1 5862 145 SUPERTAG METHYLATION-SPECIFIC DIGITAL KARYOTYPING REVEALS UREMIA-INDUCED EPIGENETIC DYSREGULATION OF ATHEROSCLEROSIS-RELATED GENES. BACKGROUND: ACCELERATED ATHEROSCLEROSIS IS A HALLMARK OF CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH THE ROLE OF EPIGENETIC DYSREGULATION IN ATHEROSCLEROSIS IS INCREASINGLY APPRECIATED, ONLY A FEW STUDIES FOCUSED ON EPIGENETICS IN CKD-ASSOCIATED CARDIOVASCULAR DISEASE, VIRTUALLY ALL OF WHICH ASSESSED EPIGENETIC DYSREGULATION GLOBALLY. WE HYPOTHESIZED THAT GENE-SPECIFIC EPIGENETIC DYSREGULATION IN CKD EXISTS, AFFECTING GENES PERTINENT TO INFLAMMATION AND ATHEROSCLEROSIS. METHODS AND RESULTS: TEN CLINICALLY STABLE PATIENTS UNDERGOING HEMODIALYSIS THERAPY AND 10 HEALTHY AGE- AND SEX-MATCHED CONTROLS WERE RECRUITED. GENOME-WIDE ANALYSIS OF DNA METHYLATION WAS PERFORMED BY SUPERTAG METHYLATION-SPECIFIC DIGITAL KARYOTYPING, IN ORDER TO IDENTIFY GENES DIFFERENTIALLY METHYLATED IN CKD. ANALYSIS OF 27 043 436 TAGS REVEALED 4288 GENOMIC LOCI WITH DIFFERENTIAL DNA METHYLATION (P<10(-10)) BETWEEN HEMODIALYSIS PATIENTS AND CONTROL SUBJECTS. ANNOTATION OF UNITAGS TO PROMOTER DATABASES ALLOWED US TO IDENTIFY 52 CANDIDATE GENES ASSOCIATED WITH CARDIOVASCULAR DISEASE AND 97 CANDIDATE GENES ASSOCIATED WITH IMMUNE/INFECTION DISEASES. THESE CANDIDATE GENES COULD BE CLASSIFIED TO DISTINCT PROATHEROGENIC PROCESSES, INCLUDING LIPID METABOLISM AND TRANSPORT (EG, HMGCR, SREBF1, LRP5, EPHX2, AND FDPS), CELL PROLIFERATION AND CELL-CYCLE REGULATION (EG, MIK67, TP53, AND ALOX12), ANGIOGENESIS (EG, ANGPT2, ADAMTS10, AND FLT4), AND INFLAMMATION (EG, TNFSF10, LY96, IFNGR1, HSPA1A, AND IL12RB1). CONCLUSIONS: WE PROVIDE A COMPREHENSIVE ANALYSIS OF GENOME-WIDE EPIGENETIC ALTERATIONS IN CKD, IDENTIFYING CANDIDATE GENES ASSOCIATED WITH PROATHEROGENIC AND INFLAMMATORY PROCESSES. THESE RESULTS MAY SPUR FURTHER RESEARCH IN THE FIELD OF EPIGENETICS IN KIDNEY DISEASE AND POINT TO NEW THERAPEUTIC STRATEGIES IN CKD-ASSOCIATED ATHEROSCLEROTIC DISEASE. 2012 2 546 36 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT. 2023 3 1990 31 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE. 2021 4 2629 28 EPIGENOME-WIDE ASSOCIATION STUDY OF DIABETIC CHRONIC KIDNEY DISEASE PROGRESSION IN THE KOREAN POPULATION: THE KNOW-CKD STUDY. SINCE THE ETIOLOGY OF DIABETIC CHRONIC KIDNEY DISEASE (CKD) IS MULTIFACTORIAL, STUDIES ON DNA METHYLATION FOR KIDNEY FUNCTION DETERIORATION HAVE RARELY BEEN PERFORMED DESPITE THE NEED FOR AN EPIGENETIC APPROACH. THEREFORE, THIS STUDY AIMED TO IDENTIFY EPIGENETIC MARKERS ASSOCIATED WITH CKD PROGRESSION BASED ON THE DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE IN DIABETIC CKD IN KOREA. AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING WHOLE BLOOD SAMPLES FROM 180 CKD RECRUITED FROM THE KNOW-CKD COHORT. PYROSEQUENCING WAS ALSO PERFORMED ON 133 CKD PARTICIPANTS