO THE CASP6 AND FZD9 GENES, RESPECTIVELY. IN SUMMARY, THIS STUDY IDENTIFIED MULTIPLE POTENTIAL CANDIDATE CPG SITES ASSOCIATED WITH EVER-SMOKING AND CRP LEVEL IN AAT-DEFICIENT SUBJECTS. PHENOTYPIC VARIABILITY IN MENDELIAN DISEASES MAY BE DUE TO EPIGENETIC FACTORS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  2922  43 GENE-SPECIFIC DNA METHYLATION ASSOCIATION WITH SERUM LEVELS OF C-REACTIVE PROTEIN IN AFRICAN AMERICANS. A MORE THOROUGH UNDERSTANDING OF THE DIFFERENCES IN DNA METHYLATION (DNAM) PROFILES IN POPULATIONS MAY HOLD PROMISE FOR IDENTIFYING MOLECULAR MECHANISMS THROUGH WHICH GENETIC AND ENVIRONMENTAL FACTORS JOINTLY CONTRIBUTE TO HUMAN DISEASES. INFLAMMATION IS A KEY MOLECULAR MECHANISM UNDERLYING SEVERAL CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASE, AND IT AFFECTS DNAM PROFILE ON BOTH GLOBAL AND LOCUS-SPECIFIC LEVELS. TO UNDERSTAND THE IMPACT OF INFLAMMATION ON THE DNAM OF THE HUMAN GENOME, WE INVESTIGATED DNAM PROFILES OF PERIPHERAL BLOOD LEUKOCYTES FROM 966 AFRICAN AMERICAN PARTICIPANTS IN THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY (GENOA) STUDY. BY TESTING THE ASSOCIATION OF DNAM SITES ON CPG ISLANDS OF OVER 14,000 GENES WITH C-REACTIVE PROTEIN (CRP), AN INFLAMMATORY BIOMARKER OF CARDIOVASCULAR DISEASE, WE IDENTIFIED 257 DNAM SITES IN 240 GENES SIGNIFICANTLY ASSOCIATED WITH SERUM LEVELS OF CRP ADJUSTED FOR AGE, SEX, BODY MASS INDEX AND SMOKING STATUS, AND CORRECTED FOR MULTIPLE TESTING. OF THE SIGNIFICANTLY ASSOCIATED DNAM SITES, 80.5% WERE HYPOMETHYLATED WITH HIGHER CRP LEVELS. THE MOST SIGNIFICANT GENE ONTOLOGY TERMS ENRICHED IN THE GENES ASSOCIATED WITH THE CRP LEVELS WERE IMMUNE SYSTEM PROCESS, IMMUNE RESPONSE, DEFENSE RESPONSE, RESPONSE TO STIMULUS, AND RESPONSE TO STRESS, WHICH ARE ALL LINKED TO THE FUNCTIONS OF LEUKOCYTES. WHILE THE CRP-ASSOCIATED DNAM MAY BE CELL-TYPE SPECIFIC, UNDERSTANDING THE DNAM ASSOCIATION WITH CRP IN PERIPHERAL BLOOD LEUKOCYTES OF MULTI-ETHNIC POPULATIONS CAN ASSIST IN UNVEILING THE MOLECULAR MECHANISM OF HOW THE PROCESS OF INFLAMMATION AFFECTS THE RISKS OF DEVELOPING COMMON DISEASE THROUGH EPIGENETIC MODIFICATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7    52  42 A DNA METHYLATION BASED MEASURE OUTPERFORMS CIRCULATING CRP AS A MARKER OF CHRONIC INFLAMMATION AND PARTLY REFLECTS THE MONOCYTIC RESPONSE TO LONG-TERM INFLAMMATORY EXPOSURE: A CANADIAN LONGITUDINAL STUDY ON AGING ANALYSIS. A KEY HALLMARK IN THE AGE-RELATED DYSFUNCTION OF PHYSIOLOGICAL SYSTEMS IS DISRUPTION RELATED TO THE REGULATION OF INFLAMMATION, OFTEN RESULTING IN A CHRONIC, LOW-GRADE INFLAMMATORY STATE (I.E., INFLAMMAGING). IN ORDER TO UNDERSTAND THE CAUSES OF OVERALL SYSTEM DECLINE, METHODS TO QUANTIFY THE LIFE-LONG EXPOSURE OR DAMAGE RELATED TO CHRONIC INFLAMMATION ARE CRITICAL. HERE, WE CHARACTERIZE A COMPREHENSIVE EPIGENETIC INFLAMMATION SCORE (EIS) BASED ON DNA METHYLATION LOCI (CPGS) THAT ARE ASSOCIATED WITH CIRCULATING LEVELS OF C-REACTIVE PROTEIN (CRP). IN A COHORT OF 1446 