1 2951 127 GENETIC AND EPIGENETIC EPIDEMIOLOGY OF CHRONIC WIDESPREAD PAIN. THE ETIOLOGY UNDERLYING CHRONIC WIDESPREAD PAIN (CWP) REMAINS LARGELY UNKNOWN. AN INTEGRATIVE BIOPSYCHOSOCIAL MODEL SEEMS TO YIELD THE MOST PROMISING EXPLANATIONS FOR THE PATHOGENESIS OF THE CONDITION, WITH GENETIC FACTORS ALSO CONTRIBUTING TO DISEASE DEVELOPMENT AND MAINTENANCE. HERE, WE CONDUCTED A SEARCH OF STUDIES INVESTIGATING THE GENETIC AND EPIGENETIC EPIDEMIOLOGY OF CWP THROUGH ELECTRONIC DATABASES INCLUDING WEB OF SCIENCE, MEDLINE, PUBMED, EMBASE, AND GOOGLE SCHOLAR. COMBINATIONS OF KEYWORDS INCLUDING CWP, CHRONIC PAIN, MUSCULOSKELETAL PAIN, GENETICS, EPIGENETICS, GENE, TWINS, SINGLE-NUCLEOTIDE POLYMORPHISM, GENOTYPE, AND ALLELES WERE USED. IN THE END, A TOTAL OF 15 PUBLICATIONS WERE CONSIDERED RELEVANT TO BE INCLUDED IN THIS REVIEW: EIGHT WERE TWIN STUDIES ON CWP, SIX WERE MOLECULAR GENETIC STUDIES ON CWP, AND ONE WAS AN EPIGENETIC STUDY ON CWP. THE FINDINGS SUGGEST GENETIC AND UNIQUE ENVIRONMENTAL FACTORS TO CONTRIBUTE TO CWP. VARIOUS CANDIDATES SUCH AS SEROTONIN-RELATED PATHWAY GENES WERE FOUND TO BE ASSOCIATED WITH CWP AND SOMATOFORM SYMPTOMS. HOWEVER, STUDIES SHOW SOME LIMITATIONS AND NEED REPLICATION. THE PRESENTED RESULTS FOR CWP COULD SERVE AS A TEMPLATE FOR GENETIC STUDIES ON OTHER CHRONIC PAIN CONDITIONS. ULTIMATELY, A MORE IN-DEPTH UNDERSTANDING OF DISEASE MECHANISMS WILL HELP WITH THE DEVELOPMENT OF MORE EFFECTIVE TREATMENT, INFORM NOSOLOGY, AND REDUCE THE STIGMA STILL LINGERING ON THIS DIAGNOSIS. 2017 2 6458 36 TIME COURSE OF DNA METHYLATION IN PAIN CONDITIONS: FROM EXPERIMENTAL MODELS TO HUMANS. BACKGROUND AND OBJECTIVE: THROUGHOUT THE LAST DECADE, RESEARCH HAS UNCOVERED ASSOCIATIONS BETWEEN PAIN AND EPIGENETIC ALTERATIONS CAUSED BY ENVIRONMENTAL FACTORS. SPECIFICALLY, STUDIES HAVE DEMONSTRATED CORRELATIONS BETWEEN PAIN CONDITIONS AND ALTERED DNA METHYLATION PATTERNS. THUS, DNA METHYLATION HAS BEEN REVEALED AS A POSSIBLE MODULATOR OR CONTRIBUTOR TO PAIN CONDITIONS, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR TREATMENT BY DNA METHYLATION MODIFICATION. TO DEVELOP SUCH TREATMENTS, IT IS NECESSARY TO CLARIFY A WIDE NUMBER OF ASPECTS ON HOW DNA METHYLATION AFFECTS PAIN PERCEPTION; FIRST AND FOREMOST, THE TEMPORAL DYNAMICS. THE OBJECTIVE OF THE PRESENT REVIEW IS TO PROVIDE AN OVERVIEW OF CURRENT KNOWLEDGE ON TEMPORAL DYNAMICS OF DNA METHYLATION IN RESPONSE TO PAIN, AND TO INVESTIGATE IF A TIMEFRAME CAN BE ESTABLISHED BASED ON THE DATA OF CURRENTLY PUBLISHED STUDIES. DATABASES AND DATA TREATMENT: PUBMED, MEDLINE, GOOGLE SCHOLAR AND EMBASE WERE SEARCHED COMPREHENSIVELY FOR STUDIES OF DNA METHYLATION IN NEUROPATHIC, INFLAMMATORY AND ALTERNATIVE ANIMAL PAIN MODELS, AND IN CHRONIC PAIN PATIENTS INCLUDING COMPLEX REGIONAL PAIN SYNDROME, CHRONIC POSTSURGICAL PAIN, CHRONIC WIDESPREAD PAIN, FIBROMYALGIA AND CROHN'S DISEASE. RESULTS: WE IDENTIFIED 34 ARTICLES HIGHLIGHTING VARIATIONS IN TEMPORAL DYNAMICS OF DNA METHYLATION ACROSS SPECIES AND BETWEEN DIFFERENT TYPES OF PAIN. THESE STUDIES REPRESENT A STARTING POINT TO UNCOVER NEW INSIGHTS IN THE DNA METHYLATION TIME COURSE IN PAIN. CONCLUSIONS: NO TIMEFRAME CAN CURRENTLY BE MADE FOR THE DNA METHYLATION RESPONSE TO PAIN IN ANY OF THE REVIEWED CONDITIONS, HIGHLIGHTING AN IMPORTANT FOCUS AREA FOR FUTURE RESEARCH. 