1   774 112 CELL TYPE-SPECIFIC MECHANISM OF SETD1A HETEROZYGOSITY IN SCHIZOPHRENIA PATHOGENESIS. SCHIZOPHRENIA (SCZ) IS A CHRONIC, SERIOUS MENTAL DISORDER. ALTHOUGH MORE THAN 200 SCZ-ASSOCIATED GENES HAVE BEEN IDENTIFIED, THE UNDERLYING MOLECULAR AND CELLULAR MECHANISMS REMAIN LARGELY UNKNOWN. HERE, WE GENERATED A SETD1A (SET DOMAIN CONTAINING 1A) HAPLOINSUFFICIENCY MOUSE MODEL TO UNDERSTAND HOW THIS SCZ-ASSOCIATED EPIGENETIC FACTOR AFFECTS GENE EXPRESSION IN BRAIN REGIONS HIGHLY RELEVANT TO SCZ. SINGLE-CELL RNA SEQUENCING REVEALED THAT SETD1A HETEROZYGOSITY CAUSES HIGHLY VARIABLE TRANSCRIPTIONAL ADAPTATIONS ACROSS DIFFERENT CELL TYPES IN PREFRONTAL CORTEX (PFC) AND STRIATUM. THE FOXP2(+) NEURONS EXHIBIT THE MOST PROMINENT GENE EXPRESSION CHANGES AMONG THE DIFFERENT NEURON SUBTYPES IN PFC, WHICH CORRELATE WITH CHANGES IN HISTONE H3 LYSINE 4 TRIMETHYLATION. MANY OF THE GENES DYSREGULATED IN SETD1A(+/-) MICE ARE INVOLVED IN NEURON MORPHOGENESIS AND SYNAPTIC FUNCTION. CONSISTENTLY, SETD1A(+/-) MICE EXHIBIT CERTAIN BEHAVIORAL FEATURES OF PATIENTS WITH SCZ. COLLECTIVELY, OUR STUDY ESTABLISHES SETD1A(+/-) MICE AS A MODEL FOR UNDERSTANDING SCZ AND UNCOVERS A COMPLEX BRAIN REGION- AND CELL TYPE-SPECIFIC DYSREGULATION THAT POTENTIALLY UNDERLIES SCZ PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  2044  26 EPIGENETIC CLOCK ANALYSIS OF BLOOD SAMPLES IN DRUG-NAIVE FIRST-EPISODE SCHIZOPHRENIA PATIENTS. BACKGROUND: SCHIZOPHRENIA (SCZ) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH PREMATURE AGE-RELATED PHYSIOLOGICAL CHANGES. HOWEVER, NUMEROUS PREVIOUS STUDIES EXAMINED THE EPIGENETIC AGE ACCELERATION IN SCZ PATIENTS AND YIELDED INCONCLUSIVE RESULTS. IN THIS STUDY, WE PROPOSE TO EXPLORE THE EPIGENETIC AGE ACCELERATION IN DRUG-NAIVE FIRST-EPISODE SCZ (FSCZ) PATIENTS AND INVESTIGATE WHETHER EPIGENETIC AGE ACCELERATION IS ASSOCIATED WITH ANTIPSYCHOTIC TREATMENT, PSYCHOTIC SYMPTOMS, COGNITION, AND SUBCORTICAL VOLUMES. METHODS: WE ASSESSED THE EPIGENETIC AGE IN 38 DRUG-NAIVE FSCZ PATIENTS AND 38 HEALTHY CONTROLS BY USING THREE INDEPENDENT CLOCKS, INCLUDING HORVATH, HANNUM AND LEVINE ALGORITHMS. THE EPIGENETIC AGE MEASUREMENTS IN SCZ PATIENTS WERE REPEATED AFTER RECEIVING 8 WEEKS RISPERIDONE MONOTHERAPY. RESULTS: OUR FINDINGS SHOWED SIGNIFICANTLY POSITIVE CORRELATIONS BETWEEN EPIGENETIC AGES ASSESSED BY THREE CLOCKS AND CHRONOLOGICAL AGE IN BOTH FSCZ PATIENTS AND HEALTHY CONTROLS. COMPARED WITH HEALTHY CONTROLS, DRUG-NAIVE FSCZ PATIENTS HAVE A SIGNIFICANT EPIGENETIC AGE DECELERATION IN HORVATH CLOCK (P = 0.01), BUT NOT IN HANNUM CLOCK (P = 0.07) AND LEVINE CLOCK (P = 0.43). THE EPIGENETIC AGES OF HANNUM CLOCK (P = 0.002) AND LEVINE CLOCK (P = 0.01) WERE SIGNIFICANTLY ACCELERATED IN SCZ PATIENTS AFTER 8-WEEK RISPERIDONE TREATMENT. HOWEVER, NO SIGNIFICANT ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION AND PSYCHOTIC SYMPTOMS, COGNITIVE FUNCTION, AS WELL AS SUBCORTICAL VOLUMES WERE OBSERVED IN FSCZ PATIENTS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  2594  33 EPIGENETICS OF SCHIZOPHRENIA. SCHIZOPHRENIA (SCZ) IS A CHRONIC PSYCHOTIC DISORDER THAT CONTRIBUTES SIGNIFICANTLY TO DISABILITY, AFFECTING BEHAVIOR, THOUGHT, AND COGNITION. IT HAS LONG BEEN KNOWN THAT THERE IS A HERITABLE COMPONENT TO SCHIZOPHRENIA; STUDIES IN BOTH THE PRE-GENOMIC AND POST-GENOMIC ERA, HOWEVER, HAVE FAILED TO ELUCIDATE FULLY THE GENETIC BASIS FOR THIS COMPLEX DISEASE. EPIGENETIC PROCESSES - BROADLY, THOSE WHICH CONTRIBUTE TO CHANGES IN GENE EXPRESSION WITHOUT ALTERING THE GENETIC CODE ITSELF - MAY HELP TO UNDERSTAND BETTER THE MECHANISMS LEADING TO DEVELOPMENT OF SCZ. THE OBJECTIVE OF THIS REVIEW IS TO SYNTHESIZE CURRENT KNOWLEDGE OF THE EPIGENETIC MECHANISMS INVOLVED IN SCHIZOPHRENIA. SPECIFICALLY, DNA METHYLATION STUDIES IN BOTH PERIPHERAL AND POST-MORTEM BRAIN SAMPLES IN SCZ ARE REVIEWED, AS ARE EPIGENETIC MECHANISMS INCLUDING HISTONE MODIFICATION. THE PROMISING ROLE OF NON-CODING RNA INCLUDING MICRO-RNA (MIRNA) AND ITS ROLE AS A POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKER IS OUTLINED, AS ARE EPIGENETIC AGE ACCELERATION AND TELOMERE SHORTENING. FINALLY, WE DISCUSS LIMITATIONS IN CURRENT KNOWLEDGE AND PROPOSE FUTURE