1 3112 122 GEOEPIDEMIOLOGY AND (EPI-)GENETICS IN PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A RARE FEMALE PREPONDERANT CHRONIC AUTOIMMUNE CHOLESTATIC LIVER DISEASE, CHARACTERIZED BY INTRAHEPATIC DUCTOPENIA AND PROGRESSIVE FIBROSIS. DURING LAST DECADES INCIDENCE AND PREVALENCE SHOWED AN INCREASING RATE WHICH VARY WIDELY WORLDWIDE DEMONSTRATING AN IMPORTANT INTERACTION BETWEEN ENVIRONMENTAL AND GENETIC FACTORS. HERITABILITY SUGGESTED BY FAMILIAL OCCURRENCE AND MONOZYGOTIC TWINS CONCORDANCE HAVE BEEN CONFIRMED IN MORE STUDIES. EPIGENETICS MECHANISMS SUCH AS HISTONE MODIFICATION AND DNA METHYLATION CAN PARTIALLY EXPLAIN PREDISPOSITION AND INHERITANCE OF THIS DISEASE. NEVERTHELESS, AN ASSOCIATION WITH SPECIFIC CLASS II HUMAN LEUKOCYTE ANTIGEN (HLA) VARIANTS HAVE BEEN REPORTED, SHOWING AN INCREASE RISK IN SUSCEPTIBILITY. MORE RECENTLY, DATA REGARDING A STRONG PROTECTIVE ASSOCIATION BETWEEN PBC AND HLA ALLELES CONFIRMED THIS ASSOCIATION. AFTER RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS), A MORE INTRICATE INTERACTION BETWEEN PBC AND THE HLA REGION HAS BEEN SHOWN. FURTHERMORE, GWAS ALSO IDENTIFIED SEVERAL IMMUNE-RELATED-GENES IMPLICATED. MORE GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE ARE NEEDED TO REACH A COMPLETE AND SYSTEMATIC KNOWLEDGE OF THIS DISEASE. IN THIS REVIEW WE DISCUSS MORE RECENT ISSUED DATA ON GEOEPIDEMIOLOGY OF PBC AND THE ROLE OF (EPI-)GENETIC MECHANISMS IN ITS PATHOGENESIS. 2018 2 2512 60 EPIGENETICS AND PRIMARY BILIARY CIRRHOSIS: A COMPREHENSIVE REVIEW AND IMPLICATIONS FOR AUTOIMMUNITY. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT DEVELOPS BASED UPON THE INTERACTION OF GENETIC AND ENVIRONMENTAL FACTORS. RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED DOZENS OF PREDISPOSING VARIANTS INCLUDING HLA, IL12A, AND CTLA4 BUT HAVE BEEN DISAPPOINTED IN IDENTIFYING A "SMOKING GUN." THESE DISCOVERIES HIGHLIGHT THE IMPORTANCE OF THE GENETIC BACKGROUND INVOLVED IN IMMUNOLOGICAL DYSREGULATION. ALTHOUGH CONCORDANCE RATE OF PBC IN MONOZYGOTIC (MZ) TWINS IS AMONG THE HIGHEST REPORTED IN AUTOIMMUNE DISORDERS, INCOMPLETE DISEASE CONCORDANCE IN TWINS ASSOCIATED WITH DIFFERENTIALLY EXPRESSED GENES HAS BEEN DEMONSTRATED. HOWEVER, LITTLE IS UNDERSTOOD ABOUT HOW ENVIRONMENTAL ASPECTS CONTRIBUTE TO THE DISEASE AND WHY MIDDLE-AGED WOMEN ARE MORE SUSCEPTIBLE. AS A RESULT, EPIGENETIC FACTORS, WHICH CONVERT SIGNALS INDICATING ENVIRONMENTAL CHANGES INTO DYNAMIC AND HERITABLE ALTERATIONS OF TRANSCRIPTIONAL POTENTIAL, ARE GETTING INCREASED ATTENTION BY RESEARCHERS IN BOTH BASIC AND CLINICAL STUDIES. AMONG EPIGENETIC MECHANISMS, THE INSTABILITY AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY ACCOUNT FOR THE FEMALE PREPONDERANCE IN PBC. IN ADDITION, TRANSCRIPTIONAL REGULATION OF HISTONE MODIFICATION AND DNA METHYLATION UNDERSCORES POTENTIAL INVOLVEMENT IN DISEASE PATHOGENESIS. HIGH-THROUGHPUT TECHNIQUES ARE BEING USED TO IDENTIFY EPIGENETIC REGULATORS. IN THIS REVIEW, WE ATTEMPT TO OUTLINE RECENT PROGRESS REGARDING EPIGENETICS IN PBC AND OTHER AUTOIMMUNE DISEASES. 