2021 3 6159 44 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 4 4915 34 PAIN, ANALGESIA AND GENETICS. OBJECTIVES: IN THE CLINICAL SETTING, THERE IS MARKED INTERSUBJECT VARIABILITY IN THE INTENSITY OF PAIN REPORTED BY PATIENTS WITH APPARENTLY SIMILAR PAIN STATES, AS WELL AS WIDELY DIFFERING ANALGESIC DOSING REQUIREMENTS BETWEEN INDIVIDUALS TO PRODUCE SATISFACTORY PAIN RELIEF WITH TOLERABLE SIDE-EFFECTS. GENETIC AND ENVIRONMENTAL FACTORS AS WELL AS THEIR INTERACTION ARE IMPLICATED, AND THESE ARE DISCUSSED IN THIS REVIEW. KEY FINDINGS: PIONEERING WORK UNDERTAKEN IN MICE MORE THAN A DECADE AGO, SHOWED A STRONG GENETIC CONTRIBUTION TO LEVELS OF NOCICEPTION/HYPERSENSITIVITY AS WELL AS LEVELS OF ANTINOCICEPTION PRODUCED BY COMMONLY AVAILABLE ANALGESIC AGENTS. TO DATE MORE THAN 300 CANDIDATE 'PAIN' GENES HAVE BEEN IDENTIFIED AS POTENTIALLY CONTRIBUTING TO HERITABLE DIFFERENCES IN PAIN SENSITIVITY AND ANALGESIC RESPONSIVENESS IN ANIMALS AND HUMANS, WITH THIS INFORMATION AVAILABLE IN A PUBLICLY ACCESSIBLE DATABASE HTTP://WWW.JBLDESIGN.COM/JMOGIL/ENTER.HTML. SINCE THEN, MANY GENETIC ASSOCIATION STUDIES HAVE BEEN CONDUCTED IN HUMANS TO INVESTIGATE THE POSSIBILITY THAT SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN AN INDIVIDUAL GENE MAY EXPLAIN DRUG INEFFICACY OR EXCESSIVE TOXICITY EXPERIENCED BY A SMALL SUBSET OF THE WHOLE POPULATION WHO HAVE THE RARE ALLELE FOR A PARTICULAR SNP. SUMMARY: DESPITE THE FACT THAT SNPS IN MORE THAN 20 GENES THAT AFFECT PAIN SENSITIVITY OR CONTRIBUTE TO INTERINDIVIDUAL VARIABILITY IN RESPONSES TO ANALGESIC MEDICATIONS HAVE BEEN IDENTIFIED IN THE HUMAN GENOME, MUCH OF THE DATA IS CONFLICTING. APART FROM DEFICIENCIES IN THE DESIGN AND CONDUCT OF HUMAN GENETIC ASSOCIATION STUDIES, RECENT RESEARCH FROM OTHER FIELDS HAS IMPLICATED EPIGENETIC MECHANISMS THAT FACILITATE DYNAMIC GENE-ENVIRONMENT COMMUNICATION, AS A POSSIBLE EXPLANATION. 2011 5 1998 39 EPIGENETIC AND MIRNA EXPRESSION CHANGES IN PEOPLE WITH PAIN: A SYSTEMATIC REVIEW. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS MAY HOLD GREAT POTENTIAL IN THE FIELD OF PAIN. WE SYSTEMATICALLY REVIEWED THE LITERATURE EXPLORING EPIGENETIC MECHANISMS IN PEOPLE WITH PAIN. FOUR DATABASES HAVE BEEN INTERROGATED: MEDLINE, THE COCHRANE CENTRAL REGISTER OF CONTROLLED TRIAL, SCOPUS, AND WEB OF SCIENCE, FOLLOWING PRISMA GUIDELINES IN CONDUCTING STUDY SELECTION AND ASSESSMENT. THIRTY-SEVEN STUDIES WERE INCLUDED. STUDIES EXPLORED EPIGENETICS IN CONDITIONS SUCH AS FIBROMYALGIA, CRPS, NEUROPATHIES, OR OSTEOARTHRITIS. RESEARCH FOCUSSED ON GENOME-WIDE AND GENE-SPECIFIC DNA METHYLATION, AND MIRNA EXPRESSION. BIOINFORMATICS ANALYSES EXPLORING MIRNA-ASSOCIATED MOLECULAR PATHWAYS WERE ALSO PERFORMED. SEVERAL GENES ALREADY KNOWN FOR THEIR ROLE IN PAIN (BDNF, HDAC4, PRKG1, IL-17, TNFRSF13B, ETC.), AND SEVERAL MIRNAS LINKED TO INFLAMMATORY REGULATION, NOCICEPTIVE SIGNALLING AND PROTEIN KINASES FUNCTIONS HAVE BEEN FOUND TO DIFFER SIGNIFICANTLY BETWEEN PEOPLE WITH CHRONIC PAIN AND HEALTHY CONTROLS. ALTHOUGH THE STUDIES INCLUDED WERE CROSS-SECTIONAL IN NATURE, AND NO CONCLUSION ON CAUSAL LINKS BETWEEN EPIGENETIC CHANGES AND PAIN COULD BE DRAWN, WE