1 2031 77 EPIGENETIC CHANGES IN LYMPHOCYTES OF SOLVENT-EXPOSED INDIVIDUALS. AIM: WE INVESTIGATED GLOBAL DNA METHYLATION ALTERATIONS IN LYMPHOCYTES OF SOLVENT WORKERS AND CHRONIC TOXIC ENCEPHALOPATHY (CTE) PATIENTS AND EXPLORED POTENTIAL GENE-ENVIRONMENT INTERACTIONS FOR GST. POPULATION & METHODS: A CROSS-SECTIONAL STUDY WAS SET UP IN 41 REFERENTS, 128 SOLVENT WORKERS AND 23 CTE PATIENTS. RESULTS: WE FOUND A GLOBAL DNA HYPERMETHYLATION IN THE SOLVENT-EXPOSED POPULATION COMPARED WITH THE REFERENTS (P = 0.001, R = -0.544). GLOBAL DNA METHYLATION WAS NEGATIVELY ASSOCIATED WITH EXPOSURE. FURTHERMORE, GSTP1 GENOTYPIC POLYMORPHISM WAS FOUND TO BE SIGNIFICANTLY ASSOCIATED (P = 0.033) WITH GLOBAL DNA HYPOMETHYLATION, WHICH INDICATES A POTENTIAL ROLE FOR GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF SOLVENT-INDUCED NEUROBEHAVIORAL DISORDERS. CONCLUSION: THIS STUDY INDICATES THAT SOLVENT-INDUCED DNA METHYLATION ALTERATIONS HAVE AN IMPACT ON NEUROTOXICITY AND DEVELOPMENT OF CTE. 2012 2 1805 25 EFFECT OF SMOKING ON THE DNA METHYLATION PATTERN OF THE SOCS1 PROMOTER IN EPITHELIAL CELLS FROM THE SALIVA OF PATIENTS WITH CHRONIC PERIODONTITIS. BACKGROUND: THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE METHYLATION PATTERN IN THE SUPPRESSOR OF CYTOKINE SIGNALING 1 (SOCS1) GENE IN SMOKERS AND NON-SMOKERS WITH CHRONIC PERIODONTITIS (CP). METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) WAS PERFORMED TO DETERMINE THE METHYLATION STATUS OF THE SOCS1 PROMOTER IN 45 SALIVA SAMPLES FROM SMOKERS AND NON-SMOKERS WITH CP. RESULTS: CELLS FROM THE SALIVA OF CP PATIENTS WHO SMOKED WERE 7.08 TIMES MORE LIKELY TO HAVE A METHYLATED SOCS1 PROMOTER THAN CELLS FROM THE SALIVA OF NON-SMOKING PATIENTS. CONCLUSIONS: SOCS1 GENE PROMOTER METHYLATION, WITH ITS POTENTIAL EFFECTS ON THE EXPRESSION OF THIS GENE, SEEMS TO BE A CONSEQUENCE OF EXPOSURE TO TOBACCO AND NOT TO PERIODONTAL DISEASE. FURTHER STUDIES ARE NEEDED TO ELUCIDATE THE RELATIONSHIP BETWEEN THE EPIGENETIC CONTROL OF IMMUNE RESPONSE GENE EXPRESSION, EXPOSURE TO ENVIRONMENTAL FACTORS, AND THE DEVELOPMENT, PROGRESSION, AND PROGNOSIS OF CP. 2019 3 3387 22 HOMOCYSTEINE ASSOCIATED GENOMIC DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC ALCOHOLISM. HIGHER PLASMA HOMOCYSTEINE CONCENTRATIONS CAN INFLUENCE GENOMIC DNA METHYLATION IN PERIPHERAL BLOOD CELLS. IN THE PRESENT CONTROLLED STUDY WE OBSERVED A SIGNIFICANT INCREASE (10%) OF GENOMIC DNA METHYLATION IN PATIENTS WITH ALCOHOLISM (T = -3.16, DF = 158, P = 0.002) WHICH WAS SIGNIFICANTLY ASSOCIATED WITH THEIR ELEVATED HOMOCYSTEINE LEVELS (MULTIPLE LINEAR REGRESSION, P < 0.001). SINCE METHYLATION OF DNA IS AN IMPORTANT EPIGENETIC FACTOR IN REGULATION OF GENE EXPRESSION THESE FINDINGS MAY HAVE IMPORTANT IMPLICATIONS FOR A POSSIBLE SUBSEQUENT DERANGEMENT OF EPIGENETIC CONTROL THESE PATIENTS. 