AS AN EXTERNAL REPLICATION ANALYSIS. FUNCTIONAL ANALYSES, INCLUDING THE ANALYSIS OF DISEASE-GENE NETWORKS, REACTOME PATHWAYS, AND PROTEIN-PROTEIN INTERACTION NETWORKS, WERE CONDUCTED TO IDENTIFY THE BIOLOGICAL MECHANISMS OF CPG SITES. A PHENOME-WIDE ASSOCIATION STUDY WAS PERFORMED TO DETERMINE THE ASSOCIATIONS BETWEEN CPG SITES AND OTHER PHENOTYPES. TWO EPIGENETIC MARKERS, CG10297223 ON AGTR1 AND CG02990553 ON KRT28 INDICATED A POTENTIAL ASSOCIATION WITH DIABETIC CKD PROGRESSION. BASED ON THE FUNCTIONAL ANALYSES, OTHER PHENOTYPES (BLOOD PRESSURE AND CARDIAC ARRHYTHMIA FOR AGTR1) AND BIOLOGICAL PATHWAYS (KERATINIZATION AND CORNIFIED ENVELOPE FOR KRT28) RELATED TO CKD WERE ALSO IDENTIFIED. THIS STUDY SUGGESTS A POTENTIAL ASSOCIATION BETWEEN THE CG10297223 AND CG02990553 AND THE PROGRESSION OF DIABETIC CKD IN KOREANS. NEVERTHELESS, FURTHER VALIDATION IS NEEDED THROUGH ADDITIONAL STUDIES. 2023 5 1598 34 DNA METHYLATION SIGNATURE IN MONONUCLEAR CELLS AND PROINFLAMMATORY CYTOKINES MAY DEFINE MOLECULAR SUBTYPES IN SPORADIC MENIERE DISEASE. MENIERE DISEASE (MD) IS A MULTIFACTORIAL DISORDER OF THE INNER EAR CHARACTERIZED BY VERTIGO ATTACKS ASSOCIATED WITH SENSORINEURAL HEARING LOSS AND TINNITUS WITH A SIGNIFICANT HERITABILITY. ALTHOUGH MD HAS BEEN ASSOCIATED WITH SEVERAL GENES, NO EPIGENETIC STUDIES HAVE BEEN PERFORMED ON MD. HERE WE PERFORMED WHOLE-GENOME BISULFITE SEQUENCING IN 14 MD PATIENTS AND SIX HEALTHY CONTROLS, WITH THE AIM OF IDENTIFYING AN MD METHYLATION SIGNATURE AND POTENTIAL DISEASE MECHANISMS. WE OBSERVED A HIGH NUMBER OF DIFFERENTIALLY METHYLATED CPGS (DMC) WHEN COMPARING MD PATIENTS TO CONTROLS (N= 9545), SEVERAL OF THEM IN HEARING LOSS GENES, SUCH AS PCDH15,&NBSP;ADGRV1 AND CDH23. BIOINFORMATIC ANALYSES OF DMCS AND CIS-REGULATORY REGIONS PREDICTED PHENOTYPES RELATED TO ABNORMAL EXCITATORY POSTSYNAPTIC CURRENTS, ABNORMAL NMDA-MEDIATED RECEPTOR CURRENTS AND ABNORMAL GLUTAMATE-MEDIATED RECEPTOR CURRENTS WHEN COMPARING MD TO CONTROLS. MOREOVER, WE IDENTIFIED VARIOUS DMCS IN GENES PREVIOUSLY ASSOCIATED WITH COCHLEOVESTIBULAR PHENOTYPES IN MICE. WE HAVE ALSO FOUND 12 UNDERMETHYLATED REGIONS (UMR) THAT WERE EXCLUSIVE TO MD, INCLUDING TWO UMR IN AN INTER CPG ISLAND IN THE PHB GENE. WE SUGGEST THAT THE DNA METHYLATION SIGNATURE ALLOWS DISTINGUISHING BETWEEN MD PATIENTS AND CONTROLS. THE ENRICHMENT ANALYSIS CONFIRMS PREVIOUS FINDINGS OF A CHRONIC INFLAMMATORY PROCESS UNDERLYING MD. 2021 6 662 32 BLOOD MONOCYTE TRANSCRIPTOME AND EPIGENOME ANALYSES REVEAL LOCI ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. LITTLE IS KNOWN REGARDING THE EPIGENETIC BASIS OF ATHEROSCLEROSIS. HERE WE PRESENT THE CD14+ BLOOD MONOCYTE TRANSCRIPTOME AND EPIGENOME SIGNATURES ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. THE TRANSCRIPTOME SIGNATURE INCLUDES TRANSCRIPTION COACTIVATOR, ARID5B, WHICH IS KNOWN TO FORM