SUMMARISED THE LARGE AMOUNT OF DATA AVAILABLE IN LITERATURE ON THE TOPIC, HIGHLIGHTING RESULTS THAT HAVE BEEN REPLICATED BY INDEPENDENT INVESTIGATIONS. THE FIELD OF PAIN EPIGENETICS APPEARS VERY EXCITING AND HAS ALL THE POTENTIAL TO LEAD TO REMARKABLE SCIENTIFIC ADVANCES. HOWEVER, HIGH-QUALITY, WELL-POWERED, LONGITUDINAL STUDIES ARE WARRANTED. PERSPECTIVE: THOUGH MORE HIGH-QUALITY RESEARCH IS NEEDED, AVAILABLE RESEARCH EXPLORING EPIGENETIC MECHANISMS OR MIRNAS IN PEOPLE WITH PAIN SHOWS THAT GENES REGULATING SYNAPTIC PLASTICITY AND EXCITABILITY, PROTEIN KINASES, AND ELEMENTS OF THE IMMUNE SYSTEM MIGHT HOLD GREAT POTENTIAL IN UNDERSTANDING THE PATHOPHYSIOLOGY OF DIFFERENT CONDITIONS. 2020 6 5040 36 PHARMACOGENETICS OF PAIN AND ANALGESIA. PAIN SEVERITY RATINGS AND THE ANALGESIC DOSING REQUIREMENTS OF PATIENTS WITH APPARENTLY SIMILAR PAIN CONDITIONS MAY DIFFER CONSIDERABLY BETWEEN INDIVIDUALS. CONTRIBUTING FACTORS INCLUDE THOSE OF GENETIC AND ENVIRONMENTAL ORIGIN WITH EPIGENETIC MECHANISMS THAT ENABLE DYNAMIC GENE-ENVIRONMENT INTERACTION, MORE RECENTLY IMPLICATED IN PAIN MODULATION. INSIGHT INTO GENETIC FACTORS UNDERPINNING INTER-PATIENT VARIABILITY IN PAIN SENSITIVITY HAS COME FROM RODENT HERITABILITY STUDIES AS WELL AS FAMILIAL AGGREGATION AND TWIN STUDIES IN HUMANS. INDEED, MORE THAN 350 CANDIDATE PAIN GENES HAVE BEEN IDENTIFIED AS POTENTIALLY CONTRIBUTING TO HERITABLE DIFFERENCES IN PAIN SENSITIVITY. A LARGE NUMBER OF GENETIC ASSOCIATION STUDIES CONDUCTED IN PATIENTS WITH A VARIETY OF CLINICAL PAIN TYPES OR IN HUMANS EXPOSED TO EXPERIMENTALLY INDUCED PAIN STIMULI IN THE LABORATORY SETTING, HAVE EXAMINED THE IMPACT OF SINGLE-NUCLEOTIDE POLYMORPHISMS IN VARIOUS TARGET GENES ON PAIN SENSITIVITY AND/OR ANALGESIC DOSING REQUIREMENTS. HOWEVER, THE FINDINGS OF SUCH STUDIES HAVE GENERALLY FAILED TO REPLICATE OR HAVE BEEN ONLY PARTIALLY REPLICATED BY INDEPENDENT INVESTIGATORS. DEFICIENCIES IN STUDY CONDUCT INCLUDING USE OF SMALL SAMPLE SIZE, INAPPROPRIATE STATISTICAL METHODS AND INADEQUATE ATTENTION TO THE POSSIBILITY THAT BETWEEN-STUDY DIFFERENCES IN ENVIRONMENTAL FACTORS MAY ALTER PAIN PHENOTYPES THROUGH EPIGENETIC MECHANISMS, HAVE BEEN IDENTIFIED AS BEING SIGNIFICANT. 2012 7 638 48 BIOMARKERS ASSOCIATED WITH MIGRAINE AND THEIR POTENTIAL ROLE IN MIGRAINE MANAGEMENT. OBJECTIVE: THE FOCUS OF THIS REVIEW IS TO REVIEW POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKERS ASSOCIATED WITH MIGRAINE. BACKGROUND: MIGRAINE HEADACHE IS A COMMON DISEASE THAT AFFECTS MILLIONS OF INDIVIDUALS WORLDWIDE. ALTHOUGH WELL-ACCEPTED DIAGNOSTIC CRITERIA EXIST FOR MIGRAINE, IT IS STILL A COMPLEX DISORDER THAT REMAINS BOTH UNDERDIAGNOSED AND MISDIAGNOSED. THE CAUSES OF MIGRAINE ARE LIKELY A MIX OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT, TOGETHER WITH THE INDIVIDUAL'S LIFE HISTORY, TRANSLATE INTO THE OBSERVED CLINICAL HETEROGENEITY. INHERENT CLINICAL HETEROGENEITY IS AN OBSTACLE IN DEVELOPING MORE EFFECTIVE TREATMENTS. THE LACK OF APPROPRIATE BIOMARKERS IS ALSO AN IMPEDIMENT TO DEVELOPING MORE EFFECTIVE THERAPEUTIC/PREVENTIVE APPROACHES. ULTIMATELY, BIOMARKERS MAY FACILITATE THE GOAL OF INDIVIDUALIZED MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER TYPES OF HEADACHE. METHODS: A