1  1571 196 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT.	2021	
                                                                                                                                                                                                                                                                                   
2  1570  88 DNA METHYLATION PATTERNS IN CD4(+) T-CELLS SEPARATE PSORIASIS PATIENTS FROM HEALTHY CONTROLS, AND SKIN PSORIASIS FROM PSORIATIC ARTHRITIS. BACKGROUND: PSORIASIS IS AN AUTOIMMUNE/INFLAMMATORY DISORDER PRIMARILY AFFECTING THE SKIN. CHRONIC JOINT INFLAMMATION TRIGGERS THE DIAGNOSIS OF PSORIATIC ARTHRITIS (PSA) IN APPROXIMATELY ONE-THIRD OF PSORIASIS PATIENTS. ALTHOUGH JOINT DISEASE TYPICALLY FOLLOWS THE ONSET OF SKIN PSORIASIS, IN AROUND 15% OF CASES IT IS THE INITIAL PRESENTATION, WHICH CAN RESULT IN DIAGNOSTIC DELAYS. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING PSORIASIS AND PSA ARE NOT YET FULLY UNDERSTOOD, BUT THERE IS EVIDENCE POINTING TOWARDS EPIGENETIC DYSREGULATION INVOLVING CD4(+) AND CD8(+) T-CELLS. OBJECTIVES: THE AIM OF THIS STUDY WAS TO INVESTIGATE DISEASE-ASSOCIATED DNA METHYLATION PATTERNS IN CD4(+) T-CELLS FROM PSORIASIS AND PSA PATIENTS THAT MAY REPRESENT POTENTIAL DIAGNOSTIC AND/OR PROGNOSTIC BIOMARKERS. METHODS: PBMCS WERE COLLECTED FROM 12 PATIENTS WITH CHRONIC PLAQUE PSORIASIS AND 8 PSA PATIENTS, AND 8 HEALTHY CONTROLS. CD4(+) T-CELLS WERE SEPARATED THROUGH FACS SORTING, AND DNA METHYLATION PROFILING WAS PERFORMED (ILLUMINA EPIC850K ARRAYS). BIOINFORMATIC ANALYSES, INCLUDING GENE ONTOLOGY (GO) AND KEGG PATHWAY ANALYSIS, WERE PERFORMED USING R. TO IDENTIFY GENES UNDER THE CONTROL OF INTERFERON (IFN), THE INTERFEROME DATABASE WAS CONSULTED, AND DNA METHYLATION SCORES WERE CALCULATED. RESULTS: NUMBERS AND PROPORTIONS OF CD4(+) T-CELL SUBSETS (NAIVE, CENTRAL MEMORY, EFFECTOR MEMORY, CD45RA RE-EXPRESSING EFFECTOR MEMORY CELLS) DID NOT VARY BETWEEN CONTROLS, SKIN PSORIASIS AND PSA PATIENTS. 883 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AFFECTING 548 GENES WERE IDENTIFIED BETWEEN CONTROLS AND "ALL" PSORIASIS PATIENTS. PRINCIPAL COMPONENT AND PARTIAL LEAST-SQUARES DISCRIMINANT ANALYSIS SEPARATED CONTROLS FROM SKIN PSORIASIS AND PSA PATIENTS. GO ANALYSIS CONSIDERING PROMOTER DMPS DELIVERED HYPERMETHYLATION OF GENES INVOLVED IN "REGULATION OF WOUND HEALING, SPREADING OF EPIDERMAL CELLS", "NEGATIVE REGULATION OF CELL-SUBSTRATE JUNCTION ORGANIZATION" AND "NEGATIVE REGULATION OF FOCAL ADHESION ASSEMBLY". COMPARING CONTROLS AND "ALL" PSORIASIS, A MAJORITY OF DMPS MAPPED TO IFN-RELATED GENES (69.2%). NOTABLY, DNA METHYLATION PROFILES ALSO DISTINGUISHED SKIN PSORIASIS FROM PSA PATIENTS (2,949 DMPS/1,084 GENES) THROUGH GENES AFFECTING "CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ACTIVITY" AND "CAMP-DEPENDENT PROTEIN KINASE REGULATOR ACTIVITY". TREATMENT WITH CYTOKINE INHIBITORS (IL-17/TNF) CORRECTED DNA METHYLATION PATTERNS OF IL-17/TNF-ASSOCIATED GENES, AND METHYLATION SCORES CORRELATED WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: DNA METHYLATION PROFILES IN CD4(+) T-CELLS DISCRIMINATE BETWEEN SKIN PSORIASIS AND PSA. DNA METHYLATION SIGNATURES MAY BE APPLIED FOR QUANTIFICATION OF DISEASE ACTIVITY AND PATIENT STRATIFICATION TOWARDS INDIVIDUALIZED TREATMENT.	2023	
                                                                                                                                                                                                         