OLDER ADULTS, WE SHOW THAT ASSOCIATIONS TO AGE AND HEALTH-RELATED TRAITS SUCH AS SMOKING HISTORY, CHRONIC CONDITIONS, AND ESTABLISHED MEASURES OF ACCELERATED AGING WERE STRONGER FOR EIS THAN CRP, WHILE THE RISK OF LONGITUDINAL OUTCOMES SUCH AS OUTPATIENT OR INPATIENT VISITS AND INCREASED FRAILTY WERE RELATIVELY SIMILAR. TO DETERMINE WHETHER VARIATION IN EIS ACTUALLY REFLECTS THE CELLULAR RESPONSE TO CHRONIC INFLAMMATION WE EXPOSED THP1 MYELO-MONOCYTIC CELLS TO LOW LEVELS OF INFLAMMATORY MEDIATORS FOR 14 DAYS, FINDING THAT EIS INCREASED IN RESPONSE TO BOTH CRP (P = 0.011) AND TNF (P = 0.068). INTERESTINGLY, A REFINED VERSION OF EIS BASED ONLY ON THOSE CPGS THAT CHANGED IN VITRO WAS MORE STRONGLY ASSOCIATED WITH MANY OF THE AFOREMENTIONED TRAITS AS COMPARED TO EIS. IN CONCLUSION, OUR STUDY DEMONSTRATES THAT EIS OUTPERFORMS CIRCULATING CRP WITH REGARD TO ITS ASSOCIATION TO HEALTH-TRAITS THAT ARE SYNONYMOUS WITH CHRONIC INFLAMMATION AND ACCELERATED AGING, AND SUBSTANTIATES ITS POTENTIAL ROLE AS A CLINICALLY RELEVANT TOOL FOR STRATIFYING PATIENT RISK OF ADVERSE OUTCOMES PRIOR TO TREATMENT OR FOLLOWING ILLNESS.	2023	
                                                                                                                                                                                                                                                                                                                                                                         
8  2239  24 EPIGENETIC MODULATION BY APABETALONE COUNTERS CYTOKINE-DRIVEN ACUTE PHASE RESPONSE IN VITRO, IN MICE AND IN PATIENTS WITH CARDIOVASCULAR DISEASE. CHRONIC SYSTEMIC INFLAMMATION CONTRIBUTES TO CARDIOVASCULAR DISEASE (CVD) AND CORRELATES WITH THE ABUNDANCE OF ACUTE PHASE RESPONSE (APR) PROTEINS IN THE LIVER AND PLASMA. BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE INFLAMMATORY GENE TRANSCRIPTION. WE SHOW THAT BET INHIBITION BY THE SMALL MOLECULE APABETALONE REDUCES APR GENE AND PROTEIN EXPRESSION IN HUMAN HEPATOCYTES, MOUSE MODELS, AND PLASMA FROM CVD PATIENTS. STEADY-STATE EXPRESSION OF SERUM AMYLOID P, PLASMINOGEN ACTIVATOR INHIBITOR 1, AND CERULOPLASMIN, APR PROTEINS LINKED TO CVD RISK, IS REDUCED BY APABETALONE IN CULTURED HEPATOCYTES AND IN HUMANIZED MOUSE LIVER. IN CYTOKINE-STIMULATED HEPATOCYTES, APABETALONE REDUCES THE EXPRESSION OF C-REACTIVE PROTEIN (CRP), ALPHA-2-MACROGLOBULIN, AND SERUM AMYLOID P. THE LATTER TWO ARE ALSO REDUCED BY APABETALONE IN THE LIVER OF ENDOTOXEMIC MICE. BET KNOCKDOWN IN VITRO ALSO COUNTERS CYTOKINE-MEDIATED INDUCTION OF THE CRP GENE. MECHANISTICALLY, APABETALONE REDUCES THE CYTOKINE-DRIVEN INCREASE IN BRD4 BET OCCUPANCY AT THE CRP PROMOTER, CONFIRMING THAT TRANSCRIPTION OF CRP IS BET-DEPENDENT. IN PATIENTS WITH STABLE CORONARY DISEASE, PLASMA APR PROTEINS CRP, IL-1 RECEPTOR ANTAGONIST, AND FIBRINOGEN GAMMA DECREASE AFTER APABETALONE TREATMENT VERSUS PLACEBO, RESULTING IN A PREDICTED DOWNREGULATION OF THE APR PATHWAY