COMPREHENSIVE REVIEW WAS CONDUCTED OF PUBMED CITATIONS CONTAINING THE KEY WORD "MARKER" OR "BIOMARKER" COMBINED WITH "MIGRAINE" OR "HEADACHE." OTHER KEY WORDS INCLUDED "SERUM," "SALIVA," "CEREBROSPINAL FLUID," "GENES," "BLOOD," AND "INFLAMMATION." THE ONLY RESTRICTION WAS ENGLISH-LANGUAGE PUBLICATION. THE ABSTRACTS OF ALL ARTICLES MEETING THESE CRITERIA WERE REVIEWED, AND FULL TEXT WAS RETRIEVED AND EXAMINED FOR RELEVANT REFERENCES. RESULTS: DATA FROM HUMAN STUDIES HAVE BEGUN TO IDENTIFY GENETIC MUTATIONS/POLYMORPHISMS AND ALTERED LEVELS OF SPECIFIC PROINFLAMMATORY AND NEUROMODULATORY MOLECULES THAT STRONGLY CORRELATE WITH MIGRAINE AS WELL AS SYMPTOM SEVERITY. RESULTS FROM A SMALLER NUMBER OF STUDIES HAVE IDENTIFIED PARAMETERS, SUCH AS THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP), WHICH ARE SIGNIFICANTLY ASSOCIATED WITH RESPONSE TO SPECIFIC TREATMENTS FOR ACUTE MIGRAINE ATTACKS AND PROPHYLAXIS. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MIGRAINE, AND UNDERSTANDING ENVIRONMENTALLY INDUCED GENETIC CHANGES ASSOCIATED WITH THIS DISEASE MAY EVENTUALLY GUIDE THE DEVELOPMENT OF THERAPIES CAPABLE OF REVERSING THESE PATHOPHYSIOLOGICAL CHANGES IN GENE FUNCTION. CONCLUSIONS: THE UNDERSTANDING OF THE ETIOLOGY OF MIGRAINE IS INCOMPLETE. ALTHOUGH THE IDENTIFICATION AND VALIDATION OF BIOMARKERS HAS GREATLY ADVANCED DIAGNOSTIC PRECISION AND MEASURES OF THERAPEUTIC EFFICACY IN OTHER DISEASES, THERE ARE NO CURRENTLY ACCEPTED BIOMARKERS FOR CHRONIC OR EPISODIC MIGRAINE. HOWEVER, THE CONTINUED INVESTIGATION AND IDENTIFICATION OF GENETIC, EPIGENETIC, AND MOLECULAR BIOMARKERS IS LIKELY TO FACILITATE THE GOAL OF INDIVIDUALIZING MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER HEADACHE DISORDERS. 2013 8 1314 29 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 9 1736 31 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 10 2107 29 EPIGENETIC FACTORS IN SCHIZOPHRENIA: MECHANISMS AND EXPERIMENTAL APPROACHES. SCHIZOPHRENIA IS A CHRONIC MENTAL DISORDER THAT IS STILL POORLY UNDERSTOOD DESPITE DECADES OF STUDY. MANY FACTORS HAVE BEEN FOUND TO CONTRIBUTE TO THE PATHOGENESIS, INCLUDING NEURODEVELOPMENTAL DISTURBANCE, GENETIC RISK, AND ENVIRONMENTAL INSULT, BUT NO SINGLE ROOT CAUSE HAS EMERGED. WHILE EVIDENCE FROM TWIN STUDIES SUGGESTS A STRONG HERITABLE COMPONENT, FEW INDIVIDUAL LOCI HAVE BEEN IDENTIFIED IN GENOMEWIDE SCREENS, SUGGESTING A ROLE FOR EPIGENETIC EFFECTS. RATHER, LARGE NUMBERS OF WEAKLY ACTING LOCI MAY CUMULATIVELY INCREASE DISEASE RISK, INCLUDING SEVERAL MAPPING TO EPIGENETIC PATHWAYS. IN THIS REVIEW, WE DISCUSS MECHANISMS OF EPIGENETIC REGULATION AND EVIDENCE FOR AN EPIGENETIC CONTRIBUTION TO DISEASE PHENOTYPE. WE FURTHER DESCRIBE THE RANGE OF EXPERIMENTAL TOOLS CURRENTLY AVAILABLE TO STUDY EPIGENETIC EFFECTS ASSOCIATED WITH THE DISEASE. 