3  3070  58 GENOME-WIDE DNA METHYLATION PROFILING IN CD8 T-CELLS AND GAMMA DELTA T-CELLS OF ASIAN INDIAN PATIENTS WITH TAKAYASU ARTERITIS. BACKGROUND: TAKAYASU'S ARTERITIS (TA) IS A CHRONIC INFLAMMATORY DISEASE THAT AFFECTS AORTA AND ITS MAIN BRANCHES AT THEIR ORIGIN. GENETIC, PATHOLOGICAL AND FUNCTIONAL STUDIES HAVE SHOWN THAT CD8 AND GAMMA DELTA (GAMMA/DELTA) T-LYMPHOCYTES ARE INVOLVED IN INFLAMMATORY PROCESSES IN AFFECTED REGIONS OF ARTERIES CAUSING VASCULAR DAMAGE. THE MOLECULAR FUNCTION OF THESE LYMPHOCYTES REMAINS UNCLEAR AND CURRENTLY NO EPIGENETIC STUDIES ARE AVAILABLE IN TA. WE PRIMARILY PERFORMED GENOME WIDE METHYLATION ANALYSIS IN CD8 T CELLS AND GAMMADELTA T CELLS OF PATIENTS WITH TA AND COMPARED WITH HEALTHY CONTROLS. METHODS: WE RECRUITED 12 SUBJECTS IN EACH GROUP NAMELY TA PATIENT AND HEALTHY CONTROLS. BLOOD SAMPLES WERE COLLECTED AFTER OBTAINING INFORMED WRITTEN CONSENT. CD8 T CELLS AND GAMMADELTA T CELLS WERE SEPARATED FROM WHOLE BLOOD. DNA EXTRACTED FROM THESE CELLS AND WERE SUBJECTED TO BISULFITE TREATMENT. FINALLY, BISULFITE TREATED DNA WAS LOADED IN INFINIUM METHYLATION EPIC ARRAY. BIOINFORMATICS ANALYSIS WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS WHICH WERE THEN MAPPED TO GENES. RESULTS: INTERLEUKIN (IL)-32 AND LYMPHOTOXIN-A WERE GENES SIGNIFICANTLY HYPOMETHYLATED IN CD8 T-CELLS. ANTI-INFLAMMATORY CYTOKINE GENES, IL-10, IL-1RN AND IL-27 WERE HYPOMETHYLATED IN GAMMADELTA T CELLS OF TA PATIENTS AS COMPARED TO HEALTHY CONTROLS. GENE ENRICHMENT ANALYSIS USING GENE ONTOLOGY (GO) DATABASE AND KYOTO ENCYCLOPAEDIA OF GENES AND GENOMES (KEGG) IDENTIFIED THAT GENES INVOLVED IN T-CELL RECEPTOR SIGNALLING PATHWAYS WERE HYPOMETHYLATED IN CD8 T-CELLS AND HYPERMETHYLATED IN GAMMADELTA T CELLS OF TA PATIENTS. CONCLUSION: CD8 T-CELLS MIGHT PLAY A MAJOR ROLE IN IMMUNOPATHOGENESIS OF INFLAMMATION IN TA, WHEREAS GAMMADELTA T CELLS MAY PLAY A REGULATORY ROLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4  3056  48 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  1061  53 CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS IS CHARACTERIZED BY AN UPREGULATION OF PERIPHERAL T-REGULATORY CELL POLARIZED TOWARDS T-BET AND TIGIT. BACKGROUND: NON-INFECTIOUS UVEITIS CAN CAUSE CHRONIC RELAPSING AND REMITTING OCULAR INFLAMMATION, WHICH MAY REQUIRE HIGH DOSE SYSTEMIC IMMUNOSUPPRESSION TO PREVENT SEVERE SIGHT LOSS. IT HAS BEEN CLASSICALLY DESCRIBED AS AN AUTOIMMUNE DISEASE, MEDIATED BY PRO-INFLAMMATORY TH1 AND TH17 T-CELL SUBSETS. STUDIES SUGGEST THAT NATURAL IMMUNOSUPPRESSIVE CD4(+)CD25(+)FOXP3(+) T-REGULATORY CELLS (TREGS) ARE INVOLVED IN RESOLUTION OF INFLAMMATION AND MAY BE INVOLVED IN THE MAINTENANCE OF CLINICAL REMISSION. OBJECTIVE: TO INVESTIGATE WHETHER THERE IS A PERIPHERAL BLOOD IMMUNOREGULATORY PHENOTYPE ASSOCIATED WITH CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS BY COMPARING PERIPHERAL BLOOD LEVELS