1 5637 110 SEROTONIN TRANSPORTER GENE POLYMORPHISMS IN SOUTHWESTERN IRANIAN PATIENTS WITH IRRITABLE BOWEL SYNDROME. BACKGROUND AND STUDY AIMS: IRRITABLE BOWEL SYNDROME IS A COMMON CHRONIC FUNCTIONAL GASTROINTESTINAL DISORDER OF UNKNOWN ETIOLOGY. SEROTONIN IS AN IMPORTANT FACTOR IN SENSORY SIGNALING IN THE BRAIN-GUT AXIS, WHICH PLAYS A KEY ROLE IN INTESTINAL MOTILITY AND SECRETION. SEROTONIN CLEARANCE IS MEDIATED BY A SPECIFIC PROTEIN CALLED THE SEROTONIN REUPTAKE TRANSPORTER. TRANSCRIPTION ACTIVITY OF THE SEROTONIN TRANSPORTER GENE IS AFFECTED BY SOME POLYMORPHISMS IN THIS GENE. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN SEROTONIN TRANSPORTER GENE POLYMORPHISMS AND IRRITABLE BOWEL SYNDROME. PATIENTS/MATERIAL AND METHODS: THE 5-HTTLPR, RS25531 AND STIN2VNTR POLYMORPHISMS OF THE SEROTONIN TRANSPORTER GENE WERE ANALYZED BY PCR-BASED METHODS IN 50 PATIENTS WITH IRRITABLE BOWEL SYNDROME AND 100 HEALTHY CONTROLS. RESULTS: SEROTONIN TRANSPORTER POLYMORPHISMS WERE SIMILAR IN PATIENTS AND HEALTHY CONTROLS. THERE WERE NO SIGNIFICANT DIFFERENCES IN ALLELE OR GENOTYPE FREQUENCIES BETWEEN THE TWO GROUPS. CONCLUSION: OUR FINDINGS SUGGEST THAT POLYMORPHISMS IN THE GENE ENCODING FOR THE SEROTONIN TRANSPORTER ARE NOT ASSOCIATED WITH IRRITABLE BOWEL SYNDROME. INTERACTIONS BETWEEN ENVIRONMENTAL FACTORS AND PREDISPOSING GENETIC FACTORS ARE IMPORTANT IN THE PATHOPHYSIOLOGY OF IRRITABLE BOWEL SYNDROME, AND FURTHER GENETIC AND EPIGENETIC RESEARCH MAY PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS CONTRIBUTING TO THIS DISEASE. 2013 2 2252 29 EPIGENETIC MODULATION OF VISCERAL NOCICEPTION. EPIGENETICS IS A PROCESS THAT ALTERS GENE ACTIVITY OR PHENOTYPE WITHOUT ANY CHANGES IN THE UNDERLYING DNA SEQUENCE OR GENOTYPE. THESE BIOLOGICAL CHANGES MAY HAVE DELETERIOUS EFFECTS AND CAN LEAD TO VARIOUS HUMAN DISEASES. ONGOING RESEARCH IS CONTINUING TO ILLUMINATE THE ROLE OF EPIGENETICS IN A VARIETY OF PATHOPHYSIOLOGIC PROCESSES. SEVERAL CATEGORIES OF EPIGENETIC MECHANISMS HAVE BEEN STUDIED INCLUDING CHROMATIN REMODELING, DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MECHANISMS. THESE EPIGENETIC CHANGES CAN HAVE A LONG-TERM EFFECT ON GENE EXPRESSION WITHOUT ANY UNDERLYING CHANGES IN THE DNA SEQUENCES. THE UNDERLYING PATHOPHYSIOLOGY OF DISORDERS OF BRAIN-GUT INTERACTION AND STRESS-INDUCED VISCERAL PAIN ARE NOT FULLY UNDERSTOOD AND THE ROLE OF EPIGENETIC MECHANISMS IN THESE DISORDERS ARE STARTING TO BE BETTER UNDERSTOOD. CURRENT WORK IS UNDERWAY TO DETERMINE HOW EPIGENETICS PLAYS A ROLE IN THE NEUROBIOLOGY OF PATIENTS WITH CHRONIC VISCERAL PAIN AND HEIGHTENED VISCERAL NOCICEPTION. MORE RECENTLY, BOTH ANIMAL MODELS AND