2004 4 6311 24 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP. 2017 5 1497 27 DNA METHYLATION AGE IS ACCELERATED IN ALCOHOL DEPENDENCE. ALCOHOL DEPENDENCE (ALC) IS A CHRONIC, RELAPSING DISORDER THAT INCREASES THE BURDEN OF CHRONIC DISEASE AND SIGNIFICANTLY CONTRIBUTES TO NUMEROUS PREMATURE DEATHS EACH YEAR. PREVIOUS RESEARCH SUGGESTS THAT CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION PATTERNS. IN ADDITION, DNA METHYLATION LEVELS AT CERTAIN CPG SITES HAVE BEEN CORRELATED WITH AGE. WE USED AN EPIGENETIC CLOCK TO INVESTIGATE THE POTENTIAL ROLE OF EXCESSIVE ALCOHOL CONSUMPTION IN EPIGENETIC AGING. WE EXPLORED THIS QUESTION IN FIVE INDEPENDENT COHORTS, INCLUDING DNA METHYLATION DATA DERIVED FROM DATASETS FROM BLOOD (N = 129, N = 329), LIVER (N = 92, N = 49), AND POSTMORTEM PREFRONTAL CORTEX (N = 46). ONE BLOOD DATASET AND ONE LIVER TISSUE DATASET OF INDIVIDUALS WITH ALC EXHIBITED POSITIVE AGE ACCELERATION (P < 0.0001 AND P = 0.0069, RESPECTIVELY), WHEREAS THE OTHER BLOOD AND LIVER TISSUE DATASETS BOTH EXHIBITED TRENDS OF POSITIVE AGE ACCELERATION THAT WERE NOT SIGNIFICANT (P = 0.83 AND P = 0.57, RESPECTIVELY). PREFRONTAL CORTEX TISSUE EXHIBITED A TREND OF NEGATIVE AGE ACCELERATION (P = 0.19). THESE RESULTS SUGGEST THAT EXCESSIVE ALCOHOL CONSUMPTION MAY BE ASSOCIATED WITH EPIGENETIC AGING IN A TISSUE-SPECIFIC MANNER AND WARRANTS FURTHER INVESTIGATION USING MULTIPLE TISSUE SAMPLES FROM THE SAME INDIVIDUALS. 2018 6 1537 24 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD. 2018 7 3652 27 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION. 2021 8 1588 34 DNA METHYLATION PROFILING IMPLICATES EXPOSURE TO PCBS IN THE PATHOGENESIS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA. OBJECTIVES: TO CHARACTERIZE THE IMPACT OF PCB EXPOSURE ON DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES AND TO EVALUATE THE CORRESPONDING CHANGES IN RELATION TO POSSIBLE HEALTH EFFECTS, WITH A FOCUS ON B-CELL LYMPHOMA. METHODS: WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY ON 611 ADULTS FREE OF DIAGNOSED DISEASE, LIVING IN ITALY AND SWEDEN, IN WHOM WE ALSO MEASURED PLASMA CONCENTRATIONS OF 6 PCB CONGENERS, DDE AND HEXACHLOROBENZENE. RESULTS: WE IDENTIFIED 650 CPG SITES WHOSE METHYLATION CORRELATES STRONGLY (FDR < 0.01) WITH PLASMA CONCENTRATIONS OF AT LEAST ONE PCB CONGENER. STRONGER EFFECTS WERE OBSERVED IN MALES AND IN SWEDEN. THIS EPIGENETIC EXPOSURE PROFILE SHOWS EXTENSIVE AND HIGHLY STATISTICALLY SIGNIFICANT OVERLAPS WITH PUBLISHED PROFILES ASSOCIATED WITH THE RISK OF FUTURE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS WELL AS WITH CLINICAL CLL (38 AND 28 CPG SITES, RESPECTIVELY). FOR ALL THESE SITES, THE METHYLATION CHANGES WERE IN THE SAME DIRECTION FOR INCREASING EXPOSURE AND FOR HIGHER DISEASE RISK OR CLINICAL DISEASE STATUS, SUGGESTING AN ETIOLOGICAL LINK BETWEEN EXPOSURE AND CLL. MEDIATION ANALYSIS REINFORCED THE SUGGESTION OF A CAUSAL LINK BETWEEN EXPOSURE, CHANGES IN DNA METHYLATION AND DISEASE. DISEASE CONNECTIVITY ANALYSIS IDENTIFIED MULTIPLE ADDITIONAL DISEASES ASSOCIATED WITH DIFFERENTIALLY METHYLATED GENES, INCLUDING MELANOMA FOR WHICH AN ETIOLOGICAL LINK WITH PCB EXPOSURE IS ESTABLISHED, AS WELL AS DEVELOPMENTAL AND NEUROLOGICAL DISEASES FOR WHICH THERE IS CORRESPONDING EPIDEMIOLOGICAL EVIDENCE. DIFFERENTIALLY METHYLATED GENES INCLUDE MANY HOMEOBOX GENES, SUGGESTING THAT PCBS TARGET STEM CELLS. FURTHERMORE, NUMEROUS POLYCOMB PROTEIN TARGET GENES WERE HYPERMETHYLATED WITH INCREASING EXPOSURE, AN EFFECT KNOWN TO CONSTITUTE AN EARLY MARKER OF CARCINOGENESIS. CONCLUSIONS: THIS STUDY PROVIDES MECHANISTIC EVIDENCE IN SUPPORT OF A LINK BETWEEN EXPOSURE TO PCBS AND THE ETIOLOGY OF CLL AND UNDERLINES THE UTILITY OF OMIC PROFILING IN THE EVALUATION OF THE POTENTIAL TOXICITY OF ENVIRONMENTAL CHEMICALS. 2019 9 2079 25 EPIGENETIC DNA METHYLATION CHANGES ASSOCIATED WITH HEADACHE CHRONIFICATION: A RETROSPECTIVE CASE-CONTROL STUDY. BACKGROUND THE BIOLOGICAL MECHANISMS OF HEADACHE CHRONIFICATION ARE POORLY UNDERSTOOD. WE AIMED TO IDENTIFY CHANGES IN DNA METHYLATION ASSOCIATED WITH THE TRANSFORMATION FROM EPISODIC TO CHRONIC HEADACHE. METHODS PARTICIPANTS WERE RECRUITED FROM THE POPULATION-BASED NORWEGIAN HUNT STUDY. THIRTY-SIX FEMALE HEADACHE PATIENTS WHO TRANSFORMED FROM EPISODIC TO CHRONIC HEADACHE BETWEEN BASELINE AND FOLLOW-UP 11 YEARS LATER WERE MATCHED AGAINST 35 CONTROLS WITH EPISODIC HEADACHE. DNA METHYLATION WAS QUANTIFIED AT 485,000 CPG SITES, AND CHANGES IN METHYLATION LEVEL AT THESE SITES WERE COMPARED BETWEEN CASES AND CONTROLS BY LINEAR REGRESSION ANALYSIS. DATA WERE ANALYZED IN TWO STAGES (STAGES 1 AND 2) AND IN A COMBINED META-ANALYSIS. RESULTS NONE OF THE TOP 20 CPG SITES IDENTIFIED IN STAGE 1 REPLICATED IN STAGE 2 AFTER MULTIPLE TESTING CORRECTION. IN THE COMBINED META-ANALYSIS THE STRONGEST ASSOCIATED CPG SITES WERE RELATED TO SH2D5 AND NPTX2, TWO BRAIN-EXPRESSED GENES INVOLVED IN THE REGULATION OF SYNAPTIC PLASTICITY. FUNCTIONAL ENRICHMENT ANALYSIS POINTED TO PROCESSES INCLUDING CALCIUM ION BINDING AND ESTROGEN RECEPTOR PATHWAYS. CONCLUSION IN THIS FIRST GENOME-WIDE STUDY OF DNA METHYLATION IN HEADACHE CHRONIFICATION SEVERAL POTENTIALLY IMPLICATED LOCI AND PROCESSES WERE IDENTIFIED. THE STUDY EXEMPLIFIES THE USE OF PROSPECTIVELY COLLECTED POPULATION COHORTS TO SEARCH FOR EPIGENETIC MECHANISMS OF DISEASE. 