OF TREG, TH1, AND TH17, AND ASSOCIATED DNA METHYLATION AND CYTOKINE LEVELS IN PATIENTS WITH ACTIVE UVEITIC DISEASE, CONTROL SUBJECTS AND PATIENTS (WITH PREVIOUSLY ACTIVE DISEASE) IN CLINICAL REMISSION INDUCED BY IMMUNOSUPPRESSIVE DRUGS. METHODS: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM PERIPHERAL BLOOD SAMPLES FROM PROSPECTIVELY RECRUITED SUBJECTS WERE ANALYZED BY FLOW CYTOMETRY FOR CD3, CD4, FOXP3, TIGIT, T-BET, AND RELATED ORPHAN RECEPTOR GAMMAT. EPIGENETIC DNA METHYLATION LEVELS OF FOXP3 TREG-SPECIFIC DEMETHYLATED REGION (TSDR), FOXP3 PROMOTER, TBX21, RORC2, AND TIGIT LOCI WERE DETERMINED IN CRYOPRESERVED PBMC USING A NEXT-GENERATION SEQUENCING APPROACH. RELATED CYTOKINES WERE MEASURED IN BLOOD SERA. FUNCTIONAL SUPPRESSIVE CAPACITY OF TREG WAS ASSESSED USING T-CELL PROLIFERATION ASSAYS. RESULTS: FIFTY PATIENTS WITH UVEITIS (INTERMEDIATE, POSTERIOR, AND PANUVEITIS) AND 10 CONTROL SUBJECTS WERE RECRUITED. THE FREQUENCY OF CD4(+)CD25(+)FOXP3(+) TREG, TIGIT(+) TREG, AND T-BET(+) TREG AND THE RATIO OF TREG TO TH1 WERE SIGNIFICANTLY HIGHER IN REMISSION PATIENTS COMPARED WITH PATIENTS WITH ACTIVE UVEITIC DISEASE; AND TIGIT(+) TREGS WERE A SIGNIFICANT PREDICTOR OF CLINICAL REMISSION. TREG FROM PATIENTS IN CLINICAL REMISSION DEMONSTRATED A HIGH LEVEL OF IN VITRO SUPPRESSIVE FUNCTION COMPARED WITH TREG FROM CONTROL SUBJECTS AND FROM PATIENTS WITH UNTREATED ACTIVE DISEASE. PBMC FROM PATIENTS IN CLINICAL REMISSION HAD SIGNIFICANTLY LOWER METHYLATION LEVELS AT THE FOXP3 TSDR, FOXP3 PROMOTER, AND TIGIT LOCI AND HIGHER LEVELS AT RORC LOCI THAN THOSE WITH ACTIVE DISEASE. CLINICAL REMISSION WAS ALSO ASSOCIATED WITH SIGNIFICANTLY HIGHER SERUM LEVELS OF TRANSFORMING GROWTH FACTOR BETA AND IL-10, WHICH POSITIVELY CORRELATED WITH TREG LEVELS, AND LOWER SERUM LEVELS OF IFNGAMMA, IL-17A, AND IL-22 COMPARED WITH PATIENTS WITH ACTIVE DISEASE. CONCLUSION: CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS HAS AN IMMUNOREGULATORY PHENOTYPE CHARACTERIZED BY UPREGULATION OF PERIPHERAL TREG, POLARIZED TOWARD T-BET AND TIGIT. THESE FINDINGS MAY ASSIST WITH INDIVIDUALIZED THERAPY OF UVEITIS, BY INFORMING WHETHER DRUG THERAPY HAS INDUCED PHENOTYPICALLY STABLE TREG ASSOCIATED WITH LONG-TERM CLINICAL REMISSION.	2018	

6    67  38 A LONGITUDINAL STUDY OF THE ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION WITH POSTSTROKE ANXIETY. BACKGROUND: ALTHOUGH THE PRECISE ETIOLOGY OF POSTSTROKE ANXIETY (PSA) HAS YET TO BE FULLY ELUCIDATED, IT IS KNOWN THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS IMPORTANT FOR NEURAL PLASTICITY AND LONG-TERM POTENTIATION, ASSOCIATED WITH THE PATHOPHYSIOLOGY OF ANXIETY. THE EXPRESSION OF BDNF IS REGULATED BY EPIGENETIC AND GENETIC PROFILES. THUS, WE INVESTIGATED THE ASSOCIATION BETWEEN BDNF METHYLATION STATUS AND PSA AT 2 WEEKS AND 1 YEAR AFTER STROKE WHILE ACCOUNTING FOR INTERACTIONS WITH THE BDNF VAL66MET POLYMORPHISM. METHODS: THE BASELINE SAMPLE COMPRISED 286 PATIENTS WHO WERE ASSESSED AT 2 WEEKS AFTER STROKE; OF THESE PATIENTS, 222 (78%) WERE FOLLOWED UP WITH AT 1 YEAR AFTER STROKE. THE PRESENCE OF PSA WAS DETERMINED USING THE ANXIETY SUBSCALE OF THE HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS), AND THE