AND CYTOKINE TARGETS. WE CONCLUDE THAT CRP AND COMPONENTS OF THE APR PATHWAY ARE REGULATED BY BET PROTEINS AND THAT APABETALONE COUNTERS CHRONIC CYTOKINE SIGNALING IN PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  5840  39 STRUCTURAL BRAIN CORRELATES OF SERUM AND EPIGENETIC MARKERS OF INFLAMMATION IN MAJOR DEPRESSIVE DISORDER. INFLAMMATORY PROCESSES ARE IMPLICATED IN THE AETIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD); HOWEVER, THE RELATIONSHIP BETWEEN PERIPHERAL INFLAMMATION, BRAIN STRUCTURE AND DEPRESSION REMAINS UNCLEAR, PARTLY DUE TO COMPLEXITIES AROUND THE USE OF ACUTE/PHASIC INFLAMMATORY BIOMARKERS. HERE, WE REPORT THE FIRST LARGE-SCALE STUDY OF BOTH SEROLOGICAL AND METHYLOMIC SIGNATURES OF CRP (CONSIDERED TO REPRESENT ACUTE AND CHRONIC MEASURES OF INFLAMMATION RESPECTIVELY) AND THEIR ASSOCIATIONS WITH DEPRESSION STATUS/SYMPTOMS, AND STRUCTURAL NEUROIMAGING PHENOTYPES (T1 AND DIFFUSION MRI) IN A LARGE COMMUNITY-BASED SAMPLE (GENERATION SCOTLAND; N(MDD CASES) = 271, N(CONTROLS) = 609). SERUM CRP WAS ASSOCIATED WITH OVERALL MDD SEVERITY, AND SPECIFICALLY WITH CURRENT SOMATIC SYMPTOMS- GENERAL INTEREST (BETA = 0.145, P(FDR) = 6 X 10(-4)) AND ENERGY LEVELS (BETA = 0.101, P(FDR) = 0.027), ALONG WITH REDUCED ENTORHINAL CORTEX THICKNESS (BETA = -0.095, P(FDR) = 0.037). DNAM CRP WAS SIGNIFICANTLY ASSOCIATED WITH REDUCED GLOBAL GREY MATTER/CORTICAL VOLUME AND WIDESPREAD REDUCTIONS IN INTEGRITY OF 16/24 WHITE MATTER TRACTS (WITH GREATEST REGIONAL EFFECTS IN THE EXTERNAL AND INTERNAL CAPSULES, BETA(FA)= -0.12 TO -0.14). IN GENERAL, THE METHYLATION-BASED MEASURES SHOWED STRONGER ASSOCIATIONS WITH IMAGING METRICS THAN SERUM-BASED CRP MEASURES (BETAAVERAGE = -0.15 VERSUS BETAAVERAGE = 0.01 RESPECTIVELY). THESE FINDINGS PROVIDE EVIDENCE FOR CENTRAL EFFECTS OF PERIPHERAL INFLAMMATION FROM BOTH SEROLOGICAL AND EPIGENETIC MARKERS OF INFLAMMATION, INCLUDING IN BRAIN REGIONS PREVIOUSLY IMPLICATED IN DEPRESSION. THIS SUGGESTS THAT THESE IMAGING MEASURES MAY BE INVOLVED IN THE RELATIONSHIP BETWEEN PERIPHERAL INFLAMMATION AND SOMATIC/DEPRESSIVE SYMPTOMS. NOTABLY, GREATER EFFECTS ON BRAIN MORPHOLOGY WERE SEEN FOR METHYLATION-BASED RATHER THAN SERUM-BASED MEASURES OF INFLAMMATION, INDICATING THE IMPORTANCE OF SUCH MEASURES FOR FUTURE STUDIES.	2021	
                                                                                                                                                                                                                                                   
10  1780  36 EDUCATION AND LIFESTYLE FACTORS ARE ASSOCIATED WITH DNA METHYLATION CLOCKS IN OLDER AFRICAN AMERICANS. DNA METHYLATION (DNAM) CLOCKS ARE IMPORTANT BIOMARKERS OF CELLULAR AGING AND ARE ASSOCIATED WITH A VARIETY OF AGE-RELATED CHRONIC DISEASES AND ALL-CAUSE MORTALITY. EXAMINING THE RELATIONSHIP BETWEEN EDUCATION AND LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND MULTIPLE DNAM CLOCKS CAN INCREASE THE UNDERSTANDING OF HOW RISK