2018 10 3588 31 IMPACT OF TP53 GENE PROMOTER METHYLATION ON CHRONIC LYMPHOCYTIC LEUKEMIA PATHOGENESIS AND PROGRESSION. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MALIGNANT LYMPHOID DISORDER THAT RESULTS FROM THE OVERGROWTH OF MATURE-LOOKING LYMPHOID CELLS IN THE BLOOD AND LYMPHATIC TISSUE. VARIOUS CLINICAL PRESENTATIONS HAVE BEEN ATTRIBUTED TO THE DISEASE AS A RESULT OF THE DIFFERENT UNDERLYING GENETIC AND EPIGENETIC ALTERATIONS. THE CURRENT STUDY HAS BEEN INITIATED TO STUDY THE ROLE OF AN EPIGENETIC ALTERATION AFFECTING THE PROMOTER OF THE TP53GENE ON CLL PATHOGENESIS AND PROGRESSION. METHODS: THE CURRENT STUDY INVOLVED 54 NEWLY DIAGNOSED PATIENTS PRESENTING WITH CLL AS WELL AS 30 NORMAL INDIVIDUALS AS CONTROLS. AFTER OBTAINING VERBAL CONSENT, DATA COLLECTION WAS DONE AND THE BLOOD COLLECTED FROM ALL ENROLLED INDIVIDUALS FOR HEMATOLOGICAL INVESTIGATIONS AS WELL AS FOR MOLECULAR CATEGORIZATION OF TP53 METHYLATION STATUS. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MS-PCR) TECHNIQUE WAS USED TO DEFINE THE METHYLATION STATUS OF THE TP53 GENE PROMOTER THAT ENCOMPASSES DNA EXTRACTION, BISULFITE CONVERSION, CONVENTIONAL PCR AMPLIFICATION, RUNNING ON AGAROSE GEL AND DOCUMENTATION. FINALLY, STATISTICAL ANALYSIS WAS DONE TO ASSESS ANY CORRELATION OF THE TP53 EPIGENETIC ALTERATION TO THE DISEASE ETIOLOGY AND THE PROGRESSION. RESULTS: IN THE CURRENT STUDY, ALL CONTROLS AND 42 OF 54 PATIENTS SHOW UNMETHYLATED TP53 GENE PROMOTER; ON THE OTHER HAND, THE METHYLATED PROMOTER WAS DETECTED AMONG 12 PATIENTS WITH A P-VALUE OF 0.001. TP53 GENE PROMOTER METHYLATION SIGNIFICANTLY LINKED TO REDUCED PLATELET COUNT (P-VALUE OF 0.047) AND ADVANCED STAGE AT PRESENTATION (P-VALUE OF 0.076). NO SIGNIFICANT DIFFERENCES WERE SEEN AMONG BOTH METHYLATED AND UNMETHYLATED TP53 PROMOTERS IN RELATION TO THE AGE OF THE AFFECTED INDIVIDUALS, TOTAL WHITE BLOOD CELL COUNTS AND HEMOGLOBIN LEVEL OF THE AFFECTED INDIVIDUALS. CONCLUSION: THE CURRENT STUDY REVEALED A SIGNIFICANT CORRELATION OF TP53 GENE PROMOTER METHYLATION TO CHRONIC LYMPHOCYTIC LEUKEMIA PATHOGENESIS AND LOWER PLATELET COUNTS. 2019 11 1345 27 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY. 2019 12 344 29 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY. 2020 13 5628 29 SEMEN ABNORMALITIES, SPERM DNA DAMAGE AND GLOBAL HYPERMETHYLATION IN HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION. BACKGROUND: CYTOGENETIC STUDIES HAVE DEMONSTRATED THAT LOW LEVELS OF CHRONIC RADIATION EXPOSURE CAN POTENTIALLY INCREASE THE FREQUENCY OF CHROMOSOMAL ABERRATIONS AND ANEUPLOIDY IN SOMATIC CELLS. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION BEAR AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES. OBJECTIVES: TO FIND THE INFLUENCE OF OCCUPATIONAL RADIATION EXPOSURE ON SEMEN CHARACTERISTICS, INCLUDING GENETIC AND EPIGENETIC INTEGRITY OF SPERMATOZOA IN A CHRONICALLY EXPOSED POPULATION. METHODS: THIS CROSS SECTIONAL STUDY INCLUDED 134 MALE VOLUNTEERS OF WHICH 83 WERE OCCUPATIONALLY EXPOSED TO IONIZING RADIATION AND 51 WERE NON-EXPOSED CONTROL SUBJECTS. SEMEN CHARACTERISTICS, SPERM DNA FRAGMENTATION, ANEUPLOIDY AND INCIDENCE OF GLOBAL HYPERMETHYLATION IN THE SPERMATOZOA WERE DETERMINED AND COMPARED BETWEEN THE NON-EXPOSED AND THE EXPOSED GROUP. RESULTS: DIRECT COMPARISON OF THE SEMEN CHARACTERISTICS BETWEEN THE NON-EXPOSED AND THE EXPOSED POPULATION REVEALED SIGNIFICANT DIFFERENCES IN MOTILITY CHARACTERISTICS, VIABILITY, AND MORPHOLOGICAL ABNORMALITIES (P<0.05-0.0001). ALTHOUGH, THE LEVEL OF SPERM DNA FRAGMENTATION WAS SIGNIFICANTLY HIGHER IN THE EXPOSED GROUP AS COMPARED TO THE NON-EXPOSED GROUP (P<0.05-0.0001), THE INCIDENCE OF SPERM ANEUPLOIDY WAS NOT STATISTICALLY DIFFERENT BETWEEN THE TWO GROUPS. HOWEVER, A SIGNIFICANT NUMBER OF HYPERMETHYLATED SPERMATOZOA WERE OBSERVED IN THE EXPOSED GROUP IN COMPARISON TO NON-EXPOSED GROUP (P<0.05). CONCLUSIONS: WE PROVIDE THE FIRST EVIDENCE ON THE DETRIMENTAL EFFECTS OF OCCUPATIONAL RADIATION EXPOSURE ON FUNCTIONAL, GENETIC AND EPIGENETIC INTEGRITY OF SPERM IN HEALTH WORKERS. HOWEVER, FURTHER STUDIES ARE REQUIRED TO CONFIRM THE POTENTIAL DETRIMENTAL EFFECTS OF IONIZING RADIATION IN THESE SUBJECTS. 2013 14 2400 29 EPIGENETIC REPROGRAMMING OF IMMUNE CELLS IN WOMEN WITH PCOS IMPACT GENES CONTROLLING REPRODUCTIVE FUNCTION. CONTEXT: POLYCYSTIC OVARY SYNDROME (PCOS) IS A CHRONIC DISEASE AFFECTING REPRODUCTIVE FUNCTION AND WHOLE-BODY METABOLISM. ALTHOUGH THE ETIOLOGY IS UNCLEAR, EMERGING EVIDENCE INDICATES THAT THE EPIGENETICS MAY BE A CONTRIBUTING FACTOR. OBJECTIVE: TO DETERMINE THE ROLE OF GLOBAL AND GENOME-WIDE EPIGENETIC MODIFICATIONS IN SPECIFIC IMMUNE CELLS IN PCOS COMPARED WITH CONTROLS AND WHETHER THESE COULD BE RELATED TO CLINICAL FEATURES OF PCOS. DESIGN: CROSS-SECTIONAL STUDY. PARTICIPANTS: WOMEN WITH (N = 17) OR WITHOUT PCOS (N = 17). SETTING: RECRUITED FROM THE GENERAL COMMUNITY. MAIN OUTCOME MEASURES: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS WERE ANALYZED USING MULTICOLOR FLOW CYTOMETRY METHODS TO DETERMINE GLOBAL DNA METHYLATION LEVELS IN A CELL-SPECIFIC FASHION. TRANSCRIPTOMIC AND GENOME-WIDE DNA METHYLATION ANALYSES WERE PERFORMED ON T HELPER CELLS USING RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING. RESULTS: WOMEN WITH PCOS HAD LOWER GLOBAL DNA METHYLATION IN MONOCYTES (P = 0.006) AND IN T HELPER (P = 0.004), T CYTOTOXIC (P = 0.004), AND B CELLS (P = 0.03). SPECIFIC GENOME-WIDE DNA METHYLATION ANALYSIS OF T HELPER CELLS FROM WOMEN WITH PCOS IDENTIFIED 5581 DIFFERENTIALLY METHYLATED CPG SITES. FUNCTIONAL GENE ONTOLOGY ENRICHMENT ANALYSIS SHOWED THAT GENES LOCATED AT THE PROXIMITY OF DIFFERENTIALLY METHYLATED CPG SITES BELONG TO PATHWAYS RELATED TO REPRODUCTIVE FUNCTION AND IMMUNE CELL FUNCTION. HOWEVER, THESE GENES WERE NOT ALTERED AT THE TRANSCRIPTOMIC LEVEL. CONCLUSIONS: IT WAS SHOWN THAT PCOS IS ASSOCIATED WITH GLOBAL AND GENE-SPECIFIC DNA METHYLATION REMODELING IN A CELL TYPE-SPECIFIC MANNER. FURTHER INVESTIGATION IS WARRANTED TO DETERMINE WHETHER EPIGENETIC REPROGRAMMING OF IMMUNE CELLS IS IMPORTANT IN DETERMINING THE DIFFERENT PHENOTYPES OF PCOS. 2019 15 70 22 A METHOD TO DETECT DIFFERENTIALLY METHYLATED LOCI WITH NEXT-GENERATION SEQUENCING. EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION AT CPG LOCI HAVE IMPORTANT IMPLICATIONS IN CANCER AND OTHER COMPLEX DISEASES. WITH THE DEVELOPMENT OF NEXT-GENERATION SEQUENCING (NGS), IT IS FEASIBLE TO GENERATE DATA TO INTERROGATE THE DIFFERENCE IN METHYLATION STATUS FOR GENOME-WIDE LOCI USING CASE-CONTROL DESIGN. HOWEVER, A PROPER AND EFFICIENT STATISTICAL TEST IS LACKING. THERE ARE SEVERAL CHALLENGES. FIRST, UNLIKE METHYLATION EXPERIMENTS USING MICROARRAYS, WHERE THERE IS ONE MEASURE OF METHYLATION FOR ONE INDIVIDUAL AT A PARTICULAR CPG SITE, HERE WE HAVE THE COUNTS OF METHYLATION ALLELE AND UNMETHYLATION ALLELE FOR EACH INDIVIDUAL. SECOND, DUE TO THE NATURE OF SAMPLE PREPARATION, THE MEASURED METHYLATION REFLECTS THE METHYLATION STATUS OF A MIXTURE OF CELLS INVOLVED IN SAMPLE PREPARATION. THEREFORE, THE UNDERLYING DISTRIBUTION OF THE MEASURED METHYLATION LEVEL IS UNKNOWN, AND A ROBUST TEST IS MORE DESIRABLE THAN PARAMETRIC APPROACH. THIRD, CURRENTLY NGS MEASURES METHYLATION AT OVER 2 MILLION CPG SITES. ANY STATISTICAL TESTS HAVE TO BE COMPUTATIONALLY EFFICIENT IN ORDER TO BE APPLIED TO THE NGS DATA. TAKING THESE CHALLENGES INTO ACCOUNT, WE PROPOSE A TEST FOR DIFFERENTIAL METHYLATION BASED ON CLUSTERED DATA ANALYSIS BY MODELING THE METHYLATION COUNTS. WE PERFORMED SIMULATIONS TO SHOW THAT IT IS ROBUST UNDER SEVERAL DISTRIBUTIONS FOR THE MEASURED METHYLATION LEVELS. IT HAS GOOD POWER AND IS COMPUTATIONALLY EFFICIENT. FINALLY, WE APPLY THE TEST TO OUR NGS DATA ON CHRONIC LYMPHOCYTIC LEUKEMIA. THE RESULTS INDICATE THAT IT IS A PROMISING AND PRACTICAL TEST. 2013 16 2682 29 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC. 2011 17 2766 28 EXPRESSION, POLYMORPHISM AND METHYLATION PATTERN OF INTERLEUKIN-6 IN PERIODONTAL TISSUES. PERIODONTITIS IS CONSIDERED AN INFLAMMATORY DISORDER OF BACTERIAL ETIOLOGY THAT RESULTS IN PERIODONTAL TISSUE DESTRUCTION, AS