EFFECTS OF BDNF METHYLATION STATUS AND POLYMORPHISMS ON PSA STATUS WERE ASSESSED WITH MULTIVARIATE LOGISTIC REGRESSION MODELS. RESULTS: THE PREVALENCE OF PSA WAS SLIGHTLY LOWER (27 [9.4%]) AT BASELINE, AND 35 (15.8%) PATIENTS WERE IDENTIFIED AS HAVING PSA AT THE 1-YEAR FOLLOW-UP. STROKE PATIENTS WITH A HIGHER AVERAGE METHYLATION STATUS WERE MORE LIKELY TO HAVE PSA AT 1 YEAR. THE BDNF VAL66MET POLYMORPHISM WAS NOT INDEPENDENTLY ASSOCIATED WITH PSA DURING EITHER THE ACUTE OR CHRONIC PHASE AFTER STROKE, BUT THERE WAS A SIGNIFICANT INTERACTIVE EFFECT BETWEEN BDNF METHYLATION AND GENOTYPE ON PSA AT 2 WEEKS. CONCLUSIONS: IN THIS STUDY, BDNF METHYLATION IN COMBINATION WITH THE MET/MET BDNF POLYMORPHISM (VAL66MET POLYMORPHISM) WAS ASSOCIATED WITH PSA. THESE FINDINGS MAY HELP IDENTIFY PATIENTS AT HIGHER RISK FOR PSA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  3528  42 IL36G GENETIC VARIANT IS INDEPENDENTLY ASSOCIATED WITH SUSCEPTIBILITY, SEVERITY AND JOINT INVOLVEMENT IN PSORIASIS. PSORIASIS (PSO) IS A CHRONIC, IMMUNE-MEDIATED, INFLAMMATORY AND POLYGENIC DERMATOSIS ASSOCIATED WITH BOTH PHYSICAL AND PSYCHOLOGICAL BURDEN THAT CAN BE TRIGGERED BY INJURY, TRAUMA, INFECTIONS AND MEDICATIONS. THE ETIOLOGY OF PSO IS NOT FULLY ELUCIDATED BUT GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ALL LIKELY TO PLAY A ROLE. A CASE-CONTROL STUDY WAS CARRIED OUT TO EVALUATE THE FREQUENCY OF THE IL36G C>T (RS13392494) AND THE IL36G A>G (RS7584409) VARIANTS AND THEIR ASSOCIATION WITH SUSCEPTIBILITY, JOINT INVOLVEMENT AND SEVERITY OF PSO. THE STUDY INCLUDED 154 PATIENTS WITH PSO AND 154 CONTROLS FROM BRAZILIAN POPULATION. THE SEVERITY OF PSO WAS ASSESSED BY THE PSORIASIS AREA AND SEVERITY INDEX (PASI). THE IL36G (RS13392494 AND RS7584409) VARIANTS WERE GENOTYPED BY ALLELIC DISCRIMINATION ASSAY USING THE REAL-TIME POLYMERASE CHAIN REACTION. THE ASSOCIATION BETWEEN THE IL36G GENETIC VARIANTS AND THE STUDY VARIABLES WAS ANALYZED IN ALLELIC, DOMINANT, CODOMINANT, OVERDOMINANT, RECESSIVE, AND HAPLOTYPE MODELS. THE MAIN RESULTS WERE THAT PSO PATIENTS WERE OLDER (P < 0.001) AND HAD HIGHER BODY MASS INDEX (P < 0.001) THAN CONTROLS; 95.8% OF THE PATIENTS HAD PLAQUE PSO, 16.1% HAD PSORIATIC ARTHRITIS (PSA), AND 27.9% HAD PASI > 10. THE IL36G RS1339294 VARIANT SHOWED NO ASSOCIATION WITH PSO IN ALL GENETIC MODELS WHILE THE IL36G RS7584409 VARIANT SHOWED A PROTECTIVE EFFECT IN PSO. HOWEVER, THE G ALLELE OF THE IL36G RS7584409 IN THE DOMINANT MODEL WAS POSITIVELY ASSOCIATED WITH PASI > 10 (P = 0.031). MOREOVER, PATIENTS WITH THE GG GENOTYPE OF THE IL36G RS7584409 VARIANT HAD ABOUT 5.0 TIMES MORE CHANCE OF PSA THAN THOSE WITH THE AA GENOTYPE (P = 0.014). REGARDING THE HAPLOTYPES, THE C/A IN A RECESSIVE MODEL (CACA VERSUS C/G AND T/A CARRIERS) WAS ASSOCIATED WITH PSO (P = 0.035) WHILE THE C/G HAPLOTYPE IN A DOMINANT MODEL (C/A CARRIERS VERSUS C/G AND T/A CARRIERS) SHOWED A PROTECTIVE EFFECT FOR PSO (P = 0.041). IN CONCLUSION, THE G ALLELE OF THE IL36G RS7584409 VARIANT WAS ASSOCIATED WITH PROTECTION TO PSO; HOWEVER, IN PATIENTS WITH PSO, THIS SAME ALLELE WAS ASSOCIATED WITH MODERATE TO SEVERE DISEASE AND PSA. THESE RESULTS SUGGEST THAT THE IL36G RS7584409 VARIANT MAY BE USED AS A POSSIBLE GENETIC BIOMARKER TO PREDICT SEVERITY AND JOINT INVOLVEMENT OF PSO.