A CHROMATIN DEREPRESSOR COMPLEX WITH A HISTONE H3K9ME2-SPECIFIC DEMETHYLASE AND PROMOTE ADIPOGENESIS AND SMOOTH MUSCLE DEVELOPMENT. ARID5B CPG (CG25953130) METHYLATION IS INVERSELY ASSOCIATED WITH BOTH ARID5B EXPRESSION AND ATHEROSCLEROSIS, CONSISTENT WITH THIS CPG RESIDING IN AN ARID5B ENHANCER REGION, BASED ON CHROMATIN CAPTURE AND HISTONE MARKS DATA. MEDIATION ANALYSIS SUPPORTS ASSUMPTIONS THAT ARID5B EXPRESSION MEDIATES EFFECTS OF CG25953130 METHYLATION AND SEVERAL CARDIOVASCULAR DISEASE RISK FACTORS ON ATHEROSCLEROTIC BURDEN. IN LIPOPOLYSACCHARIDE-STIMULATED HUMAN THP1 MONOCYTES, ARID5B KNOCKDOWN REDUCED EXPRESSION OF GENES INVOLVED IN ATHEROSCLEROSIS-RELATED INFLAMMATORY AND LIPID METABOLISM PATHWAYS, AND INHIBITED CELL MIGRATION AND PHAGOCYTOSIS. THESE DATA SUGGEST THAT ARID5B EXPRESSION, POSSIBLY REGULATED BY AN EPIGENETICALLY CONTROLLED ENHANCER, PROMOTES ATHEROSCLEROSIS BY DYSREGULATING IMMUNOMETABOLISM TOWARDS A CHRONIC INFLAMMATORY PHENOTYPE.THE MOLECULAR MECHANISMS MEDIATING THE IMPACT OF ENVIRONMENTAL FACTORS IN ATHEROSCLEROSIS ARE UNCLEAR. HERE, THE AUTHORS EXAMINE CD14+ BLOOD MONOCYTE'S TRANSCRIPTOME AND EPIGENOME SIGNATURES TO FIND DIFFERENTIAL METHYLATION AND EXPRESSION OF ARID5B TO BE ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. 2017 7 3764 32 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY. 2015 8 3050 28 GENOME-WIDE ASSOCIATION ANALYSES FOR LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE IDENTIFY NEW LOCI AND POTENTIAL DRUGGABLE TARGETS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY REDUCED LUNG FUNCTION AND IS THE THIRD LEADING CAUSE OF DEATH GLOBALLY. THROUGH GENOME-WIDE ASSOCIATION DISCOVERY IN 48,943 INDIVIDUALS, SELECTED FROM EXTREMES OF THE LUNG FUNCTION DISTRIBUTION IN UK BIOBANK, AND FOLLOW-UP IN 95,375 INDIVIDUALS, WE INCREASED THE YIELD OF INDEPENDENT SIGNALS FOR LUNG FUNCTION FROM 54 TO 97. A GENETIC RISK SCORE WAS ASSOCIATED WITH COPD SUSCEPTIBILITY (ODDS RATIO PER 1 S.D. OF THE RISK SCORE ( APPROXIMATELY 6 ALLELES) (95% CONFIDENCE INTERVAL) = 1.24 (1.20-1.27), P = 5.05 X 10(-49)), AND WE OBSERVED A 3.7-FOLD DIFFERENCE IN COPD RISK BETWEEN INDIVIDUALS IN THE HIGHEST AND LOWEST GENETIC RISK SCORE DECILES IN UK BIOBANK. THE 97 SIGNALS SHOW ENRICHMENT IN GENES FOR DEVELOPMENT, ELASTIC FIBERS AND EPIGENETIC REGULATION PATHWAYS. WE HIGHLIGHT TARGETS FOR DRUGS AND COMPOUNDS IN DEVELOPMENT FOR COPD AND ASTHMA (GENES IN THE INOSITOL PHOSPHATE METABOLISM PATHWAY AND CHRM3) AND DESCRIBE TARGETS FOR POTENTIAL DRUG REPOSITIONING FROM OTHER CLINICAL INDICATIONS. 2017 9 1541 29 DNA METHYLATION IN GENES OF LONGEVITY-REGULATING PATHWAYS: ASSOCIATION WITH OBESITY AND METABOLIC COMPLICATIONS. AGING IS THE MAIN RISK FACTOR FOR MOST CHRONIC DISEASES. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION (DNAM) PLAYS A PIVOTAL ROLE IN THE REGULATION OF PHYSIOLOGICAL RESPONSES THAT CAN VARY ALONG LIFESPAN. THE AIM OF THIS RESEARCH WAS TO ANALYZE THE ASSOCIATION BETWEEN LEUKOCYTE DNAM IN GENES INVOLVED IN LONGEVITY AND THE OCCURRENCE OF OBESITY AND RELATED METABOLIC ALTERATIONS IN AN ADULT POPULATION. SUBJECTS FROM THE MENA COHORT (N=474) WERE CATEGORIZED ACCORDING TO AGE (<45 VS 45>) AND THE PRESENCE OF METABOLIC ALTERATIONS: INCREASED WAIST CIRCUMFERENCE, HYPERCHOLESTEROLEMIA, INSULIN RESISTANCE, AND METABOLIC SYNDROME. THE METHYLATION LEVELS OF 58 CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE STRONGLY CORRELATED (FDR-ADJUSTED< 0.0001) WITH BMI. FIFTEEN OF THEM WERE DIFFERENTIALLY METHYLATED (P<0.05) BETWEEN YOUNGER AND OLDER SUBJECTS THAT EXHIBITED AT LEAST ONE METABOLIC ALTERATION. SIX OF THESE CPG SITES, LOCATED AT MTOR (CG08862778), ULK1 (CG07199894), ADCY6 (CG11658986), IGF1R (CG01284192), CREB5 (CG11301281), AND RELA (CG08128650), WERE COMMON TO THE METABOLIC TRAITS, AND CREB5, RELA, AND ULK1 WERE STATISTICALLY ASSOCIATED WITH AGE. IN SUMMARY, LEUKOCYTE DNAM LEVELS OF SEVERAL CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME TRAITS, SUGGESTING A ROLE OF DNAM IN AGING-RELATED METABOLIC ALTERATIONS. 2019 10 6826 35 [GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS INDICATES INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE DISEASE IMMUNOPATHOGENESIS]. THE PATHOGENESIS OF MULTIPLE SCLEROSIS (MS), A CHRONIC DISEASE OF THE CNS, INCLUDES AUTOIMMUNE AND NEURODEGENERATIVE COMPONENTS. IN MOST CASES, PATIENTS DEVELOP RELAPSING-REMITTING MS (RRMS), WHILE 10-15% OF PATIENTS DEVELOP PRIMARY PROGRESSIVE MS (PPMS), WHICH DIFFERS FROM RRMS IN THE MECHANISMS OF THE PATHOLOGICAL PROCESS, SOME DEMOGRAPHIC, AND SOME CLINICAL CHARACTERISTICS. THESE DIFFERENCES MAY BE EXPLAINED BY THE EPIGENETIC REGULATION OF GENE EXPRESSION IN PPMS INCLUDING DNA METHYLATION AS ONE OF THE KEY EPIGENETIC PROCESSES. THE FEATURES OF DNA METHYLATION IN VARIOUS CELL POPULATIONS IN PPMS PATIENTS REMAIN UNDERSTUDIED. THE GOAL OF THIS STUDY IS TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES (DMSS) OF THE GENOME OF CD4+ T LYMPHOCYTES, WHICH CHARACTERIZE PPMS. THE STUDY INCLUDED EIGHT TREATMENT-NAIVE PPMS PATIENTS AND EIGHT HEALTHY CONTROLS. GENOME-WIDE ANALYSIS OF DNA METHYLATION OF CD4+ T LYMPHOCYTES WAS PERFORMED USING HIGH-DENSITY DNA MICROARRAYS. WE HAVE IDENTIFIED 108 DMSS, WHICH DISTINGUISH PPMS PATIENTS FROM HEALTHY CONTROLS. IN PPMS PATIENTS 81% OF THE DMSS ARE HYPERMETHYLATED. MORE THAN A HALF OF THE IDENTIFIED DMSS ARE LOCATED IN KNOWN GENES IN CPG ISLANDS AND ADJACENT REGIONS, WHICH INDICATES A HIGH FUNCTIONAL SIGNIFICANCE OF THESE DMSS IN PPMS DEVELOPMENT. ANALYSIS OF THE OVERREPRESENTATION OF DMS-CONTAINING GENES IN THE MAIN BIOLOGICAL PROCESSES DEMONSTRATES THEIR INVOLVEMENT IN THE REGULATION OF CELL ADHESION TO THE EXTRACELLULAR MATRIX AND THE