1 3014 120 GENETICS AND EPIGENETICS OF CHRONIC RHINOSINUSITIS. DISCERNING THE GENETICS AND EPIGENETICS OF CHRONIC RHINOSINUSITIS (CRS) MAY OPTIMIZE OUTCOMES THROUGH EARLY DIAGNOSTICS, PERSONALIZED AND NOVEL THERAPEUTICS, AND EARLY PROGNOSTICATION. CRS ASSOCIATED WITH CYSTIC FIBROSIS AND PRIMARY CILIARY DYSKINESIA HAS WELL-CHARACTERIZED GENETIC MUTATIONS. MOST CRS SUBJECTS, HOWEVER, DO NOT EXHIBIT IDENTIFIABLE MONOGENIC ALTERATIONS. CLUSTERING IN RELATED INDIVIDUALS IS SEEN IN CRS WITH NASAL POLYPS. SPOUSES OF SUBJECTS WITH CRS WITHOUT NASAL POLYPS ALSO MAY BE AT INCREASED RISK OF THE SAME DISEASE. THESE OBSERVATIONS GENERATE QUESTIONS ON GENETIC AND ENVIRONMENTAL INFLUENCES IN CRS. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED VARIATIONS AND POLYMORPHISMS BETWEEN CRS AND CONTROL SUBJECTS IN GENES RELATED TO INNATE AND ADAPTIVE IMMUNITY. CANDIDATE GENE AND TRANSCRIPTOMICS STUDIES HAVE INVESTIGATED AND IDENTIFIED GENETIC VARIATIONS RELATED TO IMMUNITY, INFLAMMATION, EPITHELIAL BARRIER FUNCTION, STRESS-RESPONSE, ANTIGEN PROCESSING, T-CELL REGULATION, AND CYTOKINES IN CRS. EPIGENETIC STUDIES HAVE IDENTIFIED MECHANISMS THROUGH WHICH ENVIRONMENTAL FACTORS MAY AFFECT THESE GENE FUNCTIONS. HOWEVER, CAUSALITY IS NOT DETERMINED FOR MOST VARIATIONS. INFERENCES DRAWN FROM THESE DATA MUST BE MEASURED BECAUSE MOST INVESTIGATIONS REPORT UNREPLICATED RESULTS FROM SMALL STUDY POPULATIONS. LARGE, REPLICATED STUDIES IN TIGHT COHORTS ACROSS DIVERSE POPULATIONS REMAIN A PRESSING NEED IN STUDYING CRS GENETICS. 2023 2 2217 29 EPIGENETIC MODIFICATIONS IN CHRONIC RHINOSINUSITIS WITH AND WITHOUT NASAL POLYPS. CHRONIC RHINOSINUSITIS (CRS) HAS BROUGHT A HUGE SOCIOECONOMIC BURDEN. HOWEVER, ITS MECHANISM IS STILL ELUSIVE, WHICH MAY INVOLVE GENETIC, ENVIRONMENTAL AND SOME OTHER FACTORS. EPIGENETIC ANALYSES HAVE BEEN CONDUCTED TO EXPLORE THE MECHANISMS UNDERLYING CRS. HERE, WE REVIEWED THE FRUITS IN THE EPIGENETIC STUDIES ON DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA REGULATION. WE CONCLUDED THAT THE EPIGENETIC RESEARCH ON CRS HAS MADE GREAT BREAKTHROUGHS, ESPECIALLY IN THE PAST 5 YEARS AND THE FIELD OF MICRORNAS. "EPIGENETIC THERAPIES" ARE EXPECTED TO BE DESIGNED TO TREAT CRS IN THE FUTURE. 2022 3 5031 34 PERSPECTIVES ON THE ETIOLOGY OF CHRONIC RHINOSINUSITIS: AN IMMUNE BARRIER HYPOTHESIS. BACKGROUND: CHRONIC RHINOSINUSITIS (CRS) HAS BEEN DEFINED AS PERSISTENT SYMPTOMATIC INFLAMMATION OF THE NASAL AND SINUS MUCOSA RESULTING FROM THE INTERACTION OF MULTIPLE HOST AND ENVIRONMENTAL FACTORS. RECENT STUDIES HAVE IMPLICATED ALTERNARIA FUNGI OR TOXIGENIC STAPHYLOCOCCUS AUREUS AS CRITICAL AGENTS IN CRS PATHOGENESIS. THE