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  3456  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  3645  45 INCREASED PRESENCE AND DIFFERENTIAL MOLECULAR IMPRINTING OF TRANSIT AMPLIFYING CELLS IN PSORIASIS. PSORIASIS IS A VERY COMMON CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL THICKENING AND SCALING RESULTING FROM KERATINOCYTE HYPERPROLIFERATION AND IMPAIRED DIFFERENTIATION. PATHOMECHANISTIC STUDIES IN PSORIASIS ARE OFTEN LIMITED BY USING WHOLE SKIN TISSUE BIOPSIES, NEGLECTING THEIR STRATIFICATION AND CELLULAR DIVERSITY. THIS STUDY AIMED AT CHARACTERIZING EPIDERMAL ALTERATIONS IN PSORIASIS AT THE LEVEL OF KERATINOCYTE POPULATIONS. EPIDERMAL CELL POPULATIONS WERE PURIFIED FROM SKIN BIOPSIES OF PSORIASIS PATIENTS AND HEALTHY DONORS USING A NOVEL CELL TYPE-SPECIFIC APPROACH. MOLECULAR CHARACTERIZATION OF THE TRANSIT-AMPLIFYING CELLS (TAC), THE KEY PLAYERS OF EPIDERMAL RENEWAL, WAS PERFORMED USING IMMUNOCYTOFLUORESCENCE-TECHNIQUE AND INTEGRATED MULTISCALE-OMICS ANALYSES. ALREADY TAC FROM NON-LESIONAL PSORIATIC SKIN SHOWED ALTERED METHYLATION AND DIFFERENTIAL EXPRESSION IN 1.7% AND 1.0% OF ALL PROTEIN-CODING GENES, RESPECTIVELY. IN PSORIATIC LESIONS, TAC WERE STRONGLY EXPANDED SHOWING FURTHER INCREASED DIFFERENTIALLY METHYLATED (10-FOLD) AND EXPRESSED (22-FOLD) GENES NUMBERS. IMPORTANTLY, 17.2% OF DIFFERENTIALLY EXPRESSED GENES WERE ASSOCIATED WITH RESPECTIVE GENE METHYLATIONS. COMPARED WITH NON-LESIONAL TAC, PATHWAY ANALYSES REVEALED METABOLIC ALTERATIONS AS ONE FEATURE PREDOMINANTLY CHANGED IN TAC DERIVED FROM ACTIVE PSORIATIC LESIONS. OVERALL, OUR STUDY SHOWED STAGE-SPECIFIC MOLECULAR ALTERATIONS, ALLOWS NEW INSIGHTS INTO THE PATHOGENESIS, AND IMPLIES THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LESION DEVELOPMENT IN PSORIASIS. KEY MESSAGES: TRANSIT AMPLIFYING CELL (TAC) NUMBERS ARE HIGHLY INCREASED IN PSORIATIC LESIONS PSORIATIC TAC SHOW PROFOUND MOLECULAR ALTERATIONS & STAGE-SPECIFIC IDENTITY TAC FROM UNAFFECTED AREAS ALREADY SHOW FIRST SIGNS OF MOLECULAR ALTERATIONS LESIONAL TAC SHOW A PREFERENCE IN METABOLIC-RELATED ALTERATIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10  3068  39 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES DIFFERENTIAL METHYLATION IN UNINVOLVED PSORIATIC EPIDERMIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH BOTH LOCAL AND SYSTEMIC COMPONENTS. GENOME-WIDE APPROACHES HAVE IDENTIFIED MORE THAN 60 PSORIASIS-SUSCEPTIBILITY LOCI, BUT GENES ARE ESTIMATED TO EXPLAIN ONLY ONE-THIRD OF THE HERITABILITY IN PSORIASIS, SUGGESTING ADDITIONAL, YET UNIDENTIFIED, SOURCES OF HERITABILITY. EPIGENETIC MODIFICATIONS HAVE BEEN LINKED TO PSORIASIS AND ALTERED DNA METHYLATION PATTERNS IN PSORIATIC VERSUS HEALTHY SKIN HAVE BEEN REPORTED IN WHOLE-SKIN BIOPSIES. IN THIS STUDY, FOCUSING ON EPIGENETIC MODIFICATIONS IN THE PSORIATIC UNINVOLVED SKIN, WE COMPARED THE LESIONAL AND NON-LESIONAL EPIDERMIS FROM PSORIASIS PATIENTS WITH EPIDERMIS FROM HEALTHY CONTROLS. WE PERFORMED AN EXHAUSTIVE GENOME-WIDE DNA METHYLATION PROFILING USING REDUCED REPRESENTATION BISULFITE SEQUENCING, WHICH INTERROGATES THE METHYLATION STATUS