2016 3 2588 47 EPIGENETICS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE WITH NON-SUPPURATIVE DESTRUCTION OF THE INTRAHEPATIC BILE DUCTS. THE INTERPLAY OF GENETICS AND ENVIRONMENTAL TRIGGERS CONTRIBUTES TO THE ONSET OF THE DISEASE AND SUBSEQUENTLY RESULTS IN CHOLESTASIS AND PROGRESSIVE FIBROSIS. RECENTLY, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED MULTIPLE GENES INFLUENCING THE SUSCEPTIBILITY TO PBC IN HLA AND NON-HLA LOCI. HOWEVER, IT IS ESTIMATED THAT THE KNOWN RISK VARIANTS MERELY ACCOUNT FOR NO MORE THAN 20% OF THE HERITABILITY OF PBC AND CAUSES OF THE REMAINING HERITABILITY REMAIN UNCERTAIN. INCREASING EVIDENCE SUGGESTS THAT THE PRESENCE OF EPIGENETIC ABNORMALITIES MAY EXPLAIN THE "MISSING HERITABILITY" THAT CANNOT BE CAPTURED BY GWAS. AMONG THESE EPIGENETIC MECHANISMS, DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS (I.E. MIRNA AND LNCRNA) ARE INVOLVED IN THE PATHOGENESIS OF PBC. ADDITIONALLY, TELOMERE DYSREGULATION IN BILIARY EPITHELIAL CELLS (BECS) MAY PLAY A ROLE IN DISEASE ONSET, WHEREAS A DEFICIENCY IN SEX CHROMOSOME AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY TO SOME EXTENT EXPLAIN THE FEMALE DOMINANCE IN PBC. 2020 4 5146 44 POTENTIAL ROLES FOR INFECTIOUS AGENTS IN THE PATHOPHYSIOLOGY OF PRIMARY BILIARY CIRRHOSIS: WHAT'S NEW? PRIMARY BILIARY CIRRHOSIS (PBC) IS A PROGRESSIVE CHOLESTATIC LIVER DISEASE SEROLOGICALLY CHARACTERIZED BY THE PRESENCE OF HIGH-TITER ANTIMITOCHONDRIAL ANTIBODIES AND, HISTOLOGICALLY BY CHRONIC NONSUPPURATIVE CHOLANGITIS AND GRANULOMATA. THE AETIOLOGY OF THE DISEASE REMAINS ELUSIVE, ALTHOUGH GENETIC, EPIGENETIC, ENVIRONMENTAL, AND INFECTIOUS FACTORS HAVE BEEN CONSIDERED IMPORTANT FOR THE INDUCTION OF THE DISEASE IN GENETICALLY PRONE INDIVIDUALS. THE DISEASE SHOWS A STRIKING FEMALE PREDOMINANCE AND BECOMES CLINICALLY OVERT AT THE FOURTH TO SIXTH DECADE. THESE CHARACTERISTICS HAVE PROMPTED INVESTIGATORS TO CONSIDER INFECTIONS THAT PREDOMINATE IN WOMEN AT THESE AGES AS THE LIKELY CANDIDATES FOR TRIGGERING THE DISEASE. RECURRENT URINARY TRACT INFECTIONS DUE TO ESCHERICHIA COLI WERE THE FIRST INFECTIONS TO BE CONSIDERED PATHOGENETICALLY RELEVANT. OVER THE YEARS, SEVERAL OTHER MICROORGANISMS HAVE BEEN LINKED TO THE PATHOGENESIS OF PBC OWING TO EPIDEMIOLOGICAL, IMMUNOLOGICAL, MICROBIOLOGICAL, OR EXPERIMENTAL FINDINGS IN ANIMAL MODELS. RECENT STUDIES HAVE PROVIDED DATA SUPPORTING THE PATHOGENIC ROLE OF NOVOSPHINGOBIUM AROMATICIVORANS AND BETARETROVIRUSES. SEVERAL REPORTS HAVE LINKED OTHER ORGANISMS TO THE INDUCTION OF THE DISEASE AND/OR THE MAINTENANCE OF THE AUTO-AGGRESSIVE RESPONSES THAT ARE PERPETUATED OVER THE COURSE OF THE DISEASE. THIS REVIEW HIGHLIGHTS THE FINDINGS OF THE MOST RECENT STUDIES INVESTIGATING THE LINK BETWEEN INFECTIONS AND PBC. WE ALSO DISCUSS THE CLOSE INTERPLAY OF THE INFECTIOUS AGENTS WITH OTHER ENVIRONMENTAL AND GENETIC FACTORS, WHICH MAY EXPLAIN THE MULTIFACETED NATURE OF THIS PUZZLING DISEASE. 