DEVELOPMENT OF THE IMMUNE RESPONSE, I.E., ANTIGEN PROCESSING AND PRESENTATION, AND DEVELOPMENT OF THE IMMUNE SYSTEM. GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PPMS PATIENTS INDICATES THE INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE IMMUNOPATHOGENESIS OF THE DISEASE. THESE RESULTS MAY HELP BETTER UNDERSTAND THE PATHOGENESIS OF THIS SEVERE FORM OF MS. 2022 11 3959 31 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS. 2019 12 3296 30 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT. 2013 13 5887 33 SYSTEMIC STEROID EXPOSURE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. RATIONALE: SYSTEMIC GLUCOCORTICOIDS ARE USED THERAPEUTICALLY TO TREAT A VARIETY OF MEDICAL CONDITIONS. EPIGENETIC PROCESSES SUCH AS DNA METHYLATION MAY REFLECT EXPOSURE TO GLUCOCORTICOIDS AND MAY BE INVOLVED IN MEDIATING THE RESPONSES AND SIDE EFFECTS ASSOCIATED WITH THESE MEDICATIONS. OBJECTIVES: TO TEST THE HYPOTHESIS THAT DIFFERENCES IN DNA METHYLATION ARE ASSOCIATED WITH CURRENT SYSTEMIC STEROID USE. METHODS: WE OBTAINED DNA METHYLATION DATA AT 27,578 CPG SITES IN 14,475 GENES THROUGHOUT THE GENOME IN TWO LARGE, INDEPENDENT COHORTS: THE INTERNATIONAL COPD GENETICS NETWORK (N(DISCOVERY) = 1,085) AND THE BOSTON EARLY ONSET COPD STUDY (N(REPLICATION) = 369). SITES WERE TESTED FOR ASSOCIATION WITH CURRENT SYSTEMIC STEROID USE USING GENERALIZED LINEAR MIXED MODELS. MEASUREMENTS AND MAIN RESULTS: A TOTAL OF 511 SITES DEMONSTRATED SIGNIFICANT DIFFERENTIAL METHYLATION BY SYSTEMIC CORTICOSTEROID USE IN ALL THREE OF OUR PRIMARY MODELS. PYROSEQUENCING VALIDATION CONFIRMED ROBUST DIFFERENTIAL METHYLATION AT CPG SITES ANNOTATED TO GENES SUCH AS SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, AND RABGEF1. FUNCTIONAL ANNOTATION CLUSTERING DEMONSTRATED SIGNIFICANT ENRICHMENT IN INTRINSIC MEMBRANE COMPONENTS, HEMOSTASIS AND COAGULATION, CELLULAR ION HOMEOSTASIS, LEUKOCYTE AND LYMPHOCYTE ACTIVATION AND CHEMOTAXIS, PROTEIN TRANSPORT, AND RESPONSES TO NUTRIENTS. CONCLUSIONS: OUR ANALYSES SUGGEST THAT SYSTEMIC STEROID USE IS ASSOCIATED WITH SITE-SPECIFIC DIFFERENTIAL METHYLATION THROUGHOUT THE GENOME. DIFFERENTIALLY METHYLATED CPG SITES WERE FOUND IN BIOLOGICALLY PLAUSIBLE AND PREVIOUSLY UNSUSPECTED PATHWAYS; THESE GENES AND PATHWAYS MAY BE RELEVANT IN THE DEVELOPMENT OF NOVEL TARGETED THERAPIES. 2012 14 11 37 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING. 2015 15 3073 44 GENOME-WIDE DNA METHYLATION STATUS OF MONGOLIANS EXHIBITS SIGNS OF CELLULAR STRESS RESPONSE RELATED TO THEIR NOMADIC LIFESTYLE. BACKGROUND: EPIGENETICS IS CRUCIAL FOR CONNECTING ENVIRONMENTAL STRESSES WITH PHYSIOLOGICAL RESPONSES IN HUMANS. MONGOLIA, WHERE NOMADIC LIVESTOCK PASTORALISM HAS BEEN THE PRIMAL LIVELIHOOD, HAS A HIGHER PREVALENCE OF VARIOUS CHRONIC DISEASES THAN THE SURROUNDING EAST ASIAN REGIONS, WHICH ARE MORE SUITABLE