OF APPROXIMATELY 3-4 MILLION CPG SITES. MORE THAN 2,000 STRONGLY DIFFERENTIALLY METHYLATED SITES WERE IDENTIFIED AND A STRIKING OVERREPRESENTATION OF THE WNT AND CADHERIN PATHWAYS AMONG THE DIFFERENTIALLY METHYLATED SITES WAS FOUND. IN PARTICULAR, WE OBSERVE A STRONG DIFFERENTIAL METHYLATION IN SEVERAL PSORIASIS CANDIDATE GENES. A SUBSTANTIAL NUMBER OF DIFFERENTIALLY METHYLATED SITES PRESENT IN THE UNINVOLVED VERSUS HEALTHY EPIDERMIS SUGGESTS THE PRESENCE OF A PRE-PSORIATIC STATE IN THE CLINICALLY HEALTHY SKIN TYPE. OUR EXPLORATORY STUDY REPRESENTS A STARTING POINT FOR IDENTIFYING BIOMARKERS FOR PSORIASIS-PRONE SKIN BEFORE DISEASE ONSET.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  1956  48 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                         
12  3989  52 LONGITUDINAL ANALYSIS OF BLOOD DNA METHYLATION IDENTIFIES MECHANISMS OF RESPONSE TO TUMOR NECROSIS FACTOR INHIBITOR THERAPY IN RHEUMATOID ARTHRITIS. BACKGROUND: RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY DISEASE OF THE JOINTS THAT HAS BEEN ASSOCIATED WITH VARIATION IN THE PERIPHERAL BLOOD METHYLOME. IN THIS STUDY, WE AIM TO IDENTIFY EPIGENETIC VARIATION THAT IS ASSOCIATED WITH THE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITOR (TNFI) THERAPY. METHODS: PERIPHERAL BLOOD GENOME-WIDE DNA METHYLATION PROFILES WERE ANALYZED IN A DISCOVERY COHORT OF 62 RA PATIENTS AT BASELINE AND AT WEEK 12 OF TNFI THERAPY. DNA METHYLATION OF INDIVIDUAL CPG SITES AND ENRICHMENT OF BIOLOGICAL PATHWAYS WERE EVALUATED FOR THEIR ASSOCIATION WITH DRUG RESPONSE. USING A NOVEL CELL DECONVOLUTION APPROACH, ALTERED DNA METHYLATION ASSOCIATED WITH TNFI RESPONSE WAS ALSO TESTED IN THE SIX MAIN IMMUNE CELL TYPES IN BLOOD. VALIDATION OF THE RESULTS WAS PERFORMED IN AN INDEPENDENT LONGITUDINAL COHORT OF 60 RA PATIENTS. FINDINGS: TREATMENT WITH TNFI WAS ASSOCIATED WITH SIGNIFICANT LONGITUDINAL PERIPHERAL BLOOD METHYLATION CHANGES IN BIOLOGICAL PATHWAYS RELATED TO RA (FDR<0.05). 139 BIOLOGICAL FUNCTIONS WERE MODIFIED BY THERAPY, WITH METHYLATION LEVELS CHANGING SYSTEMATICALLY TOWARDS A SIGNATURE SIMILAR TO THAT OF HEALTHY CONTROLS. DIFFERENCES IN THE METHYLATION PROFILE OF T CELL ACTIVATION AND DIFFERENTIATION, GTPASE-MEDIATED SIGNALING, AND ACTIN FILAMENT ORGANIZATION PATHWAYS WERE ASSOCIATED WITH THE CLINICAL RESPONSE TO THERAPY. CELL TYPE DECONVOLUTION ANALYSIS IDENTIFIED CPG SITES IN CD4+T, NK, NEUTROPHILS AND MONOCYTES THAT WERE SIGNIFICANTLY ASSOCIATED WITH THE RESPONSE TO TNFI. INTERPRETATION: OUR RESULTS SHOW THAT TREATMENT WITH TNFI RESTORES HOMEOSTATIC BLOOD METHYLATION IN RA. THE CLINICAL RESPONSE TO TNFI IS ASSOCIATED TO METHYLATION VARIATION IN SPECIFIC BIOLOGICAL PATHWAYS, AND IT INVOLVES CELLS FROM BOTH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS. FUNDING: THE INSTITUTO DE SALUD CARLOS III.