2013 5 3012 50 GENETICS AND EPIGENETICS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC, SLOWLY PROGRESSIVE CHOLESTATIC AUTOIMMUNE LIVER DISEASE PREDOMINANTLY AFFLICTING WOMEN. PBC IS CHARACTERIZED BY THE PRESENCE OF DISEASE-SPECIFIC ANTIMITOCHONDRIAL ANTIBODIES AND THE HISTOLOGICAL DESTRUCTION OF INTRAHEPATIC BILE DUCTS, WHICH EVENTUALLY LEAD TO CIRRHOSIS AND HEPATIC FAILURE. FORTUNATELY, URSODEOXYCHOLIC ACID THERAPY HAS IMPROVED THE OUTCOME OF THE VAST MAJORITY OF PBC CASES. ALTHOUGH THE ETIOLOGY OF PBC HAS NOT YET BEEN ELUCIDATED, HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II ALLELES HAVE BEEN CONSISTENTLY ASSOCIATED WITH DISEASE ONSET FOR DECADES. PBC PATIENTS MAY ALSO HAVE GENETICALLY DETERMINED RISK FACTORS IN NON-HLA REGIONS. MEANWHILE, EXPOSURE TO ENVIRONMENTAL FACTORS, SUCH AS INFECTIOUS DISEASES AND HARMFUL CHEMICALS, CAN PRODUCE EPIGENETIC ALTERATIONS IN SOME INDIVIDUALS AND SUBSEQUENT PBC ONSET. IN THIS REVIEW, WE DESCRIBE THE INFLUENCE OF HLA ALLELES AND OTHER GENE POLYMORPHISMS ON PBC ALONG WITH THE RESULTS OF GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE AND ITS FUTURE PROSPECTS IN TERMS OF EPIGENETICS. 2018 6 1524 31 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 7 5220 34 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION. 2018 8 5506 42 RHEUMATOID ARTHRITIS AND PRIMARY BILIARY CIRRHOSIS: CAUSE, CONSEQUENCE, OR COINCIDENCE? PRIMARY BILIARY CIRRHOSIS (PBC) IS A PROGRESSIVE CHOLESTATIC LIVER DISEASE CHARACTERIZED SEROLOGICALLY BY CHOLESTASIS AND THE PRESENCE OF HIGH-TITRE ANTIMITOCHONDRIAL ANTIBODIES AND HISTOLOGICALLY BY CHRONIC NONSUPPURATIVE CHOLANGITIS AND GRANULOMATA. PBC PATIENTS OFTEN HAVE CONCOMITANT AUTOIMMUNE DISEASES, INCLUDING ARTHROPATHIES. THIS RAISES THE QUESTION AS TO WHETHER THERE ARE SHARED FEATURES IN THE PATHOGENESIS OF THOSE DISEASES WITH THE PATHOGENESIS OF PBC. EPIDEMIOLOGICAL AND LARGE CASE STUDIES HAVE INDICATED THAT ALTHOUGH THE INCIDENCE OF RHEUMATOID ARTHRITIS (RA) IS NOT SIGNIFICANTLY RAISED IN PBC PATIENTS, THERE APPEARS TO BE A HIGHER RATE OF RA IN PBC PATIENTS AND THEIR RELATIVES. GENETIC STUDIES HAVE DEMONSTRATED THAT SEVERAL GENES IMPLICATED IN PBC HAVE ALSO BEEN IMPLICATED IN RA. EPIGENETIC STUDIES PROVIDED A WEALTH OF DATA REGARDING RA, BUT THE FINDINGS ON EPIGENETIC CHANGES IN PBC ARE VERY LIMITED. AS WELL, CERTAIN INFECTIOUS AGENTS IDENTIFIED IN THE PATHOGENESIS OF PBC MAY ALSO PLAY A ROLE IN THE PATHOGENESIS OF RA. THESE DATA SUGGEST THAT ALTHOUGH RA IS NOT SIGNIFICANTLY PRESENT IN PBC, SOME INDIVIDUALS WITH CERTAIN GENETIC TRAITS AND ENVIRONMENTAL EXPOSURES MAY DEVELOP BOTH CONDITIONS. THIS CONCEPT MAY ALSO APPLY TO OTHER CONCOMITANT DISEASES FOUND IN PBC PATIENTS. 2012 9 2027 48 EPIGENETIC CHANGES IN CHRONIC INFLAMMATORY DISEASES. THE NUMBER OF PEOPLE DIAGNOSED WITH CHRONIC INFLAMMATORY DISEASES HAS INCREASED NOTEWORTHY IN THE LAST 40 YEARS. SPONDYLOARTHRITIS (SPA), INFLAMMATORY BOWEL DISEASES (IBD), AND PSORIASIS ARE THE MOST FREQUENT CHRONIC INFLAMMATORY DISEASES, RESULTING FROM A COMBINATION OF GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL AND LONG NONCODING RNAS. THEY ARE INFLUENCED BY ENVIRONMENTAL EXPOSURE, LIFE-STYLE, AND AGING AND HAVE RECENTLY BEEN SHOWN TO BE ALTERED IN MANY COMPLEX DISEASES INCLUDING INFLAMMATORY DISEASES. WHILE EPIGENETIC MODIFICATIONS HAVE BEEN WELL CHARACTERIZED IN OTHER DISEASES SUCH AS CANCER AND AUTOIMMUNE DISEASES, KNOWLEDGE ON CHANGES IN INFLAMMATORY DISEASES IS LAGGING BEHIND WITH SOME DISEASE-SPECIFIC DIFFERENCES. WHILE THE DNA METHYLATION PROFILE