RESEARCH DIRECTIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  1299  27 DECREASED REELIN EXPRESSION IN THE LEFT PREFRONTAL CORTEX (BA9) IN CHRONIC SCHIZOPHRENIA PATIENTS. BACKGROUND: REELIN IS UNDER EPIGENETIC CONTROL AND HAS BEEN REPORTED TO BE DECREASED IN CORTICAL REGIONS IN SCHIZOPHRENIA. METHODS: TO ESTABLISH IF EXPRESSION OF REELIN IS ALTERED IN SPECIFIC CORTICAL, HIPPOCAMPAL OR THALAMIC REGIONS OF SCHIZOPHRENIA PATIENTS, WE MEASURED GENE EXPRESSION OF REELIN IN A POSTMORTEM STUDY OF ELDERLY PATIENTS WITH SCHIZOPHRENIA AND NON-AFFECTED CONTROLS IN BOTH HEMISPHERES DIFFERENTIATING BETWEEN GRAY AND WHITE MATTER. WE COMPARED CEREBRAL POSTMORTEM SAMPLES (DORSOLATERAL PREFRONTAL CORTEX BA9 AND BA46, SUPERIOR TEMPORAL CORTEX BA22, ENTORHINAL CORTEX BA28, SENSORIC CORTEX BA1-3, HIPPOCAMPUS, CA4, MEDIODORSAL NUCLEUS OF THE THALAMUS) FROM 12 SCHIZOPHRENIA PATIENTS WITH 13 NORMAL SUBJECTS INVESTIGATING GENE EXPRESSION OF REELIN IN THE GRAY AND WHITE MATTER OF BOTH HEMISPHERES BY IN SITU-HYBRIDIZATION. RESULTS: THE LEFT PREFRONTAL AREA (BA9) OF SCHIZOPHRENIA PATIENTS REVEALED A DECREASED EXPRESSION OF REELIN-MRNA OF 29.1% IN THE WHITE (P = 0.022) AND 13.6% IN THE GRAY MATTER (P = 0.007) COMPARED TO THE CONTROL GROUP. NONE OF THE OTHER REGIONS EXAMINED SHOWED ANY STATISTICALLY SIGNIFICANT DIFFERENCES. CONCLUSION: SINCE REELIN IS RESPONSIBLE FOR MIGRATION AND SYNAPSE FORMATION, THE DECREASED GENE EXPRESSION OF REELIN IN THE LEFT PREFRONTAL AREA OF SCHIZOPHRENIA PATIENTS POINTS TO NEURODEVELOPMENTAL DEFICITS IN NEURONAL MIGRATION AND SYNAPTIC PLASTICITY. HOWEVER, OUR STUDY GROUP WAS SMALL, AND RESULTS SHOULD BE VERIFIED USING LARGER SAMPLES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  5303  31 PROTEOME DATA OF SERUM SAMPLES FROM PATIENTS WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A COMPLEX CHRONIC DISEASE. THE MOLECULAR DETERMINANTS AND NEUROPATHOLOGY OF SCHIZOPHRENIA ARE MULTIFACETED; AN IMPORTANT ROLE IN THE PATHOGENESIS IS PLAYED BY THE DYSREGULATION OF MOLECULAR AND EPIGENETIC MECHANISMS. HOWEVER, THE MOLECULAR MECHANISMS OF THE DEVELOPMENT OF THE DISEASE HAVE NOT YET BEEN STUDIED. AN IMPORTANT TASK IS THE ACCUMULATION AND SYSTEMATIZATION OF "OMICS"-KNOWLEDGE OF THE MOLECULAR PROFILES (TRANSCRIPTOME, PROTEOME, METABOLOME) OF BLOOD SPECIFIC TO PATHOLOGY. THEREBY THE DEVELOPMENT AND IMPROVEMENT OF MASS SPECTROMETRIC METHODS FOR THE DETECTION OF BIOLOGICAL MOLECULES HAS BECOME INCREASINGLY IMPORTANT IN BIOMEDICAL RESEARCH. IN THE FIELD OF APPLIED PROBLEMS IN BIOMEDICAL RESEARCH, THE MOST PREVALENT ISSUE INVOLVES THE IDENTIFICATION OF SEROLOGICAL PROTEIN MARKERS ASSOCIATED WITH THE DEVELOPMENT OF SCHIZOPHRENIA, WHICH ACCOUNT FOR THE DISEASES THAT CAUSE THE A LIFE-SHORTENING ILLNESS, DISABILITY, DECREASED OF FUNCTIONING AND QUALITY OF LIFE AND WELLBEING OR HEALTH STATUS. OMICS APPROACHES ARE DESIGNED TO DETECT GENES (GENOMICS), MRNA (TRANSCRIPTOMICS), PROTEINS (PROTEOMICS) AND METABOLITES (METABOLOMICS) IN A SPECIFIC BIOLOGICAL SAMPLE. WE REPORT THE PROTEOMIC DATASETS ON THE SERUM SAMPLES FROM PATIENTS WITH SCHIZOPHRENIA (SERIES "SCZ") AND HEALTHY VOLUNTEERS (SERIES "CNT"). DATA WERE ACQUIRED USING SHOTGUN ULTRA-HIGH RESOLUTION MASS SPECTROMETRY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  1421  27 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  3133  22 GLOBAL DNA HYPOMETHYLATION AND ITS CORRELATION TO THE BETAINE LEVEL IN PERIPHERAL BLOOD OF PATIENTS WITH SCHIZOPHRENIA. ACCUMULATING EVIDENCE SUGGESTS THAT ABERRANT EPIGENETIC REGULATION IS INVOLVED IN THE PATHOPHYSIOLOGY OF MAJOR PSYCHIATRIC DISORDERS SUCH AS SCHIZOPHRENIA (SZ) AND BIPOLAR DISORDER (BD). WE PREVIOUSLY SHOWED THAT THE PLASMA LEVEL OF BETAINE (N,N,N-TRIMETHYLGLYCINE), A METHYL-GROUP DONOR, WAS SIGNIFICANTLY DECREASED IN PATIENTS WITH FIRST EPISODE SCHIZOPHRENIA (FESZ). IN THIS STUDY, WE IDENTIFIED DECREASE OF GLOBAL DNA METHYLATION LEVEL IN FESZ (N = 24 PATIENTS VS N = 42 CONTROLS), AND FOUND THAT GLOBAL DNA METHYLATION LEVEL WAS INVERSELY CORRELATED WITH SCORES ON THE GLOBAL ASSESSMENT OF FUNCTIONING (GAF) SCALE, AND POSITIVELY CORRELATED WITH PLASMA BETAINE LEVEL. NOTABLY, CORRELATIONS BETWEEN LEVELS OF BETAINE AND