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  5118  40 POSSIBLE ASSOCIATION BETWEEN GERMLINE METHYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND PSORIASIS RISK IN A TURKISH POPULATION. BACKGROUND: PSORIASIS IS A COMMON CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY GENETIC AND EPIGENETIC FACTORS. THERE ARE CONFLICTING RESULTS IN THE LITERATURE ABOUT THE ASSOCIATION BETWEEN PSORIASIS AND THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE (MTHFR), RANGING FROM STRONG LINKAGE TO NO ASSOCIATION. AIM: TO INVESTIGATE THE ASSOCIATION BETWEEN THE GERMLINE MTHFR POLYMORPHISMS C677T AND A1298C WITH PSORIASIS RISK IN A TURKISH POPULATION. METHODS: THE STUDY ENROLLED 84 PATIENTS WITH PSORIASIS AND 212 HEALTHY CONTROLS (HCS) WITHOUT ANY HISTORY OF PSORIASIS. DNA WAS EXTRACTED FROM PERIPHERAL BLOOD SAMPLES OF PATIENTS AND HCS, AND REAL-TIME PCR WAS USED FOR GENOTYPING. RESULTS WERE COMPARED BY PEARSON CHI(2) TEST AND MULTIPLE LOGISTIC REGRESSION MODELS. RESULTS: THE FREQUENCY OF BOTH THE MTHFR 677TT AND A1298C (HOMOZYGOUS) GENOTYPES WAS STATISTICALLY SIGNIFICANTLY DIFFERENT FROM HCS. POINT MUTATIONS WERE DETECTED IN ALL PATIENTS WITH EARLY-ONSET PSORIASIS (BEFORE THE AGE OF 20 YEARS). THE T ALLELE OF MTHFR 677 AND THE C ALLELE OF MTHFR 1298 INCREASED PSORIASIS RISK BY 12.4- AND 17.0-FOLD, RESPECTIVELY, IN PATIENTS COMPARED WITH HCS. CONCLUSION: A POSSIBLE ASSOCIATION WAS DETECTED BETWEENGERMLINE MTHFR 677 C>T AND 1298 A>C GENOTYPES AND PSORIASIS RISK IN A TURKISH POPULATION. THESE RESULTS NEED TO BE CONFIRMED IN FURTHER STUDIES WITH LARGER SAMPLE SIZES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  1194  47 CORRELATION OF EPIGENETIC CHANGE AND IDENTIFICATION OF RISK FACTORS FOR ORAL SUBMUCOUS FIBROSIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES IS AN EPIGENETIC CHANGE THAT IS ESSENTIAL FOR TUMORIGENESIS. ORAL SUBMUCOUS FIBROSIS (OSF) IS A PRECANCEROUS CONDITION OF ORAL MUCOSA WITH INFLAMMATION AND PROGRESSIVE FIBROSIS OF THE LAMINA PROPRIA AND DEEPER CONNECTIVE TISSUE. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION MAY DEMONSTRATE A MILD LESION/MUTATION AT EPIGENETIC LEVELS. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES IN PATIENTS WITH ORAL CANCER AND PATIENTS WITH OSF AND ALSO AIMS TO IDENTIFY RISK FACTORS FOR THE DEVELOPMENT OF OSF. METHODS: DNA WAS EXTRACTED FROM BLOOD SAMPLES OF 50 HEALTHY SUBJECTS, 50 PATIENTS WITH OSF AND 60 PATIENTS WITH ORAL CANCER. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. SURVEYS ABOUT ORAL HEALTH HABITS AND CLINICAL PERIODONTAL EXAMINATIONS IN PATIENTS WITH OSF AND HEALTHY SUBJECTS WERE ALSO CONDUCTED BY WELL-TRAINED DENTISTS, AND LOGISTIC REGRESSION WAS PERFORMED TO IDENTIFY RISK FACTORS FOR OSF. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 36% AND 22% OF ORAL CANCER SAMPLES, RESPECTIVELY. IN PATIENTS WITH OSF, THE RATES WERE 52% AND 30%, AND IN HEALTHY CONTROLS THE RATES WERE 4% AND 6%. HYPERMETHYLATION WAS SHOWN TO BE CORRELATED BETWEEN THE 3 GROUPS WITH STATISTICAL SIGNIFICANCE (P<0.01). METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 OCCURRED MORE FREQUENTLY IN PATIENTS WITH OSF THAN IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN PATIENTS WITH ORAL CANCER. IN THE LOGISTIC REGRESSION ANALYSIS, SMOKING, BRUSHING MORE THAN TWICE DAILY, PERIODONTAL PROBING DEPTH AND PLAQUE INDEX WERE IDENTIFIED AS 4 MAJOR RISK FACTORS FOR OSF. CONCLUSIONS: THESE DATA CONFIRM THAT E-CADHERIN AND COX-2 EXPRESSIONS ARE RELATED TO OSF. THE EPIGENETIC CHANGES PRESENTED IN PATIENTS WITH CHRONIC INFLAMMATION MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC OSF WAS SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION, A CANCER RISK FACTOR.