OF DIFFERENT CELL TYPES IN PATIENTS WITH IBD HAS BEEN RELATIVELY WELL DESCRIBED, LESS IS KNOWN ON CHANGES IMPLICATED IN PSORIASIS, AND NO SYSTEMATIC GENOME-WIDE STUDIES HAVE SO FAR BEEN PERFORMED IN SPA. IN THIS CHAPTER, WE REVIEW IN DETAIL THE REPORTED CHANGES IN PATTERNS OF DNA METHYLATION AND POSTTRANSLATIONAL HISTONE MODIFICATIONS IN CHRONIC INFLAMMATORY DISEASES HIGHLIGHTING POTENTIAL CONNECTIONS BETWEEN DISEASE-ASSOCIATED PATHOPHYSIOLOGICAL CHANGES SUCH AS THE DYSBIOSIS OF THE MICROBIOME OR GENETIC VARIATIONS ASSOCIATED WITH DISEASE SUSCEPTIBILITY AND THE EPIGENOME. WE ALSO DISCUSS IMPORTANT PARAMETERS OF MEANINGFUL EPIGENETIC STUDIES SUCH AS THE USE OF WELL DEFINED, DISEASE-RELEVANT CELL POPULATIONS, AND ELUDE ON THE POTENTIAL FUTURE OF ENGINEERING OF THE EPIGENOME IN INFLAMMATORY DISEASES. 2017 10 3020 39 GENETICS AND EPIGENETICS OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGE-RELATED DISEASE THAT AFFECTS THE TISSUES OF THE SYNOVIAL JOINT, LEADING TO LOSS OF FUNCTION AND PAIN. IT IMPACTS ON BOTH PATIENT MORBIDITY AND MORTALITY. IT IS A COMPLEX, POLYGENIC DISEASE THAT LACKS ANY LARGE-EFFECT SUSCEPTIBILITY LOCI. INSTEAD, OA SUSCEPTIBILITY ALLELES INDIVIDUALLY CONTRIBUTE ONLY MODESTLY TO THE OVERALL DISEASE RISK, MAKING THEIR IDENTIFICATION CHALLENGING. DESPITE THIS, BREAKTHROUGHS HAVE OCCURRED WITH COMPELLING ASSOCIATIONS SO FAR REPORTED TO POLYMORPHISMS WITHIN THE GENES GDF5 AND MCF2L AND TO THE GENOMIC REGION 7Q22. THE LATTER TWO HAVE EMERGED FROM GENOME-WIDE ASSOCIATION SCANS, WHICH ARE LIKELY TO YIELD MORE HITS IN THE NEAR FUTURE. AS FOR MANY COMPLEX DISEASES, IT IS NOW APPARENT THAT EPIGENETIC EFFECTS ARE ALSO IMPORTANT MEDIATORS OF DISEASE BIOLOGY, WITH DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS ALL HAVING A ROLE. AT PRESENT, MUCH OF THE EPIGENETIC FOCUS HAS BEEN ON CARTILAGE, THE TISSUE AT THE CENTER OF THE OA DISEASE PROCESS. IF WE ARE TO GET CLOSE TO A QUALITATIVE AND QUANTITATIVE UNDERSTANDING OF THE IMPACT OF EPIGENETICS ON OA, THEN IN FUTURE THE OTHER TISSUES OF THE JOINT WILL ALSO NEED TO BE INVESTIGATED. ONE OF THE MORE EXCITING INSIGHTS TO HAVE EMERGED RECENTLY IS THE FACT THAT EPIGENETIC EFFECTS CAN IMPACT ON OA GENETIC EFFECTS AND THIS MAY BE A PARTICULARLY FRUITFUL AVENUE FOR INTEGRATING BOTH AS WE MOVE TOWARD A CLEARER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF THIS INTRIGUING DISEASE. 2012 11 6262 44 THE MULTIFACETED FUNCTIONAL ROLE OF DNA METHYLATION IN IMMUNE-MEDIATED RHEUMATIC DISEASES. GENOMIC PREDISPOSITION CANNOT EXPLAIN THE ONSET OF COMPLEX DISEASES, AS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELLING AND NON-CODING RNA, ARE CONSIDERED TO BE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. THE PARADIGMATIC CASES OF RHEUMATOID ARTHRITIS (RA), SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), SYSTEMIC SCLEROSIS (SSC), SJOGREN'S SYNDROME (SJS) AND TYPE-1 DIABETES (T1D) SHARE THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGEN INFLUENCED BY SEVERAL FACTORS, WITH A LARGELY INCOMPLETE ROLE OF INDIVIDUAL GENOMIC SUSCEPTIBILITY. THE MOST WIDELY INVESTIGATED EPIGENETIC MECHANISM IS DNA METHYLATION WHICH IS ASSOCIATED WITH GENE SILENCING AND