ITS METABOLITES (N,N-DIMETHYLGLYCINE AND SARCOSINE, N-METHYLGLYCINE) WERE LOWER OR LOST IN FESZ PLASMA, BUT REMAINED HIGH IN CONTROLS. WE FURTHER EXAMINED GLOBAL DNA METHYLATION LEVELS IN PATIENTS WITH CHRONIC SZ (N = 388) AND BD (N = 414) AS WELL AS CONTROLS (N = 430), AND CONFIRMED SIGNIFICANT HYPOMETHYLATION AND DECREASED BETAINE LEVEL IN SZ. WE ALSO FOUND THAT PATIENTS WITH BD TYPE I, BUT NOT THOSE WITH BD TYPE II, SHOWED SIGNIFICANT GLOBAL HYPOMETHYLATION. THESE RESULTS SUGGEST THAT GLOBAL HYPOMETHYLATION ASSOCIATED WITH DECREASED BETAINE LEVEL IN BLOOD CELLS IS COMMON TO SZ AND BD, AND MAY REFLECT COMMON PATHOPHYSIOLOGY SUCH AS PSYCHOTIC SYMPTOMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  3416  26 HTR1A, HTR1B, HTR2A, HTR2C AND HTR6 GENE POLYMORPHISMS AND EXTRAPYRAMIDAL SIDE EFFECTS IN HALOPERIDOL-TREATED PATIENTS WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A SERIOUS, CHRONIC PSYCHIATRIC DISORDER REQUIRING LIFELONG TREATMENT. EXTRAPYRAMIDAL SIDE EFFECTS (EPS) ARE COMMON ADVERSE REACTIONS TO ANTIPSYCHOTIC MEDICATIONS. IN ADDITION TO THE DOPAMINERGIC SYSTEM, SEROTONERGIC MECHANISMS, INCLUDING SEROTONIN (5-HT) RECEPTORS, MIGHT BE INVOLVED IN EPS DEVELOPMENT. THIS STUDY AIMED TO EXAMINE MOLECULAR ASSOCIATIONS OF HTR1A, HTR1B, HTR2A, HTR2C AND HTR6 GENE POLYMORPHISMS WITH ACUTE EPS IN 229 MALE SCHIZOPHRENIA PATIENTS, FOLLOWING TWO WEEKS OF HALOPERIDOL MONOTHERAPY. THE SIMPSON-ANGUS RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS (SAS), BARNES AKATHISIA RATING SCALE (BARS) AND EXTRAPYRAMIDAL SYMPTOM RATING SCALE (ESRS) WERE USED TO EVALUATE EPS SEVERITY. GENOTYPING WAS PERFORMED USING REAL-TIME PCR, FOLLOWING EXTRACTION OF BLOOD DNA. SIGNIFICANT ACUTE EPS APPEARED IN 48.03% OF SCHIZOPHRENIA PATIENTS. FOR THE RS13212041 HTR1B GENE POLYMORPHISM, AFFECTING MICRORNA REGULATION OF HTR1B GENE EXPRESSION, A HIGHER FREQUENCY OF TT CARRIERS WAS FOUND AMONG HALOPERIDOL-TREATED PATIENTS WITH AKATHISIA WHEN COMPARED TO THE GROUP WITHOUT AKATHISIA SYMPTOMS. IN COMPARISON TO C-ALLELE CARRIERS, PATIENTS CARRYING THE TT GENOTYPE HAD HIGHER AKATHISIA SEVERITY, AS DETERMINED BY THE SAS, BARS AND ESRS SCALES. THESE MOLECULAR FINDINGS SUGGEST POTENTIAL INVOLVEMENT OF 5-HT(1B) RECEPTORS IN AKATHISIA DEVELOPMENT FOLLOWING HALOPERIDOL TREATMENT, AS WELL AS POSSIBLE EPIGENETIC MECHANISMS OF SEROTONERGIC MODULATION ASSOCIATED WITH ANTIPSYCHOTIC-INDUCED EPS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  1554  29 DNA METHYLATION LEVELS OF RELN PROMOTER REGION IN ULTRA-HIGH RISK, FIRST EPISODE AND CHRONIC SCHIZOPHRENIA COHORTS OF SCHIZOPHRENIA. THE ESSENTIAL ROLE OF THE REELIN GENE (RELN) DURING BRAIN DEVELOPMENT MAKES IT A PROMINENT CANDIDATE IN HUMAN EPIGENETIC STUDIES OF SCHIZOPHRENIA. PREVIOUS LITERATURE HAS REPORTED DIFFERING LEVELS OF DNA METHYLATION (DNAM) IN PATIENTS WITH PSYCHOSIS. THEREFORE, THIS STUDY AIMED TO (1) EXAMINE AND COMPARE RELN DNAM LEVELS IN SUBJECTS AT DIFFERENT STAGES OF PSYCHOSIS CROSS-SECTIONALLY, (2) ANALYSE THE EFFECT OF ANTIPSYCHOTICS (AP) ON DNAM, AND (3) EVALUATE THE EFFECTIVENESS AND APPLICABILITY OF RELN PROMOTER DNAM AS A POSSIBLE BIOLOGICAL-BASED MARKER FOR SYMPTOM SEVERITY IN PSYCHOSIS.. THE STUDY COHORT CONSISTED OF 56 HEALTHY CONTROLS, 87 ULTRA-HIGH RISK (UHR) INDIVIDUALS, 26 FIRST-EPISODE (FE) PSYCHOSIS INDIVIDUALS AND 30 CHRONIC SCHIZOPHRENIA (CS) INDIVIDUALS. THE POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) WAS USED TO ASSESS SCHIZOPHRENIA SEVERITY. AFTER PYROSEQUENCING SELECTED CPG SITES OF PERIPHERAL BLOOD, THE AVERAGE MEAN DNAM LEVELS WERE COMPARED AMONGST THE 4 SUBGROUPS. OUR RESULTS SHOWED DIFFERING LEVELS OF DNAM, WITH UHR HAVING THE LOWEST (7.72 +/- 0.19) WHILE THE CS HAD THE HIGHEST LEVELS (HC: 8.78 +/- 0.35; FE: 7.75 +/- 0.37; CS: 8.82 +/- 0.48). SIGNIFICANTLY HIGHER AVERAGE MEAN DNAM LEVELS WERE FOUND IN CS SUBJECTS ON AP (9.12 +/- 0.61) COMPARED TO UHR WITHOUT MEDICATION (UHR(-)) (7.39 +/- 0.18). A SIGNIFICANT ASSOCIATION WAS ALSO OBSERVED BETWEEN THE AVERAGE MEAN DNAM OF FE AND PANSS NEGATIVE SYMPTOM FACTOR (R(2) = 0.237, SS = -0.401, *P = 0.033). IN CONCLUSION, OUR FINDINGS SUGGESTED DIFFERENT LEVELS OF DNAM FOR SUBJECTS AT DIFFERENT STAGES OF