2019 11 2108 34 EPIGENETIC FACTORS RELATED TO LOW BACK PAIN: A SYSTEMATIC REVIEW OF THE CURRENT LITERATURE. LOW BACK PAIN (LBP) IS ONE OF THE MOST COMMON CAUSES OF PAIN AND DISABILITY. AT PRESENT, TREATMENT AND INTERVENTIONS FOR ACUTE AND CHRONIC LOW BACK PAIN OFTEN FAIL TO PROVIDE SUFFICIENT LEVELS OF PAIN RELIEF, AND FULL FUNCTIONAL RESTORATION CAN BE CHALLENGING. CONSIDERING THE SIGNIFICANT SOCIO-ECONOMIC BURDEN AND RISK-TO-BENEFIT RATIO OF MEDICAL AND SURGICAL INTERVENTION IN LOW BACK PAIN PATIENTS, THE IDENTIFICATION OF RELIABLE BIOMARKERS SUCH AS EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN COULD BE USEFUL IN CLINICAL PRACTICE. THE AIM OF THIS STUDY WAS TO REVIEW THE AVAILABLE LITERATURE REGARDING THE EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN. THIS REVIEW WAS CARRIED OUT IN ACCORDANCE WITH PREFERENTIAL REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. THE SEARCH WAS CARRIED OUT IN OCTOBER 2022. ONLY PEER-REVIEWED ARTICLES WERE CONSIDERED FOR INCLUSION. FOURTEEN STUDIES WERE INCLUDED AND SHOWED PROMISING RESULTS IN TERMS OF RELIABLE MARKERS. EPIGENETIC MARKERS FOR LBP HAVE THE POTENTIAL TO SIGNIFICANTLY MODIFY DISEASE MANAGEMENT. MOST RECENT EVIDENCE SUGGESTS THAT EPIGENETICS IS A MORE PROMISING FIELD FOR THE IDENTIFICATION OF FACTORS ASSOCIATED WITH LBP, OFFERING A RATIONALE FOR FURTHER INVESTIGATION IN THIS FIELD WITH THE LONG-TERM GOAL OF FINDING EPIGENETIC BIOMARKERS THAT COULD CONSTITUTE BIOLOGICAL TARGETS FOR DISEASE MANAGEMENT AND TREATMENT. 2023 12 2075 29 EPIGENETIC DIFFERENCES IN INFLAMMATION GENES OF MONOZYGOTIC TWINS ARE RELATED TO PARENT-CHILD EMOTIONAL AVAILABILITY AND HEALTH. THE INFLAMMATORY RESPONSE IS AN IMMUNE DEFENSE ENGAGED IMMEDIATELY AFTER INJURY OR INFECTION. CHRONIC INFLAMMATION CAN BE DELETERIOUS FOR VARIOUS HEALTH OUTCOMES AND IS CHARACTERIZED BY HIGH LEVELS OF PRO-INFLAMMATORY MARKERS SUCH AS C-REACTIVE PROTEIN (CRP), INTERLEUKIN 6 (IL-6), AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA). A LARGE BODY OF RESEARCH DEMONSTRATES THESE INFLAMMATORY MARKERS ARE RESPONSIVE TO STRESS AND QUALITY OF SOCIAL RELATIONSHIPS THROUGHOUT THE LIFESPAN. FOR EXAMPLE, THE QUALITY OF THE EARLY PARENTAL BOND PREDICTS VARIOUS HEALTH OUTCOMES AND MAY BE DRIVEN BY CHANGES IN IMMUNE FUNCTION. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, MAY BE ONE MECHANISM BY WHICH EARLY SOCIAL EXPERIENCES SHAPE IMMUNE FUNCTIONING. THE PRESENT STUDY USED A MONOZYGOTIC TWIN DIFFERENCE DESIGN TO ASSESS IF MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR AND 2.5 YEARS PREDICTED IMMUNE GENE METHYLATION AT 8 YEARS OF AGE. FURTHER, WE ASSESSED IF INFLAMMATION GENE METHYLATION WAS RELATED TO GENERAL HEALTH PROBLEMS (E.G. INFECTIONS, ALLERGIES, ETC.). WE FOUND THAT MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR, BUT NOT 2.5 YEARS, WAS RELATED TO METHYLATION OF VARIOUS IMMUNE GENES IN MONOZYGOTIC TWINS. FURTHERMORE, TWIN PAIRS DISCORDANT IN HEALTH PROBLEMS HAVE MORE DIFFERENCE IN IMMUNE GENE METHYLATION COMPARED TO TWIN PAIRS CONCORDANT FOR HEALTH PROBLEMS, SUGGESTING THAT METHYLATION OF IMMUNE GENES MAY HAVE FUNCTIONAL CONSEQUENCES FOR GENERAL HEALTH. THESE RESULTS SUGGEST THAT THE EMOTIONAL COMPONENT OF ATTACHMENT QUALITY DURING INFANCY CONTRIBUTES TO IMMUNE EPIGENETIC PROFILES IN CHILDHOOD, WHICH MAY INFLUENCE GENERAL HEALTH. 