FACTORS CONTRIBUTE TO AGING AT THE CELLULAR LEVEL. THIS STUDY EXPLORED THE ASSOCIATION BETWEEN EDUCATION OR LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND THE ACCELERATION OF FOUR DNAM CLOCKS, INCLUDING INTRINSIC (IEAA) AND EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA), PHENOAGE ACCELERATION (PHENOAA), AND GRIMAGE ACCELERATION (GRIMAA) IN THE AFRICAN AMERICAN PARTICIPANTS OF THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY. WE PERFORMED BOTH CROSS-SECTIONAL AND LONGITUDINAL ANALYSES. IN CROSS-SECTIONAL ANALYSES, GENDER, EDUCATION, BMI, SMOKING, AND ALCOHOL CONSUMPTION WERE ALL INDEPENDENTLY ASSOCIATED WITH GRIMAA, WHEREAS ONLY SOME OF THEM WERE ASSOCIATED WITH OTHER CLOCKS. THE EFFECT OF SMOKING AND EDUCATION ON GRIMAA VARIED BY GENDER. LONGITUDINAL ANALYSES SUGGEST THAT AGE AND BMI CONTINUED TO INCREASE GRIMAA, AND THAT AGE AND CURRENT SMOKING CONTINUED TO INCREASE PHENOAA AFTER CONTROLLING DNAM CLOCKS AT BASELINE. IN CONCLUSION, EDUCATION AND COMMON LIFESTYLE RISK FACTORS WERE ASSOCIATED WITH MULTIPLE DNAM CLOCKS. HOWEVER, THE ASSOCIATION WITH EACH RISK FACTOR VARIED BY CLOCK, WHICH SUGGESTS THAT DIFFERENT CLOCKS MAY CAPTURE ADVERSE EFFECTS FROM DIFFERENT ENVIRONMENTAL STIMULI.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11   173  34 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  3637  32 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  3456  39 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                        
14  5395  35 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                            
15  5302  39 PROTEIN-C REACTIVE AS BIOMARKER PREDICTOR OF SCHIZOPHRENIA PHASES OF ILLNESS? A SYSTEMATIC REVIEW. BACKGROUND: SCHIZOPHRENIA IS A COMPLEX ILLNESS IN WHICH GENETIC, ENVIRONMENTAL, AND EPIGENETIC COMPONENTS HAVE BEEN IMPLICATED. HOWEVER, RECENTLY, PSYCHIATRIC DISORDERS APPEAR TO BE RELATED TO A CHRONIC INFLAMMATORY STATE, AT THE LEVEL OF SPECIFIC CEREBRAL AREAS WHICH HAVE BEEN FOUND AS WELL IMPAIRED AND RESPONSIBLE FOR SCHIZOPHRENIA SYMPTOMATOLOGY. HENCE, A ROLE OF INFLAMMATORY MEDIATORS AND CYTOKINES HAS BEEN AS WELL DEFINED. ACCORDINGLY, THE ROLE OF AN ACUTE INFLAMMATORY PHASE PROTEIN, THE C-REACTIVE PROTEIN (CRP) HAS BEEN RECENTLY INVESTIGATED. OBJECTIVE: THE OBJECTIVE OF THE PRESENT STUDY IS TO EVALUATE HOW PCR MAY REPRESENT A BIOMARKER IN SCHIZOPHRENIA, I.E. CORRELATED WITH ILLNESS PHASES AND/OR CLINICAL MANIFESTATION AND/OR PSYCHOPATHOLOGICAL SEVERITY. METHODS: A SYSTEMATIC REVIEW WAS HERE CARRIED OUT BY SEARCHING THE FOLLOWING KEYWORDS ((C-REACTIVE PROTEIN AND ((SCHIZOPHRENIA) OR (PSYCHOTIC DISORDER))) FOR THE TOPICS 'PCR' AND 'SCHIZOPHRENIA', BY USING MESH TERMS. RESULTS: AN IMMUNE DYSFUNCTION AND INFLAMMATION HAVE BEEN DESCRIBED AMONGST SCHIZOPHRENIC PATIENTS. FINDINGS REPORTED ELEVATED CRP LEVELS IN SCHIZOPHRENIA, MAINLY CORRELATED WITH THE SEVERITY OF ILLNESS AND DURING THE RECRUDESCENT PHASE. CRP LEVELS ARE HIGHER WHEN CATATONIC FEATURES, NEGATIVE