PSYCHOSIS. THOSE SUBJECTS THAT TOOK AP HAVE DIFFERENT DNAM LEVELS. THERE WERE SIGNIFICANT ASSOCIATIONS BETWEEN FE DNAM AND NEGATIVE PANSS SCORES. WITH MORE FUTURE EXPERIMENTS AND ON LARGER COHORTS, THERE MAY BE POTENTIAL USE OF DNAM OF THE RELN GENE AS ONE OF THE GENES FOR THE BIOLOGICAL-BASED MARKER FOR SYMPTOM SEVERITY IN PSYCHOSIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  2746  29 EXPRESSION ANALYSIS OF LONG NON-CODING RNAS AND THEIR TARGET GENES IN MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS) IS A PROGRESSIVE CHRONIC AUTOIMMUNE-MEDIATED DISEASE. RECENTLY, LONG NON-CODING RNAS (LNCRNAS) ARE CHARACTERIZED TO PARTICIPATE IN THE ADJUSTMENT OF IMMUNE RESPONSES. HERE, WE EVALUATED THE EXPRESSION LEVELS OF GSTT1-AS1 AND IFNG-AS1 LNCRNAS AND THEIR TARGETS (TNF AND IFNG, RESPECTIVELY) IN IRANIAN MS PATIENTS.IN THIS CASE-CONTROL STUDY, 50 RELAPSING-REMITTING MS PATIENTS AND 50 HEALTHY SUBJECTS WERE RECRUITED. EXPRESSIONS OF GSTT1-AS1 AND IFNG-AS1 LNCRNAS, AS WELL AS TNF AND IFNG GENES, WERE ASSESSED IN THEIR PERIPHERAL BLOOD SAMPLES BY SYBR GREEN-BASED REAL-TIME QUANTITATIVE PCR.EXPRESSION LEVELS OF GSTT1-AS1 AND IFNG-AS1 LNCRNAS WERE BOTH SIGNIFICANTLY DOWNREGULATED (P VALUES 0.032 AND 0.013, RESPECTIVELY). ON THE OTHER HAND, THE EXPRESSION OF TNF AND IFNG SHOWED INCREASED LEVELS, HOWEVER, DID NOT REACH STATISTICAL SIGNIFICANCE AFTER OUR ANALYSIS (P > 0.05). SPEARMAN CORRELATION ANALYSIS SHOWED THAT GSTT1-AS1 HAD A SIGNIFICANT POSITIVE MODERATE CORRELATION WITH IFNG-AS1 (R = 0.541, P < 0.0001), IFNG (R = 0.329, P = 0.001), AND TNF (R = 0.204, P = 0.041). ALSO, IFNG-AS1 REVEALED THE SAME CORRELATION WITH IFNG (R = 0.475, P < 0.0001) AS WELL AS TNF (R = 0.399, P < 0.0001). FURTHERMORE, GSTT1-AS1 (R = 0.313, P = 0.027) AND (IFNG R = 0.478, P < 0.0001) DEMONSTRATED A SIGNIFICANT POSITIVE CORRELATION WITH AGE AT ONSET.BRIEFLY, THE CURRENT STUDY PROVIDED FOR THE FIRST TIME DYSREGULATION OF GSTT1-AS1 AND IFNG-AS LNCRNAS NETWORK IN MS, WHICH HIGHLIGHTS THE SIGNIFICANT ROLE OF EPIGENETIC PATHWAYS IN THIS AUTOIMMUNE DISORDER. LARGER SAMPLE SIZE AND FURTHER INVESTIGATION ASSAYS COULD SHED LIGHT ON THE UNDERLYING MECHANISMS IN THIS AREA OF SCIENCE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  3574  21 IMPACT OF METHIONINE SYNTHASE REDUCTASE POLYMORPHISMS IN CHRONIC MYELOID LEUKEMIA PATIENTS. INTRODUCTION: METABOLISM METHIONINE AND OF FOLATE PLAY A VITAL FUNCTION IN CELLULAR METHYLATION REACTIONS, DNA SYNTHESIS AND EPIGENETIC PROCESS.HOWEVER, POLYMORPHISMS OF METHIONINE HAVE RECEIVED MUCH ATTENTION IN RECENT MEDICAL GENETICS RESEARCH. OBJECTIVES: TO ASCERTAIN WHETHER THE COMMON POLYMORPHISMS OF THE MTRR (METHIONINE SYNTHASE REDUCTASE) A66G GENE COULD PLAY A ROLE IN AFFECTING SUSCEPTIBILITY TO CHRONIC MYELOID LEUKEMIA (CML) IN SUDANESE INDIVIDUALS. METHODS: IN A CASE-CONTROLLED STUDY, WE EXTRACTED AND ANALYZED DNA FROM 200 CML PATIENTS AND 100 HEALTHY CONTROL SUBJECTS BY THE PCR-RFLP METHOD. RESULTS: WE FOUND NO SIGNIFICANT DIFFERENCE IN AGE ORGENDER BETWEEN THE PATIENT GROUP AND CONTROLS. THE MTRR A66G GENOTYPES WERE DISTRIBUTED BASED ON THE HARDY-WEINBERG EQUILIBRIUM (P > 0.05). THE VARIATION OF MTRR A66G WAS LESS SIGNIFICANTLY FREQUENT IN CASES WITH CML (68.35%) THAN IN CONTROLS (87%) (OR = 0.146, 95% CI = 0.162-0.662, P < 0.002). ADDITIONALLY, AG AND GG GENOTYPES AND G ALLELE WERE REDUCING THE CML RISK (ODDS RATIO [OR] = 0.365; 95% CI [0.179-0.746]; P = 0.006; OR = 0.292; 95% CI [0.145-0.590]; P = 0.001 AND OR = 0.146; 95% CI [0.162-0.662]; P = 0.002 AND OR = 2.0; 95% CI [1.3853-2.817]; RESPECTIVELY, (P = 0.000)). CONCLUSIONS: OUR DATA DEMONSTRATED THAT HETEROZYGOUS AND HOMOZYGOUS MUTANT GENOTYPES OF MTRR POLYMORPHISMS WERE ASSOCIATED WITH DECREASED RISK OF DEVELOPING CML IN THE SUDANESE POPULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12   486  24 ASENAPINE TRANSDERMAL PATCH FOR THE MANAGEMENT OF SCHIZOPHRENIA. PURPOSE OF REVIEW: THIS IS A COMPREHENSIVE REVIEW OF THE LITERATURE REGARDING THE USE OF ASENAPINE FOR THE TREATMENT OF SCHIZOPHRENIA (SZ) IN ADULTS. IT COVERS AN INTRODUCTION, EPIDEMIOLOGY, RISK FACTORS, PATHOPHYSIOLOGY, AND CURRENT TREATMENT MODALITIES REGARDING SZ, PROVIDES A