FOR CROP FARMING. THE GENES RELATED TO DIETARY STRESS AND PATHOGENESIS OF RELATED DISORDERS MAY HAVE VARYING EPIGENETIC STATUSES AMONG THE HUMAN POPULATIONS WITH DIVERSE DIETARY CULTURES. HENCE, TO UNDERSTAND SUCH EPIGENETIC DIFFERENCES, WE CONDUCTED A COMPARATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION OF MONGOLIANS AND CROP-FARMING EAST ASIANS. METHODS: GENOME-WIDE DNA METHYLATION STATUS OF PERIPHERAL BLOOD CELLS (PBCS) FROM 23 MONGOLIAN ADULTS AND 24 THAI ADULTS WAS DETERMINED USING THE INFINIUM HUMAN METHYLATION 450K ARRAYS AND ANALYZED IN COMBINATION WITH PREVIOUSLY PUBLISHED 450K DATA OF 20 JAPANESE AND 8 CHINESE ADULTS. CPG SITES/REGIONS DIFFERENTIALLY METHYLATED BETWEEN MONGOLIANS AND CROP-FARMING EAST ASIANS WERE DETECTED USING A LINEAR MODEL ADJUSTED FOR SEX, AGE, ETHNICITY, AND IMMUNE CELL HETEROGENEITY ON RNBEADS SOFTWARE. RESULTS: OF THE QUALITY-CONTROLLED 389,454 AUTOSOMAL CPG SITES, 223 CPG SITES WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED AMONG MONGOLIANS AND THE FOUR CROP FARMING EAST ASIAN POPULATIONS (FALSE DISCOVERY RATE < 0.05). ANALYSES FOCUSED ON GENE PROMOTER REGIONS REVEALED THAT PM20D1 (PEPTIDASE M20 DOMAIN CONTAINING 1), WHICH IS INVOLVED IN MITOCHONDRIAL UNCOUPLING AND VARIOUS PROCESSES, INCLUDING CELLULAR PROTECTION FROM REACTIVE OXYGEN SPECIES (ROS) AND THERMOGENESIS, WAS THE TOP DIFFERENTIALLY METHYLATED GENE. MOREOVER, GENE ONTOLOGY ENRICHMENT ANALYSIS REVEALED THAT BIOLOGICAL PROCESSES RELATED TO ROS METABOLISM WERE OVERREPRESENTED AMONG THE TOP 1% DIFFERENTIALLY METHYLATED GENES. THE PROMOTER REGIONS OF THESE GENES WERE GENERALLY HYPERMETHYLATED IN MONGOLIANS, SUGGESTING THAT THE METABOLIC PATHWAY DETOXIFYING ROS MIGHT BE GLOBALLY SUPPRESSED IN MONGOLIANS, RESULTING IN THE HIGH SUSCEPTIBILITY OF THIS POPULATION TO VARIOUS CHRONIC DISEASES. CONCLUSIONS: THIS STUDY SHOWED A SIGNIFICANTLY DIVERSE DNA METHYLATION STATUS AMONG MONGOLIANS AND CROP-FARMING EAST ASIANS. FURTHER, WE FOUND AN ASSOCIATION BETWEEN THE DIFFERENTIALLY METHYLATED GENES AND VARIOUS METABOLIC AND NEURODEGENERATIVE DISEASES. KNOWLEDGE OF THE EPIGENETIC REGULATORS MIGHT HELP IN PROPER UNDERSTANDING, TREATMENT, AND CONTROL OF SUCH DISORDERS, AND PHYSIOLOGICAL ADAPTATION IN THE FUTURE. 2022 16 177 35 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS. 2022 17 5845 30 STUDY PROTOCOL FOR THE EPIGENETIC CHARACTERIZATION OF ANGOR PECTORIS ACCORDING TO THE AFFECTED CORONARY COMPARTMENT: GLOBAL AND COMPREHENSIVE ASSESSMENT OF THE RELATIONSHIP BETWEEN INVASIVE CORONARY PHYSIOLOGY AND MICRORNAS. BACKGROUND: MICRORNAS (MIRNAS) ARE NONCODING RNAS INVOLVED IN POST-TRANSCRIPTIONAL GENETIC REGULATION WITH A PROPOSED ROLE IN INTERCELLULAR COMMUNICATION. MIRNAS ARE CONSIDERED PROMISING BIOMARKERS IN ISCHEMIC HEART DISEASE. INVASIVE PHYSIOLOGICAL EVALUATION ALLOWS A PRECISE ASSESSMENT OF EACH