EMPHASIS ON ENVIRONMENTAL AGENTS IN CRS ETIOLOGY HAS FOCUSED INTEREST TOWARD ELIMINATION OF THOSE AGENTS AS THE PRIME MECHANISM OF THERAPY. THIS VIEWPOINT IS IN MARKED CONTRAST TO THE CURRENT PERSPECTIVE ON SOME OTHER CHRONIC INFLAMMATORY EPITHELIAL DISORDERS THAT AFFLICT THE SKIN, LUNGS, AND GUT, WHEREIN HOST FACTORS ARE BELIEVED TO PREDISPOSE TO DISEASE EXPRESSION IN THE PRESENCE OF UBIQUITOUS ENVIRONMENTAL AGENTS. METHODS: THE CURRENT REVIEW EVALUATES CRS ETIOLOGY FROM THIS PERSPECTIVE AND CONSIDERS THAT CRS DEVELOPS, IN PART, AS AN OUTCOME OF A DYSFUNCTIONAL HOST RESPONSE. SPECIFICALLY, EVIDENCE FROM OUR LABORATORY AND OTHERS WILL BE REVIEWED INDICATING THAT CRS IS ASSOCIATED WITH A FAILURE OF THE MECHANICAL AND IMMUNOLOGIC BARRIERS ACROSS THE NASAL MUCOSA. THE HYPOTHESIS WOULD FURTHER PROPOSE THAT GENETIC AND EPIGENETIC VARIATION PREDISPOSES SUSCEPTIBLE INDIVIDUALS TO BARRIER FAILURE IN THE PRESENCE OF ENVIRONMENTAL STRESS LEADING TO CRS. RESULTS: FROM THIS UNIFYING PERSPECTIVE, BACTERIA AND FUNGI ARE SEEN AS DISEASE MODIFIERS RATHER THAN PRIMARY ETIOLOGIC AGENTS. CONCLUSION: THE GOAL IS TO PLACE CONCEPTS OF CRS PATHOPHYSIOLOGY IN A FRAMEWORK CONSISTENT WITH A CURRENT UNDERSTANDING OF CHRONIC INFLAMMATION IN GENERAL AND EPITHELIAL DISEASE IN PARTICULAR. 2008 4 3746 49 INSIGHTS INTO THE EPIGENETICS OF CHRONIC RHINOSINUSITIS WITH AND WITHOUT NASAL POLYPS: A SYSTEMATIC REVIEW. BACKGROUND: EPIGENETICS FACILITATES INSIGHTS ON THE IMPACT OF HOST ENVIRONMENT ON THE GENESIS OF CHRONIC RHINOSINUSITIS (CRS) THROUGH MODULATIONS OF HOST GENE EXPRESSION AND ACTIVITY. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION CAUSE REVERSIBLE BUT HERITABLE CHANGES IN GENE EXPRESSION OVER GENERATIONS OF PROGENY, WITHOUT ALTERING THE DNA BASE-PAIR SEQUENCES. THESE STUDIES OFFER A CRITICAL UNDERSTANDING OF THE ENVIRONMENT-INDUCED CHANGES THAT RESULT IN HOST PREDISPOSITION TO DISEASE AND MAY HELP IN DEVELOPING NOVEL BIOMARKERS AND THERAPEUTICS. THE GOAL OF THIS SYSTEMATIC REVIEW IS TO SUMMARIZE THE CURRENT EVIDENCE ON EPIGENETICS OF CRS WITH A FOCUS ON CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) AND HIGHLIGHT GAPS THAT MERIT FURTHER RESEARCH. METHODS: A SYSTEMATIC REVIEW OF THE ENGLISH LANGUAGE LITERATURE WAS PERFORMED TO IDENTIFY INVESTIGATIONS RELATED TO EPIGENETIC STUDIES IN SUBJECTS WITH CRS. RESULTS: THE REVIEW IDENTIFIED 65 STUDIES. THESE HAVE FOCUSED ON DNA METHYLATION AND NON-CODING RNAS, WITH ONLY A FEW ON HISTONE DEACETYLATION, ALTERNATIVE POLYADENYLATION, AND CHROMATIN ACCESSIBILITY. STUDIES INCLUDE THOSE INVESTIGATING IN VIVO AND IN VITRO CHANGES OR BOTH. STUDIES ALSO INCLUDE