BACKGROUND ON THE MECHANISM OF ACTION OF ASENAPINE, AND THEN REVIEWS THE EXISTING EVIDENCE FOR USE OF ASENAPINE IN BOTH ITS SUBLINGUAL AND TRANSDERMAL FORMULATION IN THE TREATMENT OF SZ. RECENT FINDINGS: SZ IS A COMPLEX AND MULTIFACTORIAL MENTAL DISORDER WHICH IS THOUGHT TO COMBINE SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS CAUSING ABNORMALITIES IN THE DOPAMINERGIC SYSTEM. SYMPTOMS ARE CATEGORIZED IN DELUSIONS, HALLUCINATIONS, DISORGANIZATION, AND NEGATIVE PRESENTATIONS LIKE AFFECTIVE FLATTENING AND APATHY. CURRENT TREATMENT FOCUSES ON ANTIPSYCHOTIC MEDICATIONS BY MEANS OF ORAL ADMINISTRATION OR LONG-ACTING INJECTION. ASENAPINE IS A SECOND-GENERATION ANTIPSYCHOTIC WITH 5HT-2A ANTAGONIST AND 5HT-1A/1B PARTIAL AGONIST PROPERTIES, WHICH PROVIDES A FAVORABLE PROFILE IN TARGETING SCHIZOPHRENIC SYMPTOMS, WHILE REDUCING MOTOR SIDE EFFECTS AND IMPROVING MOOD AND COGNITION. ASENAPINE IN ITS SUBLINGUAL FORMULATION WAS FDA APPROVED FOR TREATMENT OF SZ AND BIPOLAR I DISORDER IN ADULTS IN AUGUST OF 2009 AND HAS BEEN PROVEN TO BE BOTH EFFECTIVE AND SAFE. TRANSDERMAL PATCH OF ASENAPINE (SECUADO) WAS FDA APPROVED IN OCTOBER OF 2019, THE FIRST AND ONLY FDA APPROVED PATCH FOR SZ IN ADULTS, WHICH OFFERS ANOTHER STRATEGY FOR TREATMENT TO IMPROVE COMPLIANCE AND EASE OF ADMINISTRATION. SUMMARY: SZ IS A CHRONIC AND DEBILITATING DISEASE WHICH IS STILL NOT WELL UNDERSTOOD AND COMES AT GREAT COST WITH REGARDS TO THE QUALITY OF LIFE FOR PATIENTS. MEDICATION SIDE-EFFECTS AND COMPLIANCE ARE ENORMOUS ISSUES WHICH TAKE A TOLL ON HEALTH CARE SYSTEMS IN INDUSTRIALIZED NATIONS AND KEEP PATIENTS FROM ACHIEVING STABILITY WITH THEIR DISEASE. TRANSDERMAL ASENAPINE IS A NEW FIRST-IN-CLASS DOSAGE FORM AND PROVIDES A NOVEL MODALITY OF ADMINISTRATION. IT HAS BEEN SHOWN TO BE EFFECTIVE IN REDUCING POSITIVE, AS WELL AS NEGATIVE SYMPTOMS, WHILE STILL MAINTAINING A FAVORABLE SIDE-EFFECT PROFILE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  3494  28 IDENTIFICATION OF MICRORNAS WITH DYSREGULATED EXPRESSION IN STATUS EPILEPTICUS INDUCED EPILEPTOGENESIS. THE INVOLVEMENT OF MIRNA IN MESIAL TEMPORAL LOBE EPILEPSY (MTLE) PATHOGENESIS HAS INCREASINGLY BECOME A FOCUS OF EPIGENETIC STUDIES. DESPITE ADVANCES, THE NUMBER OF KNOWN MIRNAS WITH A CONSISTENT EXPRESSION RESPONSE DURING EPILEPTOGENESIS IS STILL SMALL. ADDRESSING THIS SITUATION REQUIRES ADDITIONAL MIRNA PROFILING STUDIES COUPLED TO DETAILED INDIVIDUAL EXPRESSION ANALYSES. HERE, WE PERFORM A MIRNA MICROARRAY ANALYSIS OF THE HIPPOCAMPUS OF WISTAR RATS 24 HOURS AFTER INTRA-HIPPOCAMPAL PILOCARPINE-INDUCED STATUS EPILEPTICUS (H-PILO SE). WE IDENTIFIED 73 MIRNAS THAT UNDERGO SIGNIFICANT CHANGES, OF WHICH 36 WERE UP-REGULATED AND 37 WERE DOWN-REGULATED. TO VALIDATE, WE SELECTED 5 OF THESE (10A-5P, 128A-3P, 196B-5P, 352 AND 324-3P) FOR RT-QPCR ANALYSIS. OUR RESULTS CONFIRMED THAT MIR-352 AND 196B-5P LEVELS WERE SIGNIFICANTLY HIGHER AND MIR-128A-3P LEVELS WERE SIGNIFICANTLY LOWER IN THE HIPPOCAMPUS OF H-PILO SE RATS. WE ALSO EVALUATED WHETHER THE 3 MIRNAS SHOW A DYSREGULATED HIPPOCAMPAL EXPRESSION AT THREE TIME PERIODS (0H, 24H AND CHRONIC PHASE) AFTER SYSTEMIC PILOCARPINE-INDUCED STATUS EPILEPTICUS (S-PILO SE). WE DEMONSTRATE THAT MIR-128A-3P TRANSCRIPTS ARE SIGNIFICANTLY REDUCED AT ALL TIME POINTS COMPARED TO THE NAIVE GROUP. MOREOVER, MIR-196B-5P WAS SIGNIFICANTLY HIGHER ONLY AT 24H POST-SE, WHILE MIR-352 TRANSCRIPTS WERE SIGNIFICANTLY UP-REGULATED AFTER 24H AND IN CHRONIC PHASE (EPILEPTIC) RATS. FINALLY, WHEN WE COMPARED HIPPOCAMPI OF EPILEPTIC AND NON-EPILEPTIC HUMANS, WE OBSERVED THAT TRANSCRIPT LEVELS OF MIRNAS SHOW SIMILAR TRENDS TO THE ANIMAL MODELS. IN SUMMARY, WE SUCCESSFULLY IDENTIFIED TWO NOVEL DYSREGULATED MIRNAS (196B-5P AND 352) AND CONFIRMED MIR-128A-3P DOWNREGULATION IN SE-INDUCED EPILEPTOGENESIS. FURTHER FUNCTIONAL ASSAYS ARE REQUIRED TO UNDERSTAND THE ROLE OF THESE MIRNAS IN MTLE PATHOGENESIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  3078  26 GENOME-WIDE METHYLATION ANALYSIS OF A LARGE POPULATION SAMPLE SHOWS NEUROLOGICAL PATHWAYS INVOLVEMENT IN CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN. CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN (CWP), HAS A