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15  3501  55 IDENTIFICATION OF POTENTIAL BIOMARKERS FOR SYSTEMIC LUPUS ERYTHEMATOSUS BY INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA. INTRODUCTION: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS AND CHRONIC AUTOIMMUNE DISEASE. ABERRANT DNA METHYLATION OCCURS DURING VARIOUS PROCESSES OF SLE DEVELOPMENT REGULATING THE MRNA EXPRESSION OF INTERRELATED GENES. THIS STUDY AIMS TO SCREEN POTENTIAL DNA METHYLATION MARKERS FOR SLE. METHODS: GENE EXPRESSION AND METHYLATION DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN SLE PATIENTS AND HEALTHY CONTROLS WERE SCREENED USING THE LIMMA R PACKAGE, AND DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND REGIONS (DMRS) WERE IDENTIFIED USING DMPFINDER AND BUMPHUNTER (MINFI). ADDITIONALLY, THE DNA METHYLATION MARKERS TO DISTINGUISH SLE PATIENTS FROM HEALTHY CONTROLS WERE EXPLORED THROUGH RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES AND LOGISTIC REGRESSION ANALYSES. FINALLY, WE VALIDATED THE RESULTS OF THE BIOINFORMATIC ANALYSIS BY PYROSEQUENCING. RESULTS: IN TOTAL, 91 DEGS, 90,092 DMPS, 15 DMRS, AND 13 DMR-ASSOCIATED GENES WERE IDENTIFIED. THROUGH THE INTEGRATIVE ANALYSIS OF DEG- AND DMR-ASSOCIATED GENES, WE IDENTIFIED FIVE TYPE I INTERFERON (IFN)-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE. GO ENRICHMENT ANALYSIS SHOWED THAT THE FIVE SLE-ASSOCIATED EPIGENETIC-DRIVEN GENES WERE MAINLY ENRICHED IN THE TYPE I IFN SIGNALING PATHWAY INVOLVED IN IMMUNE RESPONSE AND DEFENSE RESPONSE TO VIRUS. MOREOVER, WE IDENTIFIED TWO SLE-SPECIFIC DNA METHYLATION MARKERS, THREE SLE WITHOUT LUPUS NEPHRITIS (SLE-LN(-))-SPECIFIC DNA METHYLATION MARKERS, AND TWO SLE WITH LUPUS NEPHRITIS (SLE-LN(+))-SPECIFIC DNA METHYLATION MARKERS BY STEPWISE LOGISTIC REGRESSION. CONCLUSIONS: OVERALL, OUR STUDY DEMONSTRATES POTENTIAL DNA METHYLATION MARKERS OF SLE, SLE-LN(-), AND SLE-LN(+), WHICH MAY HELP THE DIAGNOSIS, BOOST THE DEVELOPMENT OF NEW EPIGENETIC THERAPY, AND CONTRIBUTE TO INDIVIDUALIZED TREATMENT. KEY POINTS * THIS STUDY IDENTIFIED FIVE TYPE I IFN-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE, WHICH SUPPORT THE IMPORTANCE OF THE TYPE I IFN PATHWAY IN THE PATHOGENESIS OF SLE * WE IDENTIFIED NOVEL DNA METHYLATION BIOMARKERS IN SLE, SLE-LN-, AND SLE-LN+ BY A COMPREHENSIVE ANALYSIS OF BIOINFORMATICS METHODS AND EXECUTED EXPERIMENTAL VALIDATION, AND BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT THEY HAVE EXCELLENT POTENTIAL * THESE RESULTS MAY PROVIDE NEW INSIGHTS INTO THE BIOLOGICAL MECHANISMS OF SLE, AND IDENTIFY RELIABLE BIOMARKERS FOR SLE, SLE-LN-, AND SLE-LN+, WHICH MAY CONTRIBUTE TO DIAGNOSIS AND INDIVIDUALIZED TREATMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16    93  39 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  3046  52 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  3063  47 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19  3850  32 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  1189  39 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