HUMAN STUDIES HAVE SHOWN HOW EPIGENETIC REGULATION MODULATES STRESS-INDUCED VISCERAL PAIN. WHILE MUCH MORE WORK IS NEEDED TO FULLY DELINEATE THE MECHANISTIC ROLE OF EPIGENETICS IN THE NEUROBIOLOGY OF CHRONIC VISCERAL NOCICEPTION, THE CURRENT STUDY BY LOUWIES ET AL., IN NEUROGASTROENTEROLOGY AND MOTILITY PROVIDES ADDITIONAL EVIDENCE SUPPORTING THE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN RODENTS. 2022 3 344 35 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 4 6159 36 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 5 4093 27 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 6 2909 33 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA. 2020 7 5869 33 SUSCEPTIBILITY TO STRESS-INDUCED VISCERAL SENSITIVITY: A BAD LEGACY FOR NEXT GENERATIONS. DESPITE HIGH PREVALENCE, THE PRECISE IRRITABLE BOWEL SYNDROME (IBS) PATHOPHYSIOLOGY REMAINS POORLY UNDERSTOOD LIKELY DUE TO THE HETEROGENEITY OF IBS POPULATIONS AND THE MULTIFACTORIAL ETIOLOGY OF THIS DISORDER. AMONG RISK FACTORS, GENETIC PREDISPOSITION AND EARLY LIFE TRAUMA HAVE BEEN REPORTED. IN THIS CONTEXT, THE DEBATE ON GENETIC OR ENVIRONMENTAL INFLUENCES IN THE IBS PATHOGENESIS IS STILL OPEN. THE STUDY BY VAN DER WIJNGAARD ET AL., REPORTING FOR THE FIRST TIME THAT SUSCEPTIBILITY TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN MATERNALLY SEPARATED RATS CAN BE TRANSFERRED TO THE NEXT GENERATION WITHOUT ANY FURTHER EXPOSURE OF F2 INDIVIDUALS TO MATERNAL SEPARATION, SUPPORTS THE IMPORTANCE OF ENVIRONMENTAL INFLUENCE IN THE IBS PHENOTYPE. EPIGENETIC MECHANISMS SUCH AS HYPERMETHYLATION IN THE PROMOTER REGION OF THE GLUCOCORTICOID RECEPTOR GENE MEDIATING THE LONG-TERM AND TRANSGENERATIONAL BEHAVIORAL EFFECTS OF MATERNAL CARE ON THE DEVELOPMENT HAVE BEEN SHOWN IN SOME BUT NOT IN ALL STUDIES. VAN DER WIJNGAARD ET AL. INCRIMINATED MATERNAL CARE IN THE TRANSMITTED SUSCEPTIBILITY TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY, BUT NOT CHANGES IN GLUCOCORTICOID RECEPTOR PROTEIN EXPRESSION IN THE BRAIN. THIS FINDING OPENS A BROAD FIELD OF FUTURE DIRECTIONS AIMED AT EVALUATING THE MECHANISMS INVOLVED IN THE TRANSMISSION ACROSS GENERATIONS OF THE DIGESTIVE FEATURES OF IBS, INCLUDING, FOR EXAMPLE, ON THE ROLE OF GUT MICROBIOTA CHANGES IN VERTICAL TRANSMISSION OR EPIGENETIC MODIFICATIONS OF INTESTINAL MAST CELLS AND THE JUNCTIONAL REGION OF INTESTINAL EPITHELIAL CELLS IN VERTICAL TRANSFER. 