IS DUE TO THE BINDING OF METHYL-CPG BINDING DOMAIN (MBD)-CONTAINING PROTEINS, SUCH AS MECP2, TO 5-METHYLCYTOSINE (5MC). INDEED, A CAUSAL RELATIONSHIP OCCURS BETWEEN DNA METHYLATION AND TRANSCRIPTION FACTORS OCCUPANCY AND RECRUITMENT AT SPECIFIC GENOMIC LOCUS. IN MOST CASES, THE RESULTS OBTAINED IN DIFFERENT STUDIES ARE CONTROVERSIAL IN TERMS OF DNA METHYLATION COMPARISON WHILE FASCINATING EVIDENCE COMES FROM THE COMPARISON OF THE EPIGENOME IN CLINICALLY DISCORDANT MONOZYGOTIC TWINS. IN THIS MANUSCRIPT, WE WILL REVIEW THE MECHANISMS OF EPIGENETICS AND DNA METHYLATION CHANGES IN SPECIFIC IMMUNE-MEDIATED RHEUMATIC DISEASES TO HIGHLIGHT REMAINING UNMET NEEDS AND TO IDENTIFY POSSIBLE SHARED MECHANISMS BEYOND DIFFERENT TISSUE INVOLVEMENTS WITH COMMON THERAPEUTIC OPPORTUNITIES. KEY POINTS * DNA METHYLATION HAS A CRUCIAL ROLE IN REGULATING AND TUNING THE IMMUNE SYSTEM. * EVIDENCES SUGGEST THAT DYSREGULATION OF DNA METHYLATION IS PIVOTAL IN THE CONTEXT OF IMMUNE-MEDIATED RHEUMATIC DISEASES. * DNA METHYLATION DYSREGULATION IN FOXP3 AND INTERFERONS-RELATED GENES IS SHARED WITHIN SEVERAL AUTOIMMUNE DISEASES. * DNA METHYLATION IS AN ATTRACTIVE MARKER FOR DIAGNOSIS AND THERAPY. 2021 12 2945 32 GENETIC AND EPIGENETIC BASIS OF PSORIASIS PATHOGENESIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WHOSE PREVALENCE VARIES AMONG DIFFERENT POPULATIONS WORLDWIDE. IT IS A COMPLEX MULTI-FACTORIAL DISEASE AND THE EXACT ETIOLOGY IS LARGELY UNKNOWN. FAMILY BASED STUDIES HAVE INDICATED A GENETIC PREDISPOSITION; HOWEVER THEY CANNOT FULLY EXPLAIN THE DISEASE PATHOGENESIS. IN ADDITION TO GENETIC SUSCEPTIBILITY, ENVIRONMENTAL AS WELL AS GENDER AND AGE RELATED FACTORS WERE ALSO BEEN FOUND TO BE ASSOCIATED. RECENTLY, IMBALANCES IN EPIGENETIC NETWORKS ARE INDICATED TO BE CAUSATIVE ELEMENTS IN PSORIASIS. THE PRESENT KNOWLEDGE OF EPIGENETIC INVOLVEMENT, MAINLY THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND MIRNA DEREGULATION IS SURVEYED HERE. AN INTEGRATED APPROACH CONSIDERING GENETIC AND EPIGENETIC ANOMALIES IN THE LIGHT OF IMMUNOLOGICAL NETWORK MAY EXPLORE THE PATHOGENESIS OF PSORIASIS. 2015 13 3690 48 INFLAMMATORY BOWEL DISEASE: GENETICS, EPIGENETICS, AND PATHOGENESIS. INFLAMMATORY BOWEL DISEASES (IBDS) ARE COMPLEX, MULTIFACTORIAL DISORDERS CHARACTERIZED BY CHRONIC RELAPSING INTESTINAL INFLAMMATION. ALTHOUGH ETIOLOGY REMAINS LARGELY UNKNOWN, RECENT RESEARCH HAS SUGGESTED THAT GENETIC FACTORS, ENVIRONMENT, MICROBIOTA, AND IMMUNE RESPONSE ARE INVOLVED IN THE PATHOGENESIS. EPIDEMIOLOGICAL EVIDENCE FOR A GENETIC CONTRIBUTION IS DEFINED: 15% OF PATIENTS WITH CROHN'S DISEASE (CD) HAVE AN AFFECTED FAMILY MEMBER WITH IBD, AND TWIN STUDIES FOR CD HAVE SHOWN 50% CONCORDANCE IN MONOZYGOTIC TWINS COMPARED TO <10% IN DIZYGOTICS. THE MOST RECENT AND LARGEST GENETIC ASSOCIATION STUDIES, WHICH EMPLOYED GENOME-WIDE ASSOCIATION DATA FOR OVER 75,000 PATIENTS AND CONTROLS, IDENTIFIED 163 SUSCEPTIBILITY LOCI FOR IBD. MORE RECENTLY, A TRANS-ETHNIC ANALYSIS, INCLUDING OVER 20,000 INDIVIDUALS, IDENTIFIED AN ADDITIONAL 38 NEW IBD LOCI. ALTHOUGH MOST CASES ARE CORRELATED WITH POLYGENIC CONTRIBUTION TOWARD GENETIC SUSCEPTIBILITY, THERE IS A SPECTRUM OF RARE GENETIC