A RESULT OF COMPLEX INTERACTIONS BETWEEN PERIODONTAL PATHOGENS, HOST AND IMMUNE RESPONSE. GENETIC AND EPIGENETIC MECHANISMS MAY MODULATE THE INDIVIDUAL RESPONSE SINCE IT IS ABLE TO INFLUENCE THE GENE EXPRESSION. THE AIM OF THIS STUDY WAS TO EVALUATE THE IMPACT OF -174 G/C POLYMORPHISM AND THE METHYLATION STATUS OF THE PROMOTER REGION OF IL-6 GENE ON THE EXPRESSION OF IL-6 IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS. GINGIVAL BIOPSIES WERE COLLECTED FROM 21 PATIENTS WITH CHRONIC PERIODONTITIS AND 21 CONTROLS. HISTOLOGIC SECTIONS STAINED BY HEMATOXYLIN-EOSIN WERE USED FOR HISTOPATHOLOGICAL EVALUATION. THE IL-6 GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. THE POLYMORPHISM IL-6 -174 C/G WAS STUDIED BY POLYMERASE CHAIN REACTION (PCR) AMPLIFICATION AND RESTRICTION ENDONUCLEASE DIGESTION (HSPII). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WAS USED TO VERIFY THE DNA METHYLATION PATTERN. THE NUMBER OF INFLAMMATORY CELLS IN TISSUE FRAGMENTS FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS WAS HIGHER THAN IN THE CONTROL GROUP AND THE INFLAMMATORY INFILTRATE WAS PREDOMINANTLY MONONUCLEAR. THE EXPRESSION OF IL-6 WAS HIGHER IN THE GROUP WITH PERIODONTITIS. IN POLYMORPHISM ASSAY, NO STATISTICAL DIFFERENCE IN THE DISTRIBUTION OF GENOTYPES AND ALLELES IN BOTH GROUPS WERE OBSERVED. THE MOST OF SAMPLES WERE PARTIALLY METHYLATED. NO DIFFERENCE WAS OBSERVED IN METHYLATION PATTERN FROM TWO DIFFERENT REGIONS OF THE IL-6 GENE AMONG GROUPS. THE HIGH EXPRESSION OF IL-6 IS AN IMPORTANT FACTOR RELATED TO CHRONIC PERIODONTITIS, BUT WAS NOT ASSOCIATED WITH METHYLATION STATUS OR THE -174 (G/C) GENETIC POLYMORPHISM, SUGGESTING THAT OTHER MECHANISMS ARE INVOLVED IN THIS GENE TRANSCRIPTION REGULATION. 2013 18 287 28 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010 19 1967 30 EPIGENETIC ALTERATION OF THE DOPAMINE TRANSPORTER GENE IN ALCOHOL-DEPENDENT PATIENTS IS ASSOCIATED WITH AGE. CHRONIC ALCOHOL ABUSE AND DEPENDENCE ARE ASSOCIATED WITH DYSFUNCTIONAL DOPAMINERGIC NEUROTRANSMISSION IN MESOCORTICOLIMBIC CIRCUITS. GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN SHOWN TO MODULATE SUSCEPTIBILITY TO ALCOHOL DEPENDENCE, AND BOTH MAY ACT THROUGH EPIGENETIC MECHANISMS THAT CAN MODULATE GENE EXPRESSION, E.G. DNA METHYLATION AT CPG SITES. RECENT STUDIES HAVE SUGGESTED THAT DNA METHYLATION PATTERNS MAY CHANGE OVER TIME. HOWEVER, FEW DATA ARE AVAILABLE CONCERNING THE RATE OF THESE CHANGES IN SPECIFIC GENES. A RECENT STUDY FOUND THAT HYPERMETHYLATION OF THE PROMOTER OF THE DOPAMINE TRANSPORTER (DAT) GENE WAS POSITIVELY CORRELATED WITH ALCOHOL DEPENDENCE AND NEGATIVELY CORRELATED WITH ALCOHOL CRAVING. THE AIM OF THE PRESENT STUDY WAS TO REPLICATE THESE FINDINGS