1 3012 109 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 2 6787 24 [CONTRIBUTION OF NON-HLA GENES TO JUVENILE IDIOPATHIC ARTHRITIS SUSCEPTIBILITY]. JUVENILE IDIOPATHIC ARTHRITIS (JAL4) IS THE MOST COMMON CHRONIC RHEUMATOLOGIC DISEASE IN CHILDREN. JIA IS A GROUP OF DISORDERS THAT SHARE THE CLINICAL MANIFESTATION OF CHRONIC JOINT INFLAMMATION. THE HUMAN LEUKOCYTE ANTIGEN REGION (HLA) SEEMS TO BE A MAJOR SUSCEPTIBILITY LOCUS FOR JIA THAT IS ESTIMATED TO ACCOUNT FOR 17% OF FAMILIAL SEGREGATION OF THE DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS), CASE-CONTROL STUDIES AND META-ANALYSES OF THE POST-GWAS ERA REVEALED OVER 20 NON-HLA LOCI CONFERRING SUSCEPTIBILITY TO JIA. AT LEAST A HALF OF THOSE ARE SHARED BETWEEN JIA AND RHEUMATOID ARTHRITIS, AN ADULT RHEUMATIC DISEASE, THEREBY SUGGESTING FOR SIMILARITY OF PATHOGENIC MECHANISMS OF BOTH DISEASES. NEW FINDINGS ALSO SUGGEST FOR A LIKELY ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF JIA THAT SHOULD BE INVESTIGATED IN THE FUTURE. 2014 3 2684 36 EVALUATION OF X CHROMOSOME INACTIVATION WITH RESPECT TO HLA GENETIC SUSCEPTIBILITY IN RHEUMATOID ARTHRITIS AND SYSTEMIC SCLEROSIS. BACKGROUND: AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS (RA) AND SYSTEMIC SCLEROSIS (SSC) ARE CHARACTERIZED BY A STRONG GENETIC SUSCEPTIBILITY FROM THE HUMAN LEUCOCYTE ANTIGEN (HLA) LOCUS. ADDITIONALLY, DISORDERS OF EPIGENETIC PROCESSES, IN PARTICULAR NON-RANDOM X CHROMOSOME INACTIVATION (XCI), HAVE BEEN REPORTED IN MANY FEMALE-PREDOMINANT AUTOIMMUNE DISEASES. HERE WE TEST THE HYPOTHESIS THAT WOMEN WITH RA OR SSC WHO ARE STRONGLY GENETICALLY PREDISPOSED ARE LESS SUSCEPTIBLE TO XCI BIAS. METHODS: USING METHYLATION SENSITIVE GENOTYPING OF THE ANDROGEN RECEPTOR (AR) GENE, XCI PROFILES WERE PERFORMED IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 161 WOMEN WITH RA, 96 WOMEN WITH SSC AND 100 HEALTHY WOMEN. HLA-DRB1 AND DQB1 WERE GENOTYPED. PRESENCE OF SPECIFIC AUTOANTIBODIES WAS DOCUMENTED FOR PATIENTS. XCI SKEWING WAS DEFINED AS HAVING A RATIO >/= 80:20 OF CELLS INACTIVATING THE SAME X CHROMOSOME. RESULTS: 110 WOMEN WITH RA, 68 WOMEN WITH SSC, AND 69 CONTROLS WERE INFORMATIVE FOR THE AR POLYMORPHISM. AMONG THEM 40.9% OF RA PATIENTS AND 36.8% OF SSC PATIENTS HAD SKEWED XCI COMPARED TO 17.4% OF HEALTHY WOMEN (P = 0.002 AND 0.018, RESPECTIVELY). PRESENCE OF RA-SUSCEPTIBILITY ALLELES CODING FOR THE "SHARED EPITOPE" CORRELATED WITH HIGHER SKEWING AMONG RA PATIENTS (P = 0.002) AND SUCH CORRELATION WAS NOT OBSERVED IN OTHER WOMEN, HEALTHY OR WITH SSC. PRESENCE OF SSC-SUSCEPTIBILITY ALLELES DID NOT CORRELATE WITH XCI PATTERNS AMONG SSC PATIENTS. CONCLUSION: DATA DEMONSTRATE XCI SKEWING IN BOTH RA AND SSC COMPARED TO HEALTHY WOMEN. UNEXPECTEDLY, SKEWED XCI OCCURS MORE OFTEN IN WOMEN WITH RA CARRYING THE SHARED EPITOPE, WHICH USUALLY REFLECTS SEVERE DISEASE. THIS REINFORCES THE VIEW THAT LOSS OF MOSAICISM IN PERIPHERAL BLOOD MAY BE A CONSEQUENCE OF CHRONIC AUTOIMMUNITY. 2016 4 2979 21 GENETIC BACKGROUND OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATOLOGIC DISEASE IN CHILDREN. JIA IS A GROUP OF DISORDERS THAT SHARE THE CLINICAL MANIFESTATION OF CHRONIC JOINT INFLAMMATION. THE HUMAN LEUKOCYTE ANTIGEN REGION (HLA) SEEMS TO BE A MAJOR SUSCEPTIBILITY LOCUS FOR JIA THAT IS ESTIMATED TO ACCOUNT FOR 17% OF FAMILIAL SEGREGATION OF THE DISEASE. TO DATE, AROUND 20 NON-HLA LOCI CONFERRING SUSCEPTIBILITY TO JIA WERE FOUND. AT LEAST A HALF OF THOSE ARE SHARED BETWEEN JIA AND RHEUMATOID ARTHRITIS (RA), AN ADULT RHEUMATIC DISEASE, THEREBY SUGGESTING FOR SIMILARITY OF PATHOGENIC MECHANISMS OF BOTH DISEASES. NEW FINDINGS ALSO SUGGEST FOR A LIKELY ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF JIA THAT SHOULD BE INVESTIGATED IN THE FUTURE. 2014 5 3112 50 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 6 3031 37 GENETICS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN INFLAMMATORY AUTOIMMUNE DISEASE INVOLVING SYMMETRIC JOINTS AND IS GENERALLY CHARACTERIZED BY PERSISTENT PAIN, TENDERNESS, AND DESTRUCTION OF JOINTS. THE VAST MAJORITY OF RA PATIENTS PRODUCE AUTOANTIBODIES, AND IMMUNE CELL INVOLVEMENT IN DISEASE DEVELOPMENT IS WELL RECOGNIZED, AS IS THE CONTRIBUTION OF OTHER TYPES OF CELLS IN SYNOVIAL TISSUE, LIKE FIBROBLASTS. IT IS KNOWN THAT THERE ARE MAJOR GENETIC ASSOCIATIONS WITH THE HLA LOCUS, WHILE MULTIPLE NON-HLA GENETIC VARIANTS DISPLAY RELATIVELY LOW RISK OF RA. BOTH HLA AND NON-HLA ASSOCIATIONS SUGGEST THAT THE PROFILES OF GENETIC ASSOCIATIONS FOR AUTOANTIBODY-POSITIVE VS. AUTOANTIBODY-NEGATIVE RA ARE DIFFERENT. SEVERAL ALLELES OF HLA-DRB1