AFFECTED CORONARY COMPARTMENT. ALTHOUGH SOME STUDIES HAVE ASSOCIATED THE EXPRESSION OF CIRCULATING MIRNAS WITH INVASIVE PHYSIOLOGICAL INDEXES, THEIR GLOBAL RELATIONSHIP WITH CORONARY COMPARTMENTS HAS NOT BEEN ASSESSED. HERE, WE WILL EVALUATE CIRCULATING MIRNAS PROFILES ACCORDING TO THE CORONARY PATTERN OF THE VASCULAR COMPARTMENT AFFECTATION. STUDY AND DESIGN: THIS IS AN INVESTIGATOR-INITIATED, MULTICENTRE, DESCRIPTIVE STUDY TO BE CONDUCTED AT THREE CENTRES IN SPAIN (NCT05374694). THE STUDY WILL INCLUDE ONE HUNDRED CONSECUTIVE PATIENTS OLDER THAN 18 YEARS WITH CHEST PAIN OF PRESUMED CORONARY CAUSE UNDERGOING INVASIVE PHYSIOLOGICAL EVALUATION, INCLUDING FRACTIONAL FLOW RESERVE (FFR) AND INDEX OF MICROVASCULAR RESISTANCE (IMR). PATIENTS WILL BE INITIALLY CLASSIFIED INTO FOUR GROUPS, ACCORDING TO FFR AND IMR: MACROVASCULAR AND MICROVASCULAR AFFECTATION (FFR/=25), ISOLATED MACROVASCULAR AFFECTATION (FFR0.80 / IMR >/=25) AND NORMAL CORONARY INDEXES (FFR>0.80 / IMR<25). PATIENTS WITH ISOLATED MICROVASCULAR AFFECTATION OR NORMAL INDEXES WILL ALSO UNDERGO THE ACETYLCHOLINE TEST AND MAY BE RECLASSIFIED AS A FIFTH GROUP IN THE PRESENCE OF SPASM. A PANEL OF MIRNAS PREVIOUSLY ASSOCIATED WITH MOLECULAR MECHANISMS LINKED TO CHRONIC CORONARY SYNDROME WILL BE ANALYSED USING RT-QPCR. CONCLUSIONS: THE RESULTS OF THIS STUDY WILL IDENTIFY MIRNA PROFILES ASSOCIATED WITH PATTERNS OF CORONARY AFFECTATION AND WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE MECHANISTIC PATHWAYS OF CORONARY PATHOLOGY. 2023 18 6358 36 THE ROLE OF IL?16 GENE POLYMORPHISMS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS ONE OF THE MOST COMMON GYNECOLOGICAL DISEASES AFFECTING UP TO 10% OF THE FEMALE POPULATION OF CHILDBEARING AGE AND A MAJOR CAUSE OF PAIN AND INFERTILITY. IT IS INFLUENCED BY MULTIPLE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. INTERLEUKIN?16 (IL?16) IS A PROINFLAMMATORY CYTOKINE PLAYING A PIVOTAL ROLE IN MANY INFLAMMATORY AND AUTOIMMUNE DISEASES AS WELL AS IN THE PATHOGENESIS OF ENDOMETRIOSIS. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE ASSOCIATION OF TWO IL?16 GENE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), RS4072111 AND RS11556218, WITH THE RISK OF ENDOMETRIOSIS IN WOMEN FROM GREECE AS WELL AS TO GAIN INSIGHT ABOUT THE STRUCTURAL CONSEQUENCES OF THESE TWO EXONIC SNPS REGARDING DEVELOPMENT OF THE DISEASE. A TOTAL OF 159 WOMEN WITH ENDOMETRIOSIS (STAGES I?IV) HOSPITALIZED FOR ENDOMETRIOSIS, DIAGNOSED BY LAPAROSCOPIC INTERVENTION AND HISTOLOGICALLY CONFIRMED, AND 146 NORMAL CONTROLS WERE RECRUITED AND GENOTYPED. SUBJECTS WERE GENOTYPED USING A POLYMERASE CHAIN REACTION RESTRICTION FRAGMENT LENGTH POLYMORPHISM (PCR?RFLP) STRATEGY. A SIGNIFICANT ASSOCIATION WAS DETECTED REGARDING THE GG AND GT GENOTYPE AS WELL AS 'G' ALLELE OF RS11556218 IN PATIENTS WITH ENDOMETRIOSIS. THE RS4072111 SNP OF