CONSIDERABLE HERITABLE COMPONENT, WHICH REMAINS TO BE EXPLAINED. EPIGENETIC FACTORS MAY CONTRIBUTE TO AND ACCOUNT FOR SOME OF THE HERITABILITY ESTIMATE. WE ANALYSED EPIGENOME-WIDE METHYLATION USING MEDIPSEQ IN WHOLE BLOOD DNA FROM 1708 MONOZYGOTIC AND DIZYGOTIC CAUCASIAN TWINS HAVING CWP PREVALENCE OF 19.9%. LONGITUDINALLY STABLE METHYLATION BINS (LSBINS), WERE ESTABLISHED BY TESTING REPEATED MEASUREMENTS CONDUCTED >/=3 YEARS APART, N = 292. DNA METHYLATION VARIATION AT LSBINS WAS TESTED FOR ASSOCIATION WITH CWP IN A DISCOVERY SET OF 50 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR CWP, AND IN AN INDEPENDENT DATASET (N = 1608 TWINS), AND THE RESULTS FROM THE 2 SAMPLES WERE COMBINED USING FISHER METHOD. FUNCTIONAL INTERPRETATION OF THE MOST ASSOCIATED SIGNALS WAS BASED ON FUNCTIONAL GENOMIC ANNOTATIONS, GENE ONTOLOGY, AND PATHWAY ANALYSES. OF 723,029 SIGNALS IDENTIFIED AS LSBINS, 26,399 LSBINS DEMONSTRATED THE SAME DIRECTION OF ASSOCIATION IN BOTH DISCOVERY AND REPLICATION DATASETS AT NOMINAL SIGNIFICANCE (P </= 0.05). IN THE COMBINED ANALYSIS ACROSS 1708 INDIVIDUALS, WHEREAS NO LSBINS SHOWED GENOME-WIDE SIGNIFICANCE (P < 10-8), 24 SIGNALS REACHED P</=9E-5, AND THESE INCLUDED ASSOCIATION SIGNALS MAPPING IN OR NEAR TO IL17A, ADIPOR2, AND TNFRSF13B. BIOINFORMATICS ANALYSES OF THE ASSOCIATED METHYLATION BINS SHOWED ENRICHMENT FOR NEUROLOGICAL PATHWAYS IN CWP. WE ESTIMATE THAT THE VARIANCE EXPLAINED BY EPIGENETIC FACTORS IN CWP IS 6%. THIS, THE LARGEST STUDY TO DATE OF DNA METHYLATION IN CWP, POINTS TOWARDS EPIGENETIC MODIFICATION OF NEUROLOGICAL PATHWAYS IN CWP AND PROVIDES PROOF OF PRINCIPLE OF THIS METHOD IN TEASING APART THE COMPLEX RISK FACTORS FOR CWP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  1645  21 DOES THE EPIGENETIC CLOCK GRIMAGE PREDICT MORTALITY INDEPENDENT OF GENETIC INFLUENCES: AN 18 YEAR FOLLOW-UP STUDY IN OLDER FEMALE TWIN PAIRS. BACKGROUND: EPIGENETIC CLOCKS ARE BASED ON DNA METHYLATION (DNAM). IT HAS BEEN SUGGESTED THAT THESE CLOCKS ARE USEABLE MARKERS OF BIOLOGICAL AGING AND PREMATURE MORTALITY. BECAUSE GENETIC FACTORS EXPLAIN VARIATIONS IN BOTH EPIGENETIC AGING AND MORTALITY, THIS ASSOCIATION COULD ALSO BE EXPLAINED BY SHARED GENETIC FACTORS. WE INVESTIGATED THE INFLUENCE OF GENETIC AND LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, CHRONIC DISEASES, BODY MASS INDEX) AND EDUCATION ON THE ASSOCIATION OF ACCELERATED EPIGENETIC AGING WITH MORTALITY USING A LONGITUDINAL TWIN DESIGN. UTILIZING A PUBLICLY AVAILABLE ONLINE TOOL, WE CALCULATED THE EPIGENETIC AGE USING TWO EPIGENETIC CLOCKS, HORVATH DNAMAGE AND DNAM GRIMAGE, IN 413 FINNISH TWIN SISTERS, AGED 63-76 YEARS, AT THE BEGINNING OF THE 18-YEAR MORTALITY FOLLOW-UP. EPIGENETIC AGE ACCELERATION WAS CALCULATED AS THE RESIDUALS FROM A LINEAR REGRESSION MODEL OF EPIGENETIC AGE ESTIMATED ON CHRONOLOGICAL AGE (AA(HORVATH), AA(GRIMAGE), RESPECTIVELY). COX PROPORTIONAL HAZARD MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS. RESULTS: THE RESULTS OF THE INDIVIDUAL-BASED ANALYSES SHOWED AN INCREASED MORTALITY HAZARD RATIO (HR) OF 1.31 (CI(95): 1.13-1.53) PER ONE STANDARD DEVIATION (SD) INCREASE IN AA(GRIMAGE). THE RESULTS INDICATED NO SIGNIFICANT ASSOCIATIONS OF AA(HORVATH) WITH MORTALITY. PAIRWISE MORTALITY ANALYSES SHOWED AN HR OF 1.50 (CI(95): 1.02-2.20) PER 1 SD INCREASE IN AA(GRIMAGE). HOWEVER, AFTER ADJUSTING FOR SMOKING, THE HR ATTENUATED SUBSTANTIALLY AND WAS STATISTICALLY NON-SIGNIFICANT (1.29; CI(95): 0.84-1.99). SIMILARLY, IN MULTIVARIABLE ADJUSTED MODELS THE HR (1.42-1.49) WAS NON-SIGNIFICANT. IN AA(HORVATH), THE NON-SIGNIFICANT HRS WERE LOWER AMONG MONOZYGOTIC PAIRS IN COMPARISON TO DIZYGOTIC PAIRS, WHILE IN AA(GRIMAGE) THERE WERE NO SYSTEMATIC DIFFERENCES BY ZYGOSITY. FURTHER, THE PAIRWISE ANALYSIS IN QUARTILES SHOWED THAT THE INCREASED WITHIN PAIR DIFFERENCE IN AA(GRIMAGE) WAS ASSOCIATED WITH A HIGHER ALL-CAUSE MORTALITY RISK. CONCLUSIONS: IN CONCLUSION, THE FINDINGS SUGGEST THAT DNAM GRIMAGE IS A STRONG PREDICTOR OF MORTALITY INDEPENDENT OF GENETIC INFLUENCES. SMOKING, WHICH IS KNOWN TO ALTER DNAM LEVELS AND IS BUILT INTO THE DNAM GRIMAGE ALGORITHM, ATTENUATED THE ASSOCIATION BETWEEN EPIGENETIC AGING AND MORTALITY