DISORDERS THAT CAN CONTRIBUTE TO EARLY-ONSET IBD (BEFORE 5 YEARS) OR VERY EARLY ONSET IBD (BEFORE 2 YEARS). GENETIC VARIANTS THAT CAUSE THESE DISORDERS HAVE A WIDE EFFECT ON GENE FUNCTION. THESE VARIANTS ARE SO RARE IN ALLELE FREQUENCY THAT THE GENETIC SIGNALS ARE NOT DETECTED IN GENOME-WIDE ASSOCIATION STUDIES OF PATIENTS WITH IBD. WITH RECENT ADVANCES IN SEQUENCING TECHNIQUES, ~50 GENETIC DISORDERS HAVE BEEN IDENTIFIED AND ASSOCIATED WITH IBD-LIKE IMMUNOPATHOLOGY. MONOGENIC DEFECTS HAVE BEEN FOUND TO ALTER INTESTINAL IMMUNE HOMEOSTASIS THROUGH MANY MECHANISMS. CANDIDATE GENE RESEQUENCING SHOULD BE CARRIED OUT IN EARLY-ONSET PATIENTS IN CLINICAL PRACTICE. THE EVIDENCE THAT GENETIC FACTORS CONTRIBUTE IN SMALL PART TO DISEASE PATHOGENESIS CONFIRMS THE IMPORTANT ROLE OF MICROBIAL AND ENVIRONMENTAL FACTORS. EPIGENETIC FACTORS CAN MEDIATE INTERACTIONS BETWEEN ENVIRONMENT AND GENOME. EPIGENETIC MECHANISMS COULD AFFECT DEVELOPMENT AND PROGRESSION OF IBD. EPIGENOMICS IS AN EMERGING FIELD, AND FUTURE STUDIES COULD PROVIDE NEW INSIGHT INTO THE PATHOGENESIS OF IBD. 2015 14 738 33 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 15 3564 37 IMPACT OF GENETIC AND ENVIRONMENTAL FACTORS ON AUTOIMMUNE HEPATITIS. AUTOIMMUNE HEPATITIS (AIH) IS A CHRONIC NON-RESOLVING LIVER DISEASE CHARACTERIZED BY DIFFUSE HYPERGAMMAGLOBULINEMIA, THE PRESENCE OF AUTOANTIBODIES AND CHARACTERISTIC HISTOLOGICAL FINDINGS. THE DISEASE CAN HAVE CATASTROPHIC OUTCOME WITH THE DEVELOPMENT OF END-STAGE LIVER DISEASE IF MISDIAGNOSED/UNDIAGNOSED AND LEFT UNTREATED. AIH PATHOGENESIS REMAINS OBSCURE AND THE MAIN HYPOTHESIS SUPPORTS ITS DEVELOPMENT IN GENETICALLY PREDISPOSED INDIVIDUALS AFTER BEING EXPOSED TO CERTAIN ENVIRONMENTAL TRIGGERS. GENETIC PREDISPOSITION IS LINKED TO THE PRESENCE OF CERTAIN HLA ALLELES, MAINLY HLA-DR3 AND HLA-DR4. HOWEVER, A WIDE NUMBER OF NON-HLA EPITOPES HAVE ALSO BEEN ASSOCIATED WITH THE DISEASE ALTHOUGH DATA VARY SIGNIFICANTLY AMONG DIFFERENT ETHNIC GROUPS. THEREFORE, IT IS LIKELY THAT EPIGENETIC ALTERATIONS MAY ALSO PLAY A CRUCIAL ROLE IN DISEASE'S PATHOGENESIS, ALTHOUGH NOT YET EXTENSIVELY STUDIED. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE GENETIC AND ENVIRONMENTAL FACTORS THAT HAVE BEEN ASSOCIATED WITH AIH, BUT ALSO TO OPEN NEW INSIGHTS TOWARDS THE ROLE OF EPIGENETIC MODIFICATIONS IN THE ETIOLOGY OF THE DISEASE. 2021 16 2507 39 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 17 6345 38 THE ROLE OF EPIGENETICS IN AUTOIMMUNE/INFLAMMATORY DISEASE. HISTORICALLY, SYSTEMIC SELF-INFLAMMATORY CONDITIONS WERE CLASSIFIED AS EITHER AUTOINFLAMMATORY AND CAUSED BY THE INNATE IMMUNE SYSTEM OR AUTOIMMUNE AND DRIVEN BY ADAPTIVE IMMUNE RESPONSES. HOWEVER, IT BECAME CLEAR THAT REALITY IS MUCH MORE COMPLEX AND THAT AUTOIMMUNE/INFLAMMATORY CONDITIONS RANGE ALONG AN "INFLAMMATORY SPECTRUM" WITH PRIMARILY AUTOINFLAMMATORY VS. AUTOIMMUNE CONDITIONS RESEMBLING EXTREMES AT EITHER END. EPIGENETIC MODIFICATIONS INFLUENCE GENE EXPRESSION AND ALTER CELLULAR FUNCTIONS WITHOUT MODIFYING THE GENOMIC SEQUENCE. METHYLATION OF CPG DNA DINUCLEOTIDES AND/OR THEIR HYDROXYMETHYLATION, POST-TRANSLATIONAL MODIFICATIONS TO AMINO TERMINI OF HISTONE PROTEINS, AND