IN A LARGER SAMPLE OF ALCOHOL-DEPENDENT PATIENTS AND POPULATION-BASED CONTROLS MATCHED FOR AGE AND SEX. NO DIFFERENCE IN METHYLATION LEVEL WAS OBSERVED BETWEEN PATIENTS AND CONTROLS, AND NO DIFFERENCE IN METHYLATION LEVEL WAS OBSERVED BEFORE AND AFTER ALCOHOL WITHDRAWAL IN PATIENTS. HOWEVER, PATIENTS WITH MORE SEVERE CRAVING SHOWED A TREND TOWARDS LOWER DAT METHYLATION LEVELS (P = 0.07), WHICH IS CONSISTENT WITH PREVIOUS FINDINGS. FURTHERMORE, IN OUR OVERALL SAMPLE, DAT METHYLATION LEVELS INCREASED WITH AGE. INTERESTINGLY, A SEPARATE ANALYSIS OF PATIENTS SUGGESTED THAT THIS FINDING WAS MAINLY DRIVEN BY THE PATIENT GROUP. ALTHOUGH THE PRESENT DATA DO NOT CLARIFY WHETHER CHRONIC ALCOHOL ABUSE IS RESPONSIBLE FOR THIS PHENOMENON OR MERELY ENHANCES AN AGEING-SPECIFIC PROCESS, OUR FINDINGS SUGGEST THAT HYPERMETHYLATION IN ALCOHOL-DEPENDENT PATIENTS IS A CONSEQUENCE, RATHER THAN A CAUSE, OF THE DISORDER. 2014 20 353 29 ALTERED LEVELS OF IMMUNE-REGULATORY MICRORNAS IN PLASMA SAMPLES OF PATIENTS WITH LUPUS NEPHRITIS. INTRODUCTION: LUPUS NEPHRITIS (LN) IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THE PATIENTS WITH LUPUS, A CHRONIC AUTOIMMUNE DISEASE. THE ROLE OF GENETIC AND EPIGENETIC FACTORS IS EMPHASIZED IN THE PATHOGENESIS OF LN. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE LEVELS OF IMMUNE-REGULATORY MICRORNAS (E.G., MIR-31, MIR-125A, MIR-142-3P, MIR-146A, AND MIR-155) IN PLASMA SAMPLES OF PATIENTS WITH LN. METHODS: IN THIS STUDY, 26 PATIENTS WITH LN AND 26 HEALTHY INDIVIDUALS WERE INCLUDED. THE PLASMA LEVELS OF THE MICRORNAS WERE EVALUATED BY A QUANTITATIVE REAL-TIME PCR. MOREOVER, THE CORRELATION OF CIRCULATING PLASMA MICRORNAS WITH DISEASE ACTIVITY AND PATHOLOGICAL FINDINGS ALONG WITH THEIR ABILITY TO DISTINGUISH PATIENTS WITH LN WERE ASSESSED. RESULTS: PLASMA LEVELS OF MIR-125A (P = 0.048), MIR-146A (P = 0.005), AND MIR-155 (P< 0.001) WERE SIGNIFICANTLY HIGHER IN COMPARISON BETWEEN THE CASES AND CONTROLS. THE PLASMA LEVEL OF MIR-146A SIGNIFICANTLY CORRELATED WITH THE LEVEL OF ANTI-DOUBLE STRAND-DNA ANTIBODY AND PROTEINURIA. MOREOVER, THERE WAS A SIGNIFICANT CORRELATION BETWEEN MIR-142-3P LEVELS AND DISEASE CHRONICITY AND ACTIVITY INDEX (P <0.05). THE MULTIVARIATE ROC CURVE ANALYSIS INDICATED THE PLASMA CIRCULATING MIR-125A, MIR-142-3P, MIR-146, AND MIR-155 TOGETHER COULD DISCRIMINATE MOST OF THE PATIENTS WITH LN FROM CONTROLS WITH AREA AN UNDER CURVE (AUC) OF 0.89 [95% CI, 0.80-0.98, P<0.001], 88% SENSITIVITY, AND 78% SPECIFICITY. CONCLUSION: BASED ON THE FINDINGS OF THE PRESENT STUDY, THE STUDIED MICRORNAS MAY BE INVOLVED IN THE PATHOGENESIS AND DEVELOPMENT OF LN AND HAVE THE POTENTIAL TO BE USED AS DIAGNOSTIC AND THERAPEUTIC MARKERS IN LN. 2018