SYMPTOMATOLOGY AND AGGRESSIVENESS ARE ASSOCIATED. CRP LEVELS APPEARED NOT TO BE RELATED TO SUICIDAL BEHAVIOUR AND IDEATION. CONCLUSION: CRP AND ITS BLOOD LEVELS HAVE BEEN REPORTED HIGHER AMONGST SCHIZOPHRENIC PATIENTS, BY SUGGESTING A ROLE OF INFLAMMATION IN THE PATHOGENESIS OF SCHIZOPHRENIA. FURTHER STUDIES ARE NEEDED TO BETTER UNDERSTAND IF CRP MAY BE CONSIDERED A BIOMARKER IN SCHIZOPHRENIA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  6083  50 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	
                                                                                                                                                                                                                                                                                                                                                                            
17  1025  37 CIRCULATING MIRNAS ARE ASSOCIATED WITH INFLAMMATION BIOMARKERS IN CHILDREN WITH OVERWEIGHT AND OBESITY: RESULTS OF THE I.FAMILY STUDY. INCREASING DATA SUGGEST THAT OVERNUTRITION-INDUCED OBESITY MAY TRIGGER AN INFLAMMATORY PROCESS IN ADIPOSE TISSUE AND UPTURN IN THE INNATE IMMUNE SYSTEM. NUMEROUS PLAYERS HAVE BEEN INVOLVED IN GOVERNING THE INFLAMMATORY RESPONSE, INCLUDING EPIGENETICS. AMONG EPIGENETIC PLAYERS, MIRNAS ARE EMERGING AS CRUCIAL REGULATORS OF IMMUNE CELL DEVELOPMENT, IMMUNE RESPONSES, AUTOIMMUNITY, AND INFLAMMATION. IN THIS STUDY, WE AIMED AT IDENTIFYING THE INVOLVEMENT OF CANDIDATE MIRNAS IN RELATION TO INFLAMMATION-ASSOCIATED BIOMARKERS IN A SUBSAMPLE OF EUROPEAN CHILDREN WITH OVERWEIGHT AND OBESITY PARTICIPATING IN THE I.FAMILY STUDY. THE STUDY SAMPLE INCLUDED INDIVIDUALS WITH INCREASED ADIPOSITY SINCE THIS CONDITION CONTRIBUTES TO THE EARLY OCCURRENCE OF CHRONIC LOW-GRADE INFLAMMATION. WE FOCUSED ON THE ACUTE-PHASE REAGENT C-REACTIVE PROTEIN (CRP) AS THE PRIMARY OUTCOME AND SELECTED CYTOKINES AS PLAUSIBLE BIOMARKERS OF INFLAMMATION. WE FOUND THAT CHRONIC LOW-GRADE CRP ELEVATION SHOWS A HIGHLY SIGNIFICANT ASSOCIATION WITH MIR-26B-3P AND HSA-MIR-576-5P IN BOYS. FURTHERMORE, THE ASSOCIATION OF CRP WITH HSA-MIR-10B-5P AND HSA-MIR-31-5P IS HIGHLY SIGNIFICANT IN GIRLS. WE ALSO OBSERVED MAJOR SEX-RELATED ASSOCIATIONS OF CANDIDATE MIRNAS WITH SELECTED CYTOKINES. EXCEPT FOR IL-6, A SIGNIFICANT ASSOCIATION OF HSA-MIR-26B-3P AND HSA-MIR-576-5P WITH TNF-ALPHA, IL1-RA, IL-8, AND IL-15 LEVELS WAS FOUND EXCLUSIVELY IN BOYS. THE FINDINGS OF THIS EXPLORATORY STUDY SUGGEST SEX DIFFERENCES IN THE ASSOCIATION OF CIRCULATING MIRNAS WITH INFLAMMATORY RESPONSE BIOMARKERS, AND INDICATE A POSSIBLE ROLE OF MIRNAS AMONG THE CANDIDATE EPIGENETIC MECHANISMS RELATED TO THE PROCESS OF LOW-GRADE INFLAMMATION IN CHILDHOOD OBESITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  2643  36 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  1955  42 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  2734  41 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022