NON-CODING RNA EXPRESSION ARE MAIN EPIGENETIC EVENTS. THE PATHOPHYSIOLOGY OF AUTOIMMUNE/INFLAMMATORY DISEASES HAS BEEN CLOSELY LINKED WITH DISEASE CAUSING GENE MUTATIONS (RARE) OR A COMBINATION OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS ARISING FROM EXPOSURE TO THE ENVIRONMENT (MORE COMMON). OVER RECENT YEARS, PROGRESS HAS BEEN MADE IN UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN SYSTEMIC INFLAMMATION AND THE CONTRIBUTION OF INNATE AND ADAPTIVE IMMUNE RESPONSES. EPIGENETIC EVENTS HAVE BEEN IDENTIFIED AS (I) CENTRAL PATHOPHYSIOLOGICAL FACTORS IN ADDITION TO GENETIC DISEASE PREDISPOSITION AND (II) AS CO-FACTORS DETERMINING CLINICAL PICTURES AND OUTCOMES IN INDIVIDUALS WITH MONOGENIC DISEASE. THUS, A COMPLETE UNDERSTANDING OF EPIGENETIC CONTRIBUTORS TO AUTOIMMUNE/INFLAMMATORY DISEASE WILL RESULT IN APPROACHES TO PREDICT INDIVIDUAL DISEASE OUTCOMES AND THE INTRODUCTION OF EFFECTIVE, TARGET-DIRECTED, AND TOLERABLE THERAPIES. HERE, WE SUMMARIZE RECENT FINDINGS THAT SIGNIFY THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN AUTOIMMUNE/INFLAMMATORY DISORDERS ALONG THE INFLAMMATORY SPECTRUM CHOOSING THREE EXAMPLES: THE AUTOINFLAMMATORY BONE CONDITION CHRONIC NONBACTERIAL OSTEOMYELITIS (CNO), THE "MIXED PATTERN" DISORDER PSORIASIS, AND THE AUTOIMMUNE DISEASE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). 2019 18 2279 41 EPIGENETIC REGULATION IN ALLERGIC DISEASES AND RELATED STUDIES. ASTHMA, A CHRONIC INFLAMMATORY DISORDER OF THE AIRWAY, HAS FEATURES OF BOTH HERITABILITY AS WELL AS ENVIRONMENTAL INFLUENCES WHICH CAN BE INTRODUCED IN UTERO EXPOSURES AND MODIFIED THROUGH AGING, AND THE FEATURES MAY ATTRIBUTE TO EPIGENETIC REGULATION. EPIGENETIC REGULATION EXPLAINS THE ASSOCIATION BETWEEN EARLY PRENATAL MATERNAL SMOKING AND LATER ASTHMA-RELATED OUTCOMES. EPIGENETIC MARKS (DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS OR NONCODING RNAS) WORK WITH OTHER COMPONENTS OF THE CELLULAR REGULATORY MACHINERY TO CONTROL THE LEVELS OF EXPRESSED GENES, AND SEVERAL ALLERGY- AND ASTHMA-RELATED GENES HAVE BEEN FOUND TO BE SUSCEPTIBLE TO EPIGENETIC REGULATION, INCLUDING GENES IMPORTANT TO T-EFFECTOR PATHWAYS (IFN-GAMMA, INTERLEUKIN [IL] 4, IL-13, IL-17) AND T-REGULATORY PATHWAYS (FOXP3). THEREFORE, THE MECHANISM BY WHICH EPIGENETIC REGULATION CONTRIBUTES TO ALLERGIC DISEASES IS A CRITICAL ISSUE. IN THE PAST MOST PUBLISHED EXPERIMENTAL WORK, WITH FEW EXCEPTIONS, HAS ONLY COMPRISED SMALL OBSERVATIONAL STUDIES AND MODELS IN CELL SYSTEMS AND ANIMALS. HOWEVER, VERY RECENTLY EXCITING AND ELEGANT EXPERIMENTAL STUDIES AND NOVEL TRANSLATIONAL RESEARCH WORKS WERE PUBLISHED WITH NEW AND ADVANCED TECHNOLOGIES INVESTIGATING EPIGENETIC MARK ON A GENOMIC SCALE AND COMPREHENSIVE APPROACHES TO DATA ANALYSIS. INTERESTINGLY, A POTENTIAL LINK BETWEEN EXPOSURE TO ENVIRONMENTAL POLLUTANTS AND THE OCCURRENCE OF ALLERGIC DISEASES IS REVEALED RECENTLY, PARTICULAR IN DEVELOPED AND INDUSTRIALIZED COUNTRIES, AND ENDOCRINE DISRUPTING CHEMICALS (EDCS) AS ENVIRONMENTAL HORMONE MAY PLAY A KEY ROLE. THIS REVIEW ADDRESSES THE IMPORTANT QUESTION OF HOW EDCS (NONYLPHENOL, 4 OCTYLPHENOL, AND PHTHALATES) INFLUENCES ON ASTHMA-RELATED GENE EXPRESSION VIA EPIGENETIC REGULATION IN IMMUNE CELLS, AND HOW ANTI-ASTHMATIC AGENTS PROHIBIT EXPRESSION OF INFLAMMATORY GENES VIA EPIGENETIC MODIFICATION. THE DISCOVERY AND VALIDATION OF EPIGENETIC BIOMARKERS LINKING EXPOSURE TO ALLERGIC DISEASES MIGHT LEAD TO BETTER EPIGENOTYPING OF RISK, PROGNOSIS, TREATMENT PREDICTION, AND DEVELOPMENT OF NOVEL THERAPIES. 