ANIMAL MODELS OF CRS. ALMOST ALL HAVE BEEN CONDUCTED IN ASIA. THE GENOME-WIDE STUDIES OF DNA METHYLATION FOUND DIFFERENCES IN GLOBAL METHYLATION BETWEEN CRSWNP AND CONTROLS, WHILE OTHERS SPECIFICALLY FOUND SIGNIFICANT DIFFERENCES IN METHYLATION OF THE CPG SITES OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP), IL-8, AND PLAT. IN ADDITION, DNA METHYLTRANSFERASE INHIBITORS AND HISTONE DEACETYLASE INHIBITORS WERE STUDIED AS POTENTIAL THERAPEUTIC AGENTS. MAJORITY OF THE STUDIES INVESTIGATING NON-CODING RNAS FOCUSED ON MICRO-RNAS (MIRNA) AND FOUND DIFFERENCES IN GLOBAL EXPRESSION OF MIRNA LEVELS. THESE STUDIES ALSO REVEALED SOME PREVIOUSLY KNOWN AS WELL AS NOVEL TARGETS AND PATHWAYS SUCH AS TUMOR NECROSIS FACTOR ALPHA, TGF BETA-1, IL-10, EGR2, ARYL HYDROCARBON RECEPTOR, PI3K/AKT PATHWAY, MUCIN SECRETION, AND VASCULAR PERMEABILITY. OVERALL, THE STUDIES HAVE FOUND A DYSREGULATION IN PATHWAYS/GENES INVOLVING INFLAMMATION, IMMUNE REGULATION, TISSUE REMODELING, STRUCTURAL PROTEINS, MUCIN SECRETION, ARACHIDONIC ACID METABOLISM, AND TRANSCRIPTION. CONCLUSIONS: EPIGENETIC STUDIES IN CRS SUBJECTS SUGGEST THAT THERE IS LIKELY A MAJOR IMPACT OF THE ENVIRONMENT. HOWEVER, THESE ARE ASSOCIATION STUDIES AND DO NOT DIRECTLY IMPLY PATHOGENESIS. LONGITUDINAL STUDIES IN GEOGRAPHICALLY AND RACIALLY DIVERSE POPULATION COHORTS ARE NECESSARY TO QUANTIFY GENETIC VS. ENVIRONMENTAL RISKS FOR CRSWNP AND CRS WITHOUT NASAL POLYPS AND ASSESS HERITABILITY RISK, AS WELL AS DEVELOP NOVEL BIOMARKERS AND THERAPEUTIC AGENTS. 2023 5 3019 40 GENETICS AND EPIGENETICS OF NASAL POLYPOSIS: A SYSTEMATIC REVIEW. CHRONIC RHINOSINUSITIS (CRS) IS AN INFLAMMATORY DISEASE OF THE NOSE AND PARANASAL SINUSES THAT IS OFTEN ASSOCIATED WITH NASAL POLYPOSIS (CRSWNP) IN THE MOST SEVERE CASES. AS IN OTHER COMPLEX DISEASES, GENETIC FACTORS ARE THOUGHT TO PLAY AN IMPORTANT ROLE IN THE RISK AND DEVELOPMENT OF THE DISEASE. ENVIRONMENT MAY ALSO MODULATE THE EPIGENETIC SIGNATURE IN AFFECTED PATIENTS. IN THE PRESENT SYSTEMATIC REVIEW, WE AIMED TO COMPILE ALL PUBLISHED DATA ON GENETIC AND EPIGENETIC VARIATIONS IN CRSWNP SINCE 2000. WE FOUND 104 ARTICLES, 24 OF WHICH WERE RELATED TO EPIGENETIC STUDIES. WE IDENTIFIED MORE THAN 150 GENETIC VARIANTS IN 99 GENES INVOLVED IN THE PATHOGENESIS OF NASAL POLYPOSIS. THESE WERE CLUSTERED INTO 8 MAIN NETWORKS, LINKING GENES INVOLVED IN INFLAMMATION AND IMMUNE RESPONSE (EG, MHC), CYTOKINE GENES (EG, TNF), LEUKOTRIENE METABOLISM, AND THE EXTRACELLULAR MATRIX. A TOTAL OF 89 MIRNAS WERE ALSO IDENTIFIED; THESE ARE ASSOCIATED MAINLY WITH BIOLOGICAL FUNCTIONS SUCH AS THE CELL CYCLE, INFLAMMATION, AND THE IMMUNE RESPONSE. WE PROPOSE A POTENTIAL RELATIONSHIP BETWEEN GENES AND THE MIRNAS IDENTIFIED THAT MAY OPEN NEW LINES OF INVESTIGATION. AN IN-DEPTH KNOWLEDGE OF GENE VARIANTS AND EPIGENETIC TRAITS COULD HELP US TO DESIGN MORE TAILORED TREATMENT FOR PATIENTS WITH CRSWNP. 