RISK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16   475  25 ARSENIC EXPOSURE AND HUMAN BLOOD DNA METHYLATION AND HYDROXYMETHYLATION PROFILES IN TWO DIVERSE POPULATIONS FROM BANGLADESH AND SPAIN. BACKGROUND: ASSOCIATIONS OF ARSENIC (AS) WITH THE SUM OF 5-MC AND 5-HMC LEVELS HAVE BEEN REPORTED; HOWEVER, AS EXPOSURE-RELATED DIFFERENCES OF THE SEPARATED 5-MC AND 5-HMC MARKERS HAVE RARELY BEEN STUDIED. METHODS: IN THIS STUDY, WE EVALUATED THE ASSOCIATION OF ARSENIC EXPOSURE BIOMARKERS AND 5-MC AND 5-HMC IN 30 HEALTHY MEN (43-55 YEARS) FROM THE ARAGON WORKERS HEALTH STUDY (AWHS) (SPAIN) AND 31 HEALTHY MEN (31-50 YEARS) FROM THE FOLIC ACID AND CREATININE TRIAL (FACT) (BANGLADESH). WE CONDUCTED 5-MC AND 5-HMC PROFILING USING INFINIUM METHYLATIONEPIC ARRAYS, ON PAIRED STANDARD AND MODIFIED (OX-BS IN AWHS AND TAB IN FACT) BISULFITE CONVERTED BLOOD DNA SAMPLES. RESULTS: THE MEDIAN FOR THE SUM OF URINE INORGANIC AND METHYLATED AS SPECIES (SIGMAAS) (MUG/L) WAS 12.5 FOR AWHS AND 89.6 FOR FACT. THE MEDIAN OF BLOOD AS (MUG/L) WAS 8.8 FOR AWHS AND 10.2 FOR FACT. AT A STATISTICAL SIGNIFICANCE P-VALUE CUT-OFF OF 0.01, THE DIFFERENTIALLY METHYLATED (DMP) AND HYDROXYMETHYLATED (DHP) POSITIONS WERE MOSTLY LOCATED IN DIFFERENT GENOMIC SITES. SEVERAL DMPS AND DHPS WERE CONSISTENTLY FOUND IN AWHS AND FACT BOTH FOR URINE SIGMAAS AND BLOOD MODELS, BEING OF SPECIAL INTEREST THOSE ATTRIBUTED TO THE DIP2C GENE. THREE DMPS (ANNOTATED TO CLEC12A) FOR AWHS AND ONE DHP (ANNOTATED TO NPLOC4) FOR FACT REMAINED STATISTICALLY SIGNIFICANT AFTER FALSE DISCOVERY RATE (FDR) CORRECTION. PATHWAYS RELATED TO CHRONIC DISEASES INCLUDING CARDIOVASCULAR, CANCER AND NEUROLOGICAL WERE ENRICHED. CONCLUSIONS: WHILE WE IDENTIFIED COMMON 5-HMC AND 5-MC SIGNATURES IN TWO POPULATIONS EXPOSED TO VARYING LEVELS OF INORGANIC AS, DIFFERENCES IN AS-RELATED EPIGENETIC SITES ACROSS THE STUDY POPULATIONS MAY ADDITIONALLY REFLECT LOW AND HIGH AS-SPECIFIC ASSOCIATIONS. THIS WORK CONTRIBUTES A DEEPER UNDERSTANDING OF POTENTIAL EPIGENETIC DYSREGULATIONS OF AS. HOWEVER, FURTHER RESEARCH IS NEEDED TO CONFIRM BIOLOGICAL CONSEQUENCES ASSOCIATED WITH DIP2C EPIGENETIC REGULATION AND TO INVESTIGATE THE ROLE OF 5-HMC AND 5-MC SEPARATELY IN AS-INDUCED HEALTH DISORDERS AT DIFFERENT EXPOSURE LEVELS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  3453  21 HYPOMETHYLATED UBIQUITIN-CONJUGATING ENZYME2 Q1 (UBE2Q1) GENE PROMOTER IN THE SERUM IS A PROMISING BIOMARKER FOR HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. ABERRANT DNA METHYLATION, WHICH CAN BE DETECTED IN CIRCULATING CELL-FREE DNA (CFDNA), IS ONE OF THE MAJOR EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA (HCC). UBE2Q1, A PUTATIVE MEMBER OF THE UBIQUITIN-CONJUGATING ENZYME FAMILY, MIGHT PLAY SUBSTANTIAL ROLES IN TUMORIGENESIS. HOWEVER, THE METHYLATION STATUS OF THE UBE2Q1 GENE IN HCC REMAINS UNKNOWN. WE AIMED TO DETERMINE THE METHYLATION STATUS OF THE UBE2Q1 GENE PROMOTER AND TO EVALUATE ITS POTENTIAL CLINICAL SIGNIFICANCE FOR HCC DETECTION. THE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) ASSAY WAS USED TO DETECT THE UBE2Q1 GENE METHYLATION STATUS IN SERUM SAMPLES FROM 80 PATIENTS WITH HEPATITIS B VIRUS (HBV)-RELATED HCC, 40 PATIENTS WITH LIVER CIRRHOSIS (LC), 40 PATIENTS WITH CHRONIC HEPATITIS B (CHB), AND 20 HEALTHY CONTROLS (HCS). SIGNIFICANTLY LOWER METHYLATION FREQUENCIES WERE DETECTED IN HCC PATIENTS (33.75%) COMPARED WITH LC PATIENTS (55.00%, P = 0.026) AND CHB PATIENTS (60.00%, P = 0.006) AND HCS (65.00%, P = 0.011). HYPOMETHYLATION OF THE UBE2Q1 GENE WAS NEGATIVELY ASSOCIATED WITH THE TUMOR NODE METASTASIS STAGE (R(S) = -0.30, P = 0.008). THE UBE2Q1 GENE METHYLATION STATUS COMBINED WITH ALPHA FETOPROTEIN USING CUT-OFF POINTS OF 20, 200 AND 400 NG/ML SHOWED SENSITIVITY AND SPECIFICITY VALUES OF 58.8% AND 75.0%, 53.8% AND 87.5%, AND 37.5% AND 88.7%, RESPECTIVELY, AND YIELDED A SIGNIFICANTLY INCREASED AREA UNDER THE ROC CURVE (0.720, 0.760 AND 0.694, RESPECTIVELY) FOR DISCRIMINATING HCC FROM LC AND CHB. OUR STUDY RESULTS SUGGEST THAT HYPOMETHYLATION OF THE UBE2Q1 GENE PROMOTER IS A POTENTIAL BIOMARKER FOR DETECTING HBV-ASSOCIATED HCC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  