2020 13 2526 32 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 14 5028 25 PERSONALIZING PEDIATRIC PAIN MEDICINE: USING POPULATION-SPECIFIC PHARMACOGENETICS, GENOMICS, AND OTHER -OMICS APPROACHES TO PREDICT RESPONSE. PERSONALIZED MEDICINE IS THE SCIENCE OF INDIVIDUALIZED PREVENTION AND THERAPY. THE NOTION THAT "ONE SIZE FITS ALL" HAS BEEN REPLACED BY THE IDEA OF PATIENT-TAILORED HEALTH CARE. WITHIN THIS PARADIGM, THE RESEARCH COMMUNITY HAS TURNED TO EXAMINE GENETIC PREDICTORS OF DISEASE AND TREATMENT RESPONSES. PAIN RESEARCHERS HAVE PRODUCED GENETIC STUDIES OVER THE LAST DECADE THAT EVALUATE THE ASSOCIATION OF GENETIC VARIABILITY WITH PAIN SENSITIVITY AND ANALGESIC RESPONSE. WHILE MOST OF THESE STUDIES HAVE BEEN CONDUCTED AMONG COHORTS OF SUBJECTS OF EUROPEAN DESCENT, SOME HAVE INCLUDED OTHER RACIAL AND ETHNIC GROUPS, PROVIDING EVIDENCE OF VARIABLE RESPONSES TO ANALGESICS. SIMULTANEOUSLY, THERE IS AN INCREASED RECOGNITION REGARDING THE COMPLEXITY OF PAIN RESEARCH, ACKNOWLEDGING THE ADDITIONAL ROLE OF EPIGENETIC, TRANSCRIPTOMIC, PROTEOMIC, AND METABOLOMIC FACTORS IN THE DEVELOPMENT, EXPERIENCE, AND TREATMENT OF PAIN. THIS ARTICLE PROVIDES AN INTRODUCTION TO POPULATION-SPECIFIC PHARMACOGENETICS, PROTEOMICS AND OTHER "-OMICS" TECHNOLOGIES TO PREDICT DRUG RESPONSE TO PAIN MEDICATIONS IN CHILDREN. IT AIMS TO PROVIDE ANESTHESIOLOGISTS WITH THE BASIC KNOWLEDGE TO UNDERSTAND THE POTENTIAL IMPLICATIONS OF GENETIC AND EPIGENETIC FACTORS MANAGING THE PAIN OF PEDIATRIC PATIENTS. 2015 15 728 37 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 16 247 35 ADULTHOOD ASTHMA AS A CONSEQUENCE OF CHILDHOOD ADVERSITY: A SYSTEMATIC REVIEW OF EPIGENETICALLY AFFECTED GENES. THERE IS AN ACCUMULATING DATA THAT SHOWS RELATION BETWEEN CHILDHOOD ADVERSITY AND VULNERABILITY TO CHRONIC DISEASES AS WELL AS EPIGENETIC INFLUENCES THAT IN TURN GIVE RISE TO THESE DISEASES. ASTHMA IS ONE OF THE CHRONIC DISEASES THAT IS INFLUENCED FROM GENETIC REGULATION OF THE INFLAMMATORY BIOMOLECULES AND THEREFORE THE HYPOTHESIS IN THIS RESEARCH WAS CHILDHOOD ADVERSITY MIGHT HAVE CAUSED EPIGENETIC DIFFERENTIATION IN THE ASTHMA-RELATED GENES IN THE POPULATION WHO HAD CHILDHOOD TRAUMA. TO TEST THIS HYPOTHESIS, THE LITERATURE WAS SYSTEMATICALLY REVIEWED TO EXTRACT EPIGENETICALLY MODIFIED GENE DATA OF THE ADULTS WHO HAD CHILDHOOD ADVERSITY, AND AFFECTED GENES WERE FURTHER EVALUATED FOR THEIR ASSOCIATION WITH ASTHMA. PRISMA GUIDELINES WERE ADOPTED AND PUBMED AND GOOGLE SCHOLAR WERE INCLUDED IN THE SEARCHED DATABASES, TO EVALUATE EPIGENETIC MODIFICATIONS IN ASTHMA-RELATED GENES OF PHYSICALLY, EMOTIONALLY OR SEXUALLY ABUSED CHILDREN. AFTER RETRIEVING A TOTAL OF 5245 ARTICLES, 36 OF THEM WERE INCLUDED IN THE STUDY. SEVERAL GENES AND PATHWAYS THAT MAY CONTRIBUTE TO PATHOGENESIS OF ASTHMA DEVELOPMENT, INCREASED INFLAMMATION, OR RESPONSE TO ASTHMA TREATMENT WERE FOUND EPIGENETICALLY AFFECTED BY CHILDHOOD TRAUMAS. CHILDHOOD ADVERSITY, CAUSING EPIGENETIC CHANGES IN DNA, MAY LEAD TO ASTHMA DEVELOPMENT OR INFLUENCE THE COURSE OF THE DISEASE AND THEREFORE SHOULD BE TAKEN INTO ACCOUNT FOR THE PROLONGED HEALTH CONSEQUENCES. 