THE IL?16 GENE WAS NOT FOUND TO BE ASSOCIATED WITH AN INCREASED SUSCEPTIBILITY TO ENDOMETRIOSIS EITHER FOR ALL PATIENTS (STAGES I?IV) OR FOR STAGE III AND IV OF THE DISEASE ONLY. OUR RESULTS DEMONSTRATED THAT RS11556218 IS ASSOCIATED WITH ENDOMETRIOSIS IN GREEK WOMEN, PROBABLY BY RESULTING IN THE ABERRANT EXPRESSION OF IL?16, AS SUGGESTED BY THE BIOINFORMATICS ANALYSIS CONDUCTED ON THE SNP?DERIVED PROTEIN SEQUENCES, WHICH INDICATED A POSSIBLE ASSOCIATION BETWEEN MUTATION AND FUNCTIONAL MODIFICATION OF PRO?IL?16. 2018 19 1121 23 COMPARISON OF EPIGENETIC PROFILES OF HUMAN ORAL EPITHELIAL CELLS FROM HIV-POSITIVE (ON HAART) AND HIV-NEGATIVE SUBJECTS. HIV-INFECTED SUBJECTS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) ARE SUSCEPTIBLE TO COMORBID MICROBIAL INFECTIONS IN THE ORAL CAVITY. WE OBSERVED THAT PRIMARY ORAL EPITHELIAL CELLS (POECS) ISOLATED FROM HIV+ SUBJECTS ON HAART GROW MORE SLOWLY AND ARE LESS INNATE IMMUNE RESPONSIVE TO MICROBIAL CHALLENGE WHEN COMPARED WITH POECS FROM NORMAL SUBJECTS. THESE ABERRANT CELLS ALSO DEMONSTRATE EPIGENETIC DIFFERENCES THAT INCLUDE REDUCTION IN HISTONE DEACETYLASE 1 (HDAC-1) LEVELS AND REDUCED TOTAL DNA METHYLTRANSFERASE (DNMT) ACTIVITY SPECIFIC TO ENZYMES DNMT1 AND DNMT3A. THE DNMT ACTIVITY CORRELATES WELL WITH GLOBAL DNA METHYLATION, INDICATING THAT ABERRANT DNMT ACTIVITY IN HIV+ (ON HAART) POECS LEADS TO AN ABERRANTLY METHYLATED EPITHELIAL CELL PHENOTYPE. OVERALL, OUR RESULTS LEAD US TO HYPOTHESIZE THAT, IN PATIENTS WITH CHRONIC HIV INFECTION ON HAART, EPIGENETIC CHANGES IN KEY GENES RESULT IN INCREASED VULNERABILITY TO MICROBIAL INFECTION IN THE ORAL CAVITY. 2013 20 275 27 AGE-RELATED CLONAL HAEMOPOIESIS IS ASSOCIATED WITH INCREASED EPIGENETIC AGE. AGE-RELATED CLONAL HAEMOPOIESIS (ARCH) IN HEALTHY INDIVIDUALS WAS INITIALLY OBSERVED THROUGH AN INCREASED SKEWING IN X-CHROMOSOME INACTIVATION [1]. MORE RECENTLY, SEVERAL GROUPS REPORTED THAT ARCH IS DRIVEN BY SOMATIC MUTATIONS [2], WITH THE MOST PREVALENT ARCH MUTATIONS BEING IN THE DNMT3A AND TET2 GENES, PREVIOUSLY DESCRIBED AS DRIVERS OF MYELOID MALIGNANCIES. ARCH IS ASSOCIATED WITH AN INCREASED RISK FOR HAEMATOLOGICAL CANCERS [2]. ARCH ALSO CONFERS AN INCREASED RISK FOR NON-HAEMATOLOGICAL DISEASES, SUCH AS CARDIOVASCULAR DISEASE, ATHEROSCLEROSIS, AND CHRONIC ISCHEMIC HEART FAILURE, FOR WHICH AGE IS A MAIN RISK FACTOR [3,4]. WHETHER ARCH IS LINKED TO ACCELERATED AGEING HAS REMAINED UNEXPLORED. THE MOST ACCURATE AND COMMONLY USED TOOLS TO MEASURE AGE ACCELERATION ARE EPIGENETIC CLOCKS: THEY ARE BASED ON AGE-RELATED METHYLATION DIFFERENCES AT SPECIFIC CPG SITES [5]. DEVIATIONS FROM CHRONOLOGICAL AGE TOWARDS AN INCREASED EPIGENETIC AGE HAVE BEEN ASSOCIATED WITH INCREASED RISK OF EARLIER MORTALITY AND AGE-RELATED MORBIDITIES [5,6]. HERE WE PRESENT EVIDENCE OF ACCELERATED EPIGENETIC AGE IN INDIVIDUALS WITH ARCH. 2019