2021 6 1546 29 DNA METHYLATION IN NASAL EPITHELIUM: STRENGTHS AND LIMITATIONS OF AN EMERGENT BIOMARKER FOR CHILDHOOD ASTHMA. ASTHMA IS ONE OF THE MOST WIDESPREAD CHRONIC RESPIRATORY CONDITIONS. THIS DISEASE PRIMARILY DEVELOPS IN CHILDHOOD AND IS INFLUENCED BY DIFFERENT FACTORS, MAINLY GENETICS AND ENVIRONMENTAL FACTORS. DNA METHYLATION IS AN EPIGENETIC MECHANISM WHICH MAY REPRESENT A BRIDGE BETWEEN THESE TWO FACTORS, PROVIDING A TOOL TO COMPREHEND THE INTERACTION BETWEEN GENETICS AND ENVIRONMENT. MOST EPIDEMIOLOGICAL STUDIES IN THIS FIELD HAVE BEEN CONDUCTED USING BLOOD SAMPLES, ALTHOUGH DNA METHYLATION MARKS IN BLOOD MAY NOT BE RELIABLE FOR DRAWING EXHAUSTIVE CONCLUSIONS ABOUT DNA METHYLATION IN THE AIRWAYS. BECAUSE OF THE ROLE OF NASAL EPITHELIUM IN ASTHMA AND THE TISSUE SPECIFICITY OF DNA METHYLATION, STUDYING THE RELATIONSHIP BETWEEN DNA METHYLATION AND CHILDHOOD ASTHMA MIGHT REVEAL CRUCIAL INFORMATION ABOUT THIS WIDESPREAD RESPIRATORY DISEASE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE CURRENT FINDINGS IN THIS FIELD OF RESEARCH. WE WILL PRESENT A VIEWPOINT OF SELECTED STUDIES, CONSIDER STRENGTHS AND LIMITATIONS, AND PROPOSE FUTURE RESEARCH IN THIS AREA. 2020 7 2483 37 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 8 6199 43 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 9 1844 38 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016 10 6790 25 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS. 2005 11 2507 30 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 12 6159 34 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 13 1014 29 CIGARETTE SMOKING AND DNA METHYLATION. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MODIFICATION, CAPABLE OF CONTROLLING GENE EXPRESSION IN THE CONTEXTS OF NORMAL TRAITS OR DISEASES. IT IS HIGHLY DYNAMIC DURING EARLY EMBRYOGENESIS AND REMAINS RELATIVELY STABLE THROUGHOUT LIFE, AND SUCH PATTERNS ARE INTRICATELY RELATED TO HUMAN DEVELOPMENT. DNA METHYLATION IS A QUANTITATIVE TRAIT DETERMINED BY A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. GENETIC VARIANTS AT A SPECIFIC LOCUS CAN INFLUENCE BOTH REGIONAL AND DISTANT DNA METHYLATION. THE ENVIRONMENT CAN HAVE VARYING EFFECTS ON DNA METHYLATION DEPENDING ON WHEN THE EXPOSURE OCCURS, SUCH AS DURING PRENATAL LIFE OR DURING ADULTHOOD. IN PARTICULAR, CIGARETTE SMOKING IN THE CONTEXT OF BOTH CURRENT SMOKING AND PRENATAL EXPOSURE