2022 17 666 48 BLOOD-BASED DNA METHYLATION BIOMARKERS FOR TYPE 2 DIABETES: POTENTIAL FOR CLINICAL APPLICATIONS. TYPE 2 DIABETES (T2D) IS A LEADING CAUSE OF DEATH AND DISABILITY WORLDWIDE. IT IS A CHRONIC METABOLIC DISORDER THAT DEVELOPS DUE TO AN INTERPLAY OF GENETIC, LIFESTYLE, AND ENVIRONMENTAL FACTORS. THE BIOLOGICAL ONSET OF THE DISEASE OCCURS LONG BEFORE CLINICAL SYMPTOMS DEVELOP, THUS THE SEARCH FOR EARLY DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, WHICH COULD FACILITATE INTERVENTION STRATEGIES TO PREVENT OR DELAY DISEASE PROGRESSION, HAS INCREASED CONSIDERABLY IN RECENT YEARS. EPIGENETIC MODIFICATIONS REPRESENT IMPORTANT LINKS BETWEEN GENETIC, ENVIRONMENTAL AND LIFESTYLE CUES AND INCREASING EVIDENCE IMPLICATE ALTERED EPIGENETIC MARKS SUCH AS DNA METHYLATION, THE MOST CHARACTERIZED AND WIDELY STUDIED EPIGENETIC MECHANISM, IN THE PATHOGENESIS OF T2D. THIS REVIEW PROVIDES AN UPDATE OF THE CURRENT STATUS OF DNA METHYLATION AS A BIOMARKER FOR T2D. FOUR DATABASES, SCOPUS, PUBMED, COCHRANE CENTRAL, AND GOOGLE SCHOLAR WERE SEARCHED FOR STUDIES INVESTIGATING DNA METHYLATION IN BLOOD. THIRTY-SEVEN STUDIES WERE IDENTIFIED, AND ARE SUMMARIZED WITH RESPECT TO POPULATION CHARACTERISTICS, BIOLOGICAL SOURCE, AND METHOD OF DNA METHYLATION QUANTIFICATION (GLOBAL, CANDIDATE GENE OR GENOME-WIDE). WE HIGHLIGHT THAT DIFFERENTIAL METHYLATION OF THE TCF7L2, KCNQ1, ABCG1, TXNIP, PHOSPHO1, SREBF1, SLC30A8, AND FTO GENES IN BLOOD ARE REPRODUCIBLY ASSOCIATED WITH T2D IN DIFFERENT POPULATION GROUPS. THESE GENES SHOULD BE PRIORITIZED AND REPLICATED IN LONGITUDINAL STUDIES ACROSS MORE POPULATIONS IN FUTURE STUDIES. FINALLY, WE DISCUSS THE LIMITATIONS FACED BY DNA METHYLATION STUDIES, WHICH INCLUDE INCLUDING INTERPATIENT VARIABILITY, CELLULAR HETEROGENEITY, AND LACK OF ACCOUNTING FOR STUDY CONFOUNDERS. THESE LIMITATIONS AND CHALLENGES MUST BE OVERCOME BEFORE THE IMPLEMENTATION OF BLOOD-BASED DNA METHYLATION BIOMARKERS INTO A CLINICAL SETTING. WE EMPHASIZE THE NEED FOR LONGITUDINAL PROSPECTIVE STUDIES TO SUPPORT THE ROBUSTNESS OF THE CURRENT FINDINGS OF THIS REVIEW. 2018 18 3108 30 GENOMICS OF PAIN IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) ACCOUNTS FOR THE MAJORITY OF THE DISEASE BURDEN FOR MUSCULOSKELETAL DISORDERS AND IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. THIS DISABILITY IS THE RESULT NOT OF THE CARTILAGE LOSS THAT DEFINES OA RADIOGRAPHICALLY, BUT OF THE CHRONIC PAIN WHOSE PRESENCE DEFINES SYMPTOMATIC OA. IT IS BECOMING CLEAR THAT MANY GENES, EACH WITH A SMALL EFFECT SIZE, CONTRIBUTE TO THE RISK OF DEVELOPING OA. HOWEVER, THE GENETICS OF OA PAIN ARE ONLY JUST STARTING TO BE EXPLORED. THIS REVIEW WILL DESCRIBE THE FIRST GENES TO HAVE BEEN IDENTIFIED IN GENOMIC STUDIES OF OA PAIN, AS WELL AS THE POSSIBLE DUAL ROLES OF GENES PREVIOUSLY IDENTIFIED IN GENOMIC STUDIES OF OA IN THE CONTEXT OF PAIN. DIFFICULTIES ASSOCIATED WITH ATTEMPTING TO CHARACTERISE THE GENETICS OF OA PAIN WILL BE DISCUSSED AND PROMISING FUTURE AVENUES OF RESEARCH INTO GENETIC AND EPIGENETIC FACTORS AFFECTING OA PAIN DESCRIBED. 2013 19 5643 29 SEX AND AUTOIMMUNITY: PROPOSED MECHANISMS OF DISEASE ONSET AND SEVERITY. CHRONIC AUTOIMMUNE DISEASES AFFECT 5-10% OF THE POPULATION WORLDWIDE AND ARE LARGELY PREDOMINANT IN WOMEN. SEX HORMONE CHANGES HAVE BEEN WIDELY INVESTIGATED BASED ON CHANGES IN THE CLINICAL PHENOTYPES OBSERVED DURING PREGNANCY AND MENOPAUSE. IT IS KNOWN THAT FEMALES WITH AUTOIMMUNE DISEASES MANIFEST A HIGHER RATE OF CIRCULATING LEUKOCYTES WITH A SINGLE X CHROMOSOME, AND THERE HAVE BEEN SEVERAL REPORTS ON THE ROLE OF X CHROMOSOME GENE DOSAGE THROUGH INACTIVATION OR DUPLICATION IN AUTOIMMUNITY. HOWEVER, IT IS ALSO