5267  25 PROMOTER ACTIVITY-BASED CASE-CONTROL ASSOCIATION STUDY ON SLC6A4 HIGHLIGHTING HYPERMETHYLATION AND ALTERED AMYGDALA VOLUME IN MALE PATIENTS WITH SCHIZOPHRENIA. ASSOCIATIONS BETWEEN ALTERED DNA METHYLATION OF THE SEROTONIN TRANSPORTER (5-HTT)-ENCODING GENE SLC6A4 AND EARLY LIFE ADVERSITY, MOOD AND ANXIETY DISORDERS, AND AMYGDALA REACTIVITY HAVE BEEN REPORTED. HOWEVER, FEW STUDIES HAVE EXAMINED EPIGENETIC ALTERATIONS OF SLC6A4 IN SCHIZOPHRENIA (SZ). WE EXAMINED CPG SITES OF SLC6A4, WHOSE DNA METHYLATION LEVELS HAVE BEEN REPORTED TO BE ALTERED IN BIPOLAR DISORDER, USING 3 INDEPENDENT COHORTS OF PATIENTS WITH SZ AND AGE-MATCHED CONTROLS. WE FOUND SIGNIFICANT HYPERMETHYLATION OF A CPG SITE IN SLC6A4 IN MALE PATIENTS WITH SZ IN ALL 3 COHORTS. WE SHOWED THAT CHRONIC ADMINISTRATION OF RISPERIDONE DID NOT AFFECT THE DNA METHYLATION STATUS AT THIS CPG SITE USING COMMON MARMOSETS, AND THAT IN VITRO DNA METHYLATION AT THIS CPG SITE DIMINISHED THE PROMOTER ACTIVITY OF SLC6A4. WE THEN GENOTYPED THE 5-HTT-LINKED POLYMORPHIC REGION (5-HTTLPR) AND INVESTIGATED THE RELATIONSHIP AMONG 5-HTTLPR, DNA METHYLATION, AND AMYGDALA VOLUME USING BRAIN IMAGING DATA. WE FOUND THAT PATIENTS HARBORING LOW-ACTIVITY 5-HTTLPR ALLELES SHOWED HYPERMETHYLATION AND THEY SHOWED A NEGATIVE CORRELATION BETWEEN DNA METHYLATION LEVELS AND LEFT AMYGDALA VOLUMES. THESE RESULTS SUGGEST THAT HYPERMETHYLATION OF THE CPG SITE IN SLC6A4 IS INVOLVED IN THE PATHOPHYSIOLOGY OF SZ, ESPECIALLY IN MALE PATIENTS HARBORING LOW-ACTIVITY 5-HTTLPR ALLELES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19  2978  28 GENETIC ASSOCIATION AND EXPRESSION ANALYSES OF THE PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE (PIP5K1C) GENE IN ALCOHOL USE DISORDER-RELEVANCE FOR PAIN SIGNALING AND ALCOHOL USE. BACKGROUND: THE GENE ENCODING PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE (PIP5K1C) HAS BEEN RECENTLY IMPLICATED IN PAIN REGULATION. INTERESTINGLY, A RECENT CROSS-TISSUE AND CROSS-PHENOTYPIC EPIGENETIC ANALYSIS IDENTIFIED THE SAME GENE IN ALCOHOL USE DISORDER (AUD). GIVEN THE HIGH COMORBIDITY BETWEEN AUD AND CHRONIC PAIN, WE HYPOTHESIZED THAT GENETIC VARIATION IN PIP5K1C MIGHT CONTRIBUTE TO SUSCEPTIBILITY TO AUD. METHODS: WE CONDUCTED A CASE-CONTROL ASSOCIATION STUDY OF GENETIC VARIANTS IN PIP5K1C. ASSOCIATION ANALYSES OF 16 COMMON PIP5K1C SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WERE CONDUCTED IN CASES AND CONTROLS OF AFRICAN (427 CASES AND 137 CONTROLS) AND EUROPEAN ANCESTRY (488 CASES AND 324 CONTROLS) USING STANDARD METHODS. IN ADDITION, GIVEN THE PROMINENT ROLE OF THE OPIOID SYSTEM IN PAIN SIGNALING, WE INVESTIGATED THE EFFECTS OF ACUTE ALCOHOL EXPOSURE ON PIP5K1C EXPRESSION IN HUMANIZED TRANSGENIC MICE FOR THE MU-OPIOID RECEPTOR THAT INCLUDED THE OPRM1 A118G POLYMORPHISM, A WIDELY USED MOUSE MODEL TO STUDY ANALGESIC RESPONSE TO OPIOIDS IN PAIN. PIP5K1C EXPRESSION WAS MEASURED IN THE THALAMUS AND BASOLATERAL AMYGDALA (BLA) IN MICE AFTER SHORT-TERM ADMINISTRATION (SINGLE 2 G/KG DOSE) OF ALCOHOL OR SALINE USING IMMUNOHISTOCHEMISTRY AND ANALYZED BY 2-WAY ANALYSIS OF VARIANCE. RESULTS: IN THE CASE-CONTROL ASSOCIATION STUDY USING AN NIAAA DISCOVERY SAMPLE, 8 SNPS IN PIP5K1C WERE SIGNIFICANTLY ASSOCIATED WITH AUD IN THE AFRICAN ANCESTRY (AA) GROUP (P < 0.05 AFTER CORRECTION; RS4807493, RS10405681, RS2074957, RS10432303, RS8109485, RS1476592, RS10419980, AND RS4432372). HOWEVER, A REPLICATION ANALYSIS USING AN INDEPENDENT SAMPLE (N = 3,801) FOUND NO SIGNIFICANT ASSOCIATIONS AFTER CORRECTION FOR MULTIPLE TESTING. IN THE HUMANIZED TRANSGENIC MOUSE MODEL WITH THE OPRM1 POLYMORPHISM, PIP5K1C EXPRESSION WAS SIGNIFICANTLY DIFFERENT BETWEEN ALCOHOL AND SALINE-TREATED MICE, REGARDLESS OF GENOTYPE, IN BOTH THE THALAMUS (P < 0.05) AND BLA (P < 0.01). CONCLUSIONS: OUR DISCOVERY SAMPLE SHOWS THAT GENETIC VARIANTS IN PIP5K1C ARE ASSOCIATED WITH AUD IN THE AA GROUP, AND ACUTE ALCOHOL EXPOSURE LEADS TO UP-REGULATION OF PIP5K1C, POTENTIALLY EXPLAINING A MECHANISM UNDERLYING THE INCREASED RISK FOR CHRONIC PAIN CONDITIONS IN INDIVIDUALS WITH AUD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  6636  29 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020