2013 8 1810 26 EFFECTS OF ANTIPSYCHOTICS ON THE BDNF IN SCHIZOPHRENIA. BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IS INVOLVED IN THE DEVELOPMENT OF THE BRAIN, AND LIKELY INFLUENCES THE NEUROPLASTICITY IN SCHIZOPHRENIA. BDNF IS ALSO BELIEVED TO INTERACT WITH OTHER NEUROTRANSMITTER SYSTEMS IMPLICATED IN SCHIZOPHRENIA, SUCH AS DOPAMINE, GLUTAMATE, SEROTONIN AND GABA. THEREFORE, BDNF IS A CANDIDATE GENE FOR SCHIZOPHRENIA. IN PAST DECADES, THE BLOOD (SERUM OR PLASMA) BDNF PROTEIN LEVELS AND BDNF GENE ALLELES AND GENOTYPES TO THE CLINICAL FEATURES OF SCHIZOPHRENIA, SUCH AS AGE OF ONSET, CLINICAL SUBTYPES, SYMPTOM SEVERITY, AND DRUG RESPONSE, HAVE BEEN EVALUATED AMONG DIFFERENT POPULATIONS. HOWEVER, THE RESULTS ARE STILL INCONSISTENT. FURTHER, DIFFERENT DRUGS HAVE BEEN REPORTED TO HAVE DIFFERENT EFFECTS ON BDNF PROTEIN LEVELS. A CROSS-SECTIONAL SURVEY REVEALED THAT SERUM BDNF LEVELS IN CHRONIC SCHIZOPHRENIC PATIENTS TREATED WITH CLOZAPINE EXCEEDED THOSE OF PATIENTS TREATED WITH RISPERIDONE OR WITH TYPICAL ANTIPSYCHOTICS. IN RECENT TIMES, BDNF EPIGENETIC STUDIES HAVE ALSO BEEN CONDUCTED IN CLINICAL STUDIES OF SCHIZOPHRENIA TO ADDRESS THE QUESTION OF WHY PATIENTS WITH THE SAME GENE GENOTYPE AND ALLELES HAVE DIFFERENT CLINICAL PRESENTATIONS. IN ADDITION, THE EFFECTS OF DIFFERENT ANTIPSYCHOTIC DRUGS ON GENE METHYLATION AND PROTEIN ACETYLATION HAVE ALSO BEEN REPORTED. IN CONCLUSION, MORE DATA ARE NEEDED REGARDING BDNF IN THE BRAIN AND IN PERIPHERAL BLOOD, INCLUDING PROTEIN LEVELS, SINGLE NUCLEOTIDE POLYMORPHISMS, EPIGENETIC REGULATION, AND CLINICAL DATA IN ORDER TO UNDERSTAND THE ROLE OF BDNF IN SCHIZOPHRENIA. 2013 9 2297 27 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 10 1314 28 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 11 2625 34 EPIGENOME-WIDE ASSOCIATION STUDY AND MULTI-TISSUE REPLICATION OF INDIVIDUALS WITH ALCOHOL USE DISORDER: EVIDENCE FOR ABNORMAL GLUCOCORTICOID SIGNALING PATHWAY GENE REGULATION. ALCOHOL USE DISORDER (AUD) IS A CHRONIC DEBILITATING DISORDER WITH LIMITED TREATMENT OPTIONS AND POORLY DEFINED PATHOPHYSIOLOGY. THERE ARE SUBSTANTIAL GENETIC AND EPIGENETIC COMPONENTS; HOWEVER, THE UNDERLYING MECHANISMS CONTRIBUTING TO AUD REMAIN LARGELY UNKNOWN. WE CONDUCTED THE LARGEST DNA METHYLATION EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ANALYSES CURRENTLY AVAILABLE FOR AUD (TOTAL N = 625) AND EMPLOYED A TOP HIT REPLICATION (N = 4798) USING A CROSS-TISSUE/CROSS-PHENOTYPIC APPROACH WITH THE GOAL OF IDENTIFYING NOVEL EPIGENETIC TARGETS RELEVANT TO AUD. RESULTS SHOW THAT A NETWORK OF DIFFERENTIALLY METHYLATED REGIONS IN GLUCOCORTICOID SIGNALING AND INFLAMMATION-RELATED GENES WERE ASSOCIATED WITH ALCOHOL USE BEHAVIORS. A TOP PROBE CONSISTENTLY ASSOCIATED ACROSS ALL COHORTS WAS LOCATED IN THE LONG NON-CODING RNA GROWTH ARREST SPECIFIC FIVE GENE (GAS5) (P < 10(-24)). GAS5 HAS BEEN IMPLICATED IN REGULATING TRANSCRIPTIONAL ACTIVITY OF THE GLUCOCORTICOID RECEPTOR AND HAS MULTIPLE FUNCTIONS RELATED TO APOPTOSIS, IMMUNE FUNCTION AND VARIOUS CANCERS. ENDOPHENOTYPIC ANALYSES USING PERIPHERAL CORTISOL LEVELS AND NEUROIMAGING PARADIGMS SHOWED THAT METHYLOMIC VARIATION IN GAS5 NETWORK-RELATED PROBES WERE ASSOCIATED WITH STRESS PHENOTYPES. POSTMORTEM BRAIN ANALYSES DOCUMENTED INCREASED GAS5 EXPRESSION IN THE AMYGDALA OF INDIVIDUALS WITH AUD. OUR DATA SUGGEST THAT ALCOHOL USE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN THE GLUCOCORTICOID SYSTEM THAT MIGHT INFLUENCE STRESS AND INFLAMMATORY REACTIVITY AND SUBSEQUENTLY RISK FOR AUD. 2021 12 1967 40 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 13 2119 32 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 14 990 31 CHRONIC SOCIAL STRESS INDUCES DNA METHYLATION CHANGES AT AN EVOLUTIONARY CONSERVED INTERGENIC REGION IN CHROMOSOME X. CHRONIC STRESS RESULTING FROM PROLONGED EXPOSURE TO NEGATIVE LIFE EVENTS INCREASES THE RISK OF MOOD AND ANXIETY DISORDERS. ALTHOUGH CHRONIC STRESS CAN CHANGE GENE EXPRESSION RELEVANT FOR BEHAVIOR, MOLECULAR REGULATORS OF THIS CHANGE HAVE NOT BEEN FULLY DETERMINED. ONE PROCESS THAT COULD PLAY A ROLE IS DNA METHYLATION, AN EPIGENETIC PROCESS WHEREBY A METHYL GROUP IS ADDED ONTO NUCLEOTIDES, PREDOMINANTLY CYTOSINE IN THE CPG CONTEXT, AND WHICH CAN BE INDUCED BY CHRONIC STRESS. IT IS UNKNOWN TO WHAT EXTENT CHRONIC SOCIAL DEFEAT, A MODEL OF HUMAN SOCIAL STRESS, INFLUENCES DNA METHYLATION PATTERNS ACROSS THE GENOME. OUR STUDY ADDRESSED THIS QUESTION BY USING A TARGETED-CAPTURE APPROACH CALLED METHYL-SEQ TO INVESTIGATE DNA METHYLATION PATTERNS OF THE DENTATE GYRUS AT PUTATIVE REGULATORY REGIONS ACROSS THE MOUSE GENOME FROM MICE EXPOSED TO 14 DAYS OF SOCIAL DEFEAT. FINDINGS WERE REPLICATED IN INDEPENDENT COHORTS BY BISULFITE-PYROSEQUENCING. TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE IDENTIFIED. ONE DMR WAS LOCATED AT INTRON 9 OF DROSHA, AND IT SHOWED REDUCED METHYLATION IN STRESSED MICE. THIS OBSERVATION REPLICATED IN ONE OF TWO INDEPENDENT COHORTS. A SECOND DMR WAS IDENTIFIED AT AN INTERGENIC REGION OF CHROMOSOME X, AND METHYLATION IN THIS REGION WAS INCREASED IN STRESSED MICE. THIS METHYLATION DIFFERENCE REPLICATED IN TWO INDEPENDENT COHORTS AND IN MAJOR DEPRESSIVE DISORDER (MDD) POSTMORTEM BRAINS. THESE RESULTS HIGHLIGHT A REGION NOT PREVIOUSLY KNOWN TO BE DIFFERENTIALLY METHYLATED BY CHRONIC SOCIAL DEFEAT STRESS AND WHICH MAY BE INVOLVED IN MDD. 2018 15 2167 43 EPIGENETIC MECHANISMS IN IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A BRAIN-GUT AXIS DISORDER CHARACTERIZED BY ABDOMINAL PAIN AND ALTERED BOWEL HABITS. IBS IS A MULTIFACTORIAL, STRESS-SENSITIVE DISORDER WITH EVIDENCE FOR FAMILIAL CLUSTERING ATTRIBUTED TO GENETIC OR SHARED ENVIRONMENTAL FACTORS. HOWEVER, THERE ARE WEAK GENETIC ASSOCIATIONS REPORTED WITH IBS AND A LACK OF EVIDENCE TO SUGGEST THAT MAJOR GENETIC FACTOR(S) CONTRIBUTE TO IBS PATHOPHYSIOLOGY. STUDIES ON ANIMAL MODELS OF STRESS, INCLUDING EARLY LIFE STRESS, SUGGEST A ROLE FOR ENVIRONMENTAL FACTORS, SPECIFICALLY, STRESS ASSOCIATED WITH DYSREGULATION OF CORTICOTROPIN RELEASING FACTOR AND HYPOTHALAMUS-PITUITARY-ADRENAL (HPA) AXIS PATHWAYS IN THE PATHOPHYSIOLOGY OF IBS. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS, WHICH CONSTITUTE MOLECULAR CHANGES NOT DRIVEN BY A CHANGE IN GENE SEQUENCE, CAN MEDIATE ENVIRONMENTAL EFFECTS ON CENTRAL AND PERIPHERAL FUNCTION. EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION CHANGES, HISTONE MODIFICATIONS, AND DIFFERENTIAL EXPRESSION OF NON-CODING RNAS (MICRORNA [MIRNA] AND LONG NON-CODING RNA) HAVE BEEN ASSOCIATED WITH SEVERAL DISEASES. THE OBJECTIVE OF THIS REVIEW IS TO ELUCIDATE THE MOLECULAR FACTORS IN THE PATHOPHYSIOLOGY OF IBS WITH AN EMPHASIS ON EPIGENETIC MECHANISMS. EMERGING EVIDENCE FOR EPIGENETIC CHANGES IN IBS INCLUDES CHANGES IN DNA METHYLATION IN ANIMAL MODELS OF IBS AND PATIENTS WITH IBS, AND VARIOUS MIRNAS THAT HAVE BEEN ASSOCIATED WITH IBS AND ENDOPHENOTYPES, SUCH AS INCREASED VISCERAL SENSITIVITY AND INTESTINAL PERMEABILITY. DNA METHYLATION, IN PARTICULAR, IS AN EMERGING FIELD IN THE REALM OF COMPLEX DISEASES AND A PROMISING MECHANISM WHICH CAN PROVIDE IMPORTANT INSIGHTS INTO IBS PATHOGENESIS AND IDENTIFY POTENTIAL TARGETS FOR TREATMENT. 2020 16 4428 34 MOLECULAR BASIS OF THE IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER CHARACTERIZED BY ABDOMINAL PAIN, DISCOMFORT AND BLOATING. THE PATHOPHYSIOLOGY OF IBS IS POORLY UNDERSTOOD, BUT THE PRESENCE OF PSYCHOSOCIAL BASIS IS NOW KNOWN. THERE IS AN INCREASING NUMBER OF PUBLICATIONS SUPPORTING THE ROLE OF GENETICS IN IBS. MOST OF THE VARIATIONS ARE FOUND IN GENES ASSOCIATED WITH THE BRAIN-GUT AXIS, REVEALING THE STRONG CORRELATION OF BRAIN-GUT AXIS AND IBS. MIRNAS, WHICH PLAY CRITICAL ROLES IN PHYSIOLOGICAL PROCESSES, ARE NOT WELL STUDIED IN IBS. HOWEVER, SO FAR THERE IS FOUND AN INVOLVEMENT OF ALTERATIONS IN MIRNA EXPRESSION OR SEQUENCE, IN IBS SYMPTOMS. IBS PHENOTYPE IS AFFECTED BY EPIGENETIC ALTERATION AND ENVIRONMENT. CHANGES IN DNA AND HISTONE METHYLATION ARE OBSERVED IN PATIENTS WHO SUFFERED CHILDHOOD TRAUMA OR ABUSE, RESULTING IN ALTERED GENE EXPRESSION, SUCH AS THE GLUCOCORTICOID RECEPTOR GENE. FINALLY, DIET IS ANOTHER FACTOR ASSOCIATED WITH IBS, WHICH MAY CONTRIBUTE TO SYMPTOM ONSET. CERTAIN FOODS MAY AFFECT ON BACTERIAL METABOLISM AND EPIGENETIC MODIFICATIONS, PREDISPOSING TO IBS. 2014 17 4370 33 MIRNAS AND THEIR ROLE IN THE CORRELATION BETWEEN SCHIZOPHRENIA AND CANCER (REVIEW). SCHIZOPHRENIA (SZ) AND CANCER (CA) HAVE A BROAD SPECTRUM OF CLINICAL PHENOTYPES AND A COMPLEX BIOLOGICAL BACKGROUND, IMPLICATING A LARGE NUMBER OF GENETIC AND EPIGENETIC FACTORS. SZ IS A CHRONIC NEURODEVELOPMENTAL DISORDER SIGNIFIED BY AN INCREASE IN THE EXPRESSION OF APOPTOTIC MOLECULAR SIGNALS, WHEREAS CA IS CONVERSELY CHARACTERIZED BY AN INCREASE IN APPROPRIATE MOLECULAR SIGNALING THAT STIMULATES UNCONTROLLED CELL PROLIFERATION. THE RATHER LOW RISK OF DEVELOPING CA IN PATIENTS SUFFERING FROM SZ IS A HYPOTHESIS THAT IS STILL UNDER DEBATE. RECENT EVIDENCE HAS INDICATED THAT MICRORNAS (MIRNAS OR MIRS), A LARGE GROUP OF SMALL NON?CODING OLIGONOUCLEOTIDES, MAY PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF CA AND MAJOR PSYCHIATRIC DISORDERS, SUCH AS SZ, BIPOLAR DISORDER, AUTISM SPECTRUM DISORDERS, SUICIDALITY AND DEPRESSION, THROUGH THEIR INTERFERENCE WITH THE EXPRESSION OF MULTIPLE GENES. FOR INSTANCE, THE POSSIBLE ROLE OF LET?7, MIR?98 AND MIR?183 AS BIOMARKERS FOR CA AND SZ WAS INVESTIGATED IN OUR PREVIOUS RESEARCH STUDIES. THEREFORE, FURTHER INVESTIGATIONS ON THE EXPRESSION PROFILES OF THESE REGULATORY, SMALL RNA MOLECULES AND THE MOLECULAR PATHWAYS THROUGH WHICH THEY EXERT THEIR CONTROL MAY PROVIDE A PLAUSIBLE EXPLANATION AS TO WHETHER THERE IS A CORRELATION BETWEEN PSYCHIATRIC DISORDERS AND LOW RISK OF DEVELOPING CA. 2016 18 1525 32 DNA METHYLATION CHANGES IN GENES INVOLVED IN INFLAMMATION AND DEPRESSION IN FIBROMYALGIA: A PILOT STUDY. OBJECTIVES: THE PRESENT PILOT STUDY AIMS TO INVESTIGATE DNA METHYLATION CHANGES OF GENES RELATED TO FIBROMYALGIA (FM) DEVELOPMENT AND ITS MAIN COMORBID SYMPTOMS, INCLUDING SLEEP IMPAIRMENT, INFLAMMATION, DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. EPIGENETIC MODIFICATIONS MIGHT TRIGGER OR PERPETUATE COMPLEX INTERPLAY BETWEEN PAIN TRANSDUCTION/TRANSMISSION, CENTRAL PAIN PROCESSING AND EXPERIENCED STRESSORS IN VULNERABLE INDIVIDUALS. METHODS: WE CONDUCTED DNA METHYLATION ANALYSIS BY TARGETED BISULFITE NGS SEQUENCING TESTING DIFFERENTIAL METHYLATION IN 112 GENOMIC REGIONS FROM LEUKOCYTES OF EIGHT WOMEN WITH FM AND THEIR EIGHT HEALTHY SISTERS AS CONTROLS. RESULTS: TESTS FOR DIFFERENTIALLY METHYLATED REGIONS AND CYTOSINES BROUGHT FOCUS ON THE GRM2 GENE, ENCODING THE METABOTROPIC GLUTAMATE RECEPTOR2. THE SLIGHTLY INCREASED DNA METHYLATION OBSERVED IN THE GRM2 REGION OF FM PATIENTS MAY CONFIRM THE INVOLVEMENT OF THE GLUTAMATE PATHWAY IN THIS PATHOLOGICAL CONDITION. LOGISTIC REGRESSION HIGHLIGHTED THE SIMULTANEOUS ASSOCIATION OF METHYLATION LEVELS OF DEPRESSION AND INFLAMMATION-RELATED GENES WITH FM. CONCLUSIONS: ALTOGETHER, THE RESULTS EVIDENCE THE GLUTAMATE PATHWAY INVOLVEMENT IN FM AND SUPPORT THE IDEA THAT A COMBINATION OF METHYLATED AND UNMETHYLATED GENES COULD REPRESENT A RISK FACTOR TO FM OR ITS CONSEQUENCE, MORE THAN SINGLE GENES. FURTHER STUDIES ON THE IDENTIFIED BIOMARKERS COULD CONTRIBUTE TO UNRAVEL THE CAUSATIVE UNDERLYING FM MECHANISMS, GIVING RELIABLE DIRECTIONS TO RESEARCH, IMPROVING THE DIAGNOSIS AND EFFECTIVE THERAPIES. 2021 19 5696 30 SIMILARITIES AND DIFFERENCES IN PERIPHERAL BLOOD GENE-EXPRESSION SIGNATURES OF INDIVIDUALS WITH SCHIZOPHRENIA AND THEIR FIRST-DEGREE BIOLOGICAL RELATIVES. SEVERAL STUDIES HAVE EVALUATED THE POTENTIAL UTILITY OF BLOOD-BASED WHOLE-TRANSCRIPTOME SIGNATURES AS A SOURCE OF BIOMARKERS FOR SCHIZOPHRENIA. THIS ENDEAVOR HAS BEEN COMPLICATED BY THE FACT THAT INDIVIDUALS WITH SCHIZOPHRENIA TYPICALLY DIFFER FROM APPROPRIATE COMPARISON SUBJECTS ON MORE THAN JUST THE PRESENCE OF THE DISORDER; FOR EXAMPLE, INDIVIDUALS WITH SCHIZOPHRENIA TYPICALLY RECEIVE ANTIPSYCHOTIC MEDICATIONS, AND HAVE BEEN DEALING WITH THE SEQUELAE OF THIS CHRONIC ILLNESS FOR YEARS. THE INABILITY TO CONTROL SUCH FACTORS INTRODUCES A CONSIDERABLE DEGREE OF UNCERTAINTY IN THE RESULTS TO DATE. TO OVERCOME THIS, WE PERFORMED A BLOOD-BASED GENE-EXPRESSION PROFILING STUDY OF SCHIZOPHRENIA PATIENTS (N = 9) AS WELL AS THEIR UNMEDICATED, NONPSYCHOTIC, BIOLOGICAL SIBLINGS (N = 9) AND UNAFFECTED COMPARISON SUBJECTS (N = 12). THE UNAFFECTED BIOLOGICAL SIBLINGS, WHO MAY HARBOR SOME OF THE GENETIC PREDISPOSITION TO SCHIZOPHRENIA, EXHIBITED A HOST OF GENE-EXPRESSION DIFFERENCES FROM UNAFFECTED COMPARISON SUBJECTS, MANY OF WHICH WERE SHARED BY THEIR SCHIZOPHRENIC SIBLINGS, PERHAPS INDICATIVE OF UNDERLYING RISK FACTORS FOR THE DISORDER. SEVERAL GENES THAT WERE DYSREGULATED IN BOTH INDIVIDUALS WITH SCHIZOPHRENIA AND THEIR SIBLINGS RELATED TO NUCLEOSOME AND HISTONE STRUCTURE AND FUNCTION, SUGGESTING A POTENTIAL EPIGENETIC MECHANISM UNDERLYING THE RISK STATE FOR THE DISORDER. NONPSYCHOTIC SIBLINGS ALSO DISPLAYED SOME DIFFERENCES FROM COMPARISON SUBJECTS THAT WERE NOT FOUND IN THEIR AFFECTED SIBLINGS, SUGGESTING THAT THE DYSREGULATION OF SOME GENES IN PERIPHERAL BLOOD MAY BE INDICATIVE OF UNDERLYING PROTECTIVE FACTORS. THIS STUDY, WHILE EXPLORATORY, ILLUSTRATED THE POTENTIAL UTILITY AND INCREASED INFORMATIVENESS OF INCLUDING UNAFFECTED FIRST-DEGREE RELATIVES IN RESEARCH IN PURSUIT OF PERIPHERAL BIOMARKERS FOR SCHIZOPHRENIA. 2011 20 6720 32 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023