IS A STRONG MODIFIER OF DNA METHYLATION. EPIGENOME-WIDE ASSOCIATION STUDIES HAVE UNCOVERED CANDIDATE GENES ASSOCIATED WITH CIGARETTE SMOKING THAT HAVE BIOLOGICALLY RELEVANT FUNCTIONS IN THE ETIOLOGY OF SMOKING-RELATED DISEASES. AS SUCH, DNA METHYLATION IS A POTENTIAL MECHANISTIC LINK BETWEEN CURRENT SMOKING AND CANCER, AS WELL AS PRENATAL CIGARETTE-SMOKE EXPOSURE AND THE DEVELOPMENT OF ADULT CHRONIC DISEASES. 2013 14 1518 28 DNA METHYLATION AS AN EPIGENETIC MECHANISM IN THE DEVELOPMENT OF MULTIPLE SCLEROSIS. THE EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION ARE A GROUP OF THE KEY CELLULAR AND MOLECULAR PATHWAYS THAT LEAD TO INHERITED ALTERATIONS IN GENES' ACTIVITY WITHOUT CHANGING THEIR CODING SEQUENCE. DNA METHYLATION AT THE C5 POSITION OF CYTOSINE IN CPG DINUCLEOTIDES IS AMONGST THE CENTRAL EPIGENETIC MECHANISMS. CURRENTLY, THE NUMBER OF STUDIES THAT ARE DEVOTED TO THE IDENTIFICATION OF METHYLATION PATTERNS SPECIFIC TO MULTIPLE SCLEROSIS (MS), A SEVERE CHRONIC AUTOIMMUNE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS ON A RAPID RISE. HOWEVER, THE ISSUE OF THE CONTRIBUTION OF DNA METHYLATION TO THE DEVELOPMENT OF THE DIFFERENT CLINICAL PHENOTYPES OF THIS HIGHLY HETEROGENEOUS DISEASE HAS ONLY BEGUN TO ATTRACT THE ATTENTION OF RESEARCHERS. THIS REVIEW SUMMARIZES THE DATA ON THE MOLECULAR MECHANISMS UNDERLYING DNA METHYLATION AND THE MS RISK FACTORS THAT CAN AFFECT THE DNA METHYLATION PROFILE AND, THEREBY, MODULATE THE EXPRESSION OF THE GENES INVOLVED IN THE DISEASE'S PATHOGENESIS. THE FOCUS OF OUR ATTENTION IS CENTERED ON THE ANALYSIS OF THE PUBLISHED DATA ON THE DIFFERENTIAL METHYLATION OF DNA FROM VARIOUS BIOLOGICAL SAMPLES OF MS PATIENTS OBTAINED USING BOTH THE CANDIDATE GENE APPROACH AND HIGH-THROUGHPUT METHODS. 2021 15 396 28 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014 16 6013 33 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 17 1524 24 DNA METHYLATION CHANGES IN CYSTIC FIBROSIS: CAUSE OR CONSEQUENCE? TWIN AND SIBLING STUDIES HAVE SHOWN THAT LUNG DISEASE SEVERITY IS VARIABLE AMONG CYSTIC FIBROSIS (CF) PATIENTS AND AFFECTED TO THE SAME EXTENT BY GENETIC AND NONHERITABLE FACTORS. GENETIC FACTORS HAVE BEEN THOROUGHLY ASSESSED, WHEREAS THE MOLECULAR MECHANISMS WHEREBY NONHERITABLE FACTORS CONTRIBUTE TO THE PHENOTYPIC VARIABILITY OF CF PATIENTS ARE STILL UNKNOWN. EPIGENETIC MODIFICATIONS MAY REPRESENT THE MISSING LINK BETWEEN NONHERITABLE FACTORS AND PHENOTYPIC VARIATION IN CF. HEREIN, WE REVIEW RECENT STUDIES SHOWING THAT DNA METHYLATION IS ALTERED IN CF AND WE ADDRESS THREE POSSIBLE FACTORS RESPONSIBLE FOR THESE VARIATIONS: (I) OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DEPLETION OF DNA METHYLATION COFACTORS AND (III) SUSCEPTIBILITY TO ACUTE AND CHRONIC BACTERIAL INFECTIONS. ALSO, WE HYPOTHESIZE THAT THE UNIQUE DNA METHYLATION PROFILE OF EACH PATIENT CAN MODULATE THE PHENOTYPE AND DISCUSS THE INTEREST OF IMPLEMENTING INTEGRATED GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC STUDIES TO FURTHER UNDERSTAND THE CLINICAL DIVERSITY OF CF PATIENTS (GRAPHICAL ABSTRACT). 2020 18 738 26 CANCER SUSCEPTIBILITY: EPIGENETIC MANIFESTATION OF ENVIRONMENTAL EXPOSURES. CANCER IS A DISEASE THAT RESULTS FROM BOTH GENETIC AND EPIGENETIC CHANGES. DISCORDANT PHENOTYPES AND VARYING INCIDENCES OF COMPLEX DISEASES SUCH AS CANCER IN MONOZYGOTIC TWINS AS WELL AS GENETICALLY IDENTICAL LABORATORY ANIMALS HAVE LONG BEEN ATTRIBUTED TO DIFFERENCES IN ENVIRONMENTAL EXPOSURES. ACCUMULATING EVIDENCE INDICATES, HOWEVER, THAT DISPARITIES IN GENE EXPRESSION RESULTING FROM VARIABLE MODIFICATIONS IN DNA METHYLATION AND CHROMATIN STRUCTURE IN RESPONSE TO THE ENVIRONMENT ALSO PLAY A ROLE IN DIFFERENTIAL SUSCEPTIBILITY TO DISEASE. DESPITE A GROWING CONSENSUS ON THE IMPORTANCE OF EPIGENETICS IN THE ETIOLOGY OF CHRONIC HUMAN DISEASES, THE GENES MOST PRONE TO EPIGENETIC DYSREGULATION ARE INCOMPLETELY DEFINED. MOREOVER, NEITHER THE ENVIRONMENTAL AGENTS MOST STRONGLY AFFECTING THE EPIGENOME NOR THE CRITICAL WINDOWS OF VULNERABILITY TO ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS ARE ADEQUATELY CHARACTERIZED. THESE MAJOR DEFICITS IN KNOWLEDGE MARKEDLY IMPAIR OUR ABILITY TO UNDERSTAND FULLY THE ETIOLOGY OF CANCER AND THE IMPORTANCE OF THE EPIGENOME IN DIAGNOSING AND PREVENTING THIS DEVASTATING DISEASE. 2007 19 4228 24 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 20 6809 29 [EPIGENETICS IN INFLAMMATORY SYSTEMIC DISEASES]. IN ADDITION TO ANALYSIS OF THE GENETIC CODE, IN RECENT YEARS MORE AND MORE STUDIES HAVE CONCENTRATED ON CHANGES IN THE EPIGENETIC CODE. EPIGENETIC MECHANISMS DETERMINE WHICH GENES IN A CELL ARE TRANSCRIBED AND THUS FORM THE PHENOTYPE OF A CELL. THE EPIGENETIC CODE CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES, WHICH ALLOWS CELLS TO ADAPT TO LONGSTANDING CHANGES IN THE ENVIRONMENT. THEREFORE, IT IS FEASIBLE TO ASSUME THAT EPIGENETIC CHANGES ARE THE MOLECULAR BASIS FOR LONG-TERM EFFECTS OF THE ENVIRONMENT ON DISEASE DEVELOPMENT. IN PARTICULAR IN TUMORS AND CHRONIC INFLAMMATORY DISEASES EPIGENETIC CHANGES WERE FOUND TO CORRELATE WITH DISEASE SEVERITY AND PROGRESSION. KNOWLEDGE ABOUT THESE EPIGENETIC CHANGES MIGHT HELP THAT EPIGENETIC MODIFICATIONS CAN BE USED IN THE FUTURE AS BIOMARKERS, PROGNOSTIC FACTORS AND THERAPEUTIC TARGETS. 2014