IMPORTANT NOT TO OVERLOOK MEN WITH AUTOIMMUNE DISEASES, WHO MIGHT MANIFEST A MORE FREQUENT LOSS OF THE Y CHROMOSOME IN CIRCULATING LEUKOCYTES. AREAS COVERED: IN THE PRESENT REVIEW, WE WILL DISCUSS THE CURRENT EVIDENCE SUPPORTING THE MECHANISMS OF FEMALE PREDOMINANCE IN RHEUMATIC DISEASES, BY DISCUSSING THE ROLE OF REPRODUCTIVE HISTORY, SEX HORMONES AND ABNORMALITIES RELATED TO THEM, CLINICAL DIFFERENCES BETWEEN MALE AND FEMALE PATIENTS, AND EPIGENETIC CHANGES THAT HAVE BEEN EVALUATED THROUGH TWIN STUDIES ON GENETIC AND ENVIRONMENTAL CHANGES IN RHEUMATIC PATIENTS. EXPERT OPINION: THE INFLUENCE OF SEX HORMONES AND CHROMOSOMES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS NEEDS TO BE CLARIFIED, TO BETTER UNDERSTAND THE RISK OF AUTOIMMUNE DISEASES, EARLY DIAGNOSTIC TOOLS, AND THERAPEUTIC RESPONSE. 2019 20 2918 34 GENE-ENVIRONMENT INTERACTIONS IN MAJOR MENTAL DISORDERS IN THE CZECH REPUBLIC. BACKGROUND: MENTAL DISORDERS AFFECT ABOUT ONE?-THIRD OF THE HUMAN POPULATION, ARE TYPICALLY CHRONIC AND SIGNIFICANTLY DECREASE THE QUALITY OF LIFE. PRESENTLY, THE TREATMENT OF MENTAL ILLNESSES IS FAR FROM ADEQUATE WITH A SUBSTANTIAL PROPORTION OF THE PATIENTS BEING PHARMACORESISTANT AND SUFFERING FROM RELAPSES. ONE OF THE REASONS FOR THIS COMPLICATED SITUATION IS THAT WE DO NOT PRECISELY KNOW ABOUT THE CAUSES OF MENTAL DISORDERS, SO THEIR TREATMENT CANNOT BE CAUSAL. THE ETIOLOGY OF A MENTAL DISORDER IS TYPICALLY BASED ON A COMBINATION OF MOLECULAR (GENETIC) AND ENVIRONMENTAL FACTORS. AIM: THE AIM OF THE PROJECT IS TO DISCOVER THE GENE-ENVIRONMENT INTERACTIONS (GXE) IN A WIDE SPECTRUM OF MENTAL DISORDERS. METHODS: THE DESIGN OF OUR STUDY IS INNOVATIVE IN THE SENSE THAT WE INTEND TO STUDY LARGE GROUPS OF ASSOCIATED MENTAL DISORDERS AS A WHOLE INSTEAD OF IN ISOLATION. THIS WOULD ENABLE US TO MAP OUT THE POSSIBLE ENVIRONMENTAL CAUSAL FACTORS IN DETAIL IN RELATION TO THEIR CHARACTER, MAGNITUDE AND TIMING. THE PROJECT ALSO ALLOWS A STUDY OF GENETICS (INCLUDING EPIGENETICS AND MICROBIOMES) AS WELL AS THE ENVIRONMENT SIMULTANEOUSLY. WE PLAN ON INVOLVING THREE STUDY GROUPS: THE FIRST GROUP ARE PATIENTS SUFFERING FROM SCHIZOPHRENIA OR A MOOD DISORDER SUCH AS MAJOR DEPRESSION, RECURRENT DEPRESSIVE DISORDER AND BIPOLAR AFFECTIVE DISORDER; THE SECOND GROUP OF PATIENTS HAVE ANXIETY DISORDERS; AND THE THIRD GROUP ARE HEALTHY VOLUNTEERS FROM THE GENERAL POPULATION WHO ARE GENETICALLY UNRELATED. ALL OF THE STUDY SUBJECTS WILL UNDERGO THE FOLLOWING ASSESSMENTS: A PSYCHIATRIC EXAMINATION, THE IDENTIFICATION OF STRESSFUL LIFE EVENTS WITH THE AID OF A QUESTIONNAIRE, THE EXAMINATION OF THEIR REACTION TO STRESS, GENETIC AND EPIGENETIC (MICRORNA) ASSESSMENTS AND THE ANALYSIS OF ORAL AND GUT MICROBIOME. CONCLUSION: WE EXPECT THAT SOME OF THE GENETIC AS WELL AS ENVIRONMENTAL FACTORS IN THE STUDIED MENTAL DISORDERS ARE SHARED, WHILE SOME OTHERS ARE SPECIFIC. WE ALSO EXPECT THAT THE GXE (GENE-ENVIRONMENT INTERACTION) IN SCHIZOPHRENIC AND AFFECTIVE DISORDERS WILL BE DIFFERENT FROM THE GXE IN ANXIETY DISORDERS AND THAT THE GXE IN THE STUDIED MENTAL DISORDERS WILL DIFFER GENERALLY FROM THE GXE IN HEALTHY VOLUNTEERS. OUR RESULTS CAN HELP IN THE PREVENTION AND INDIVIDUALIZED TREATMENT OF A RANGE OF MENTAL DISORDERS. 2020