2014 19 1935 43 ENVIRONMENTAL RISK FACTORS AND EPIGENETIC ALTERNATIONS IN PSORIASIS. INTRODUCTION AND OBJECTIVE: PSORIASIS ISA QUITE COMMON, CHRONIC AND IMMUNE-MEDIATED SKIN DISORDER. THE PREVALENCE OF PSORIASIS DIFFERS IN VARIOUS COUNTRIES, BUT IT IS SAID TO AFFECT 2% OF THE WORLD'S POPULATION IN GENERAL. PSORIASIS HAS MANY DIFFERENT CLINICAL FEATURES BUT ALL LESIONS HAVE THE SAME CHARACTERISTIC: ERYTHEMA, THICKENING AND SCALE, ALTHOUGH OTHER CLINICAL FEATURES ARE ALSO CONNECTED, SUCH AS PSORIATIC ARTHRITIS, OBESITY AND METABOLIC SYNDROME. ALL OF THESE MAY LEAD TO CONDITIONS IMPAIRING THE QUALITY OF LIFE. THIS REVIEW IS AN ATTEMPT TO SUMMARIZE RECENT DATA REGARDING ENVIRONMENTAL FACTORS, TOGETHER WITH EPIGENETIC MARKERS AND PROCESSES PLAYING AN IMPORTANT ROLE IN PSORIASIS. STATE OF KNOWLEDGE: MANY DIFFERENT ENVIRONMENTAL FACTORS PLAY A ROLE IN GENETICALLY PREDISPOSED PATIENTS. THIS IS CAUSES EPIGENETIC ALTERNATIONS WHICH MAY BE A LINKING PART IN THE WHOLE PROCESS. MANY STUDIES HAVE INDICATED A CONNECTION BETWEEN PSORIASIS AND VARIOUS GENES AND ANTIGENS. THE PRESENCE OF HLA-CW6 IS COMMON AS WELL A STRONG LINK BETWEEN ITS PRESENCE AND THE ONSET OF PSORIASIS BEING OBSERVED. THE MAIN ALTERNATIONS ARE DNA METHYLATION, HISTONE'S MODIFICATIONS AND THE ROLE OF MICRORNA. EXCESSIVE REACTION IS USUALLY NOT PRESENT WITHOUT A TRIGGERING FACTOR. ENVIRONMENTAL FACTORS ARE MOSTLY RATED, SUCH AS DRUGS, LIFE STYLE AND HABITS (SMOKING, ALCOHOL), DIET, PHYSICAL TRAUMA (SKIN INJURY PROVOKING KOEBNER PHENOMENON), STRESS, MICROORGANISM AND INFECTIONS. CONCLUSIONS: THE CORRELATION BETWEEN PATHOGENESIS OF PSORIASIS AND ENVIRONMENTAL RISK FACTORS, TOGETHER WITH EPIGENETIC ALTERNATIONS STILL REQUIRE MORE INVESTIGATION. EDUCATION ABOUT DIET HABITS, NUTRITION, WEIGHT LOSS AND HEALTHY LIFESTYLE SEEMS TO BE IMPORTANT DURING THE TREATMENT OF PSORIASIS. 2020 20 5222 39 PRIMARY BILIARY CIRRHOSIS: FAMILY STORIES. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC IMMUNE-MEDIATED CHOLESTATIC LIVER DISEASE OF UNKNOWN AETIOLOGY WHICH AFFECTS MOSTLY WOMEN IN MIDDLE AGE. FAMILIAL PBC IS WHEN PBC AFFECTS MORE THAN ONE MEMBER OF THE SAME FAMILY, AND DATA SUGGEST THAT FIRST-DEGREE RELATIVES OF PBC PATIENTS HAVE AN INCREASED RISK OF DEVELOPING THE DISEASE. MOST OFTEN, THESE FAMILIAL CLUSTERS INVOLVE MOTHER-DAUGHTER PAIRS, WHICH IS CONSISTENT WITH THE FEMALE PREPONDERANCE OF THE DISEASE. THESE CLUSTERS PROVIDE EVIDENCE TOWARDS A GENETIC BASIS UNDERLYING PBC. HOWEVER, CLUSTERS OF NONRELATED INDIVIDUALS HAVE ALSO BEEN REPORTED, GIVING STRENGTH TO AN ENVIRONMENTAL COMPONENT. TWIN STUDIES HAVE DEMONSTRATED A HIGH CONCORDANCE FOR PBC IN MONOZYGOTIC TWINS AND A LOW CONCORDANCE AMONG DIZYGOTIC TWINS. IN CONCLUSION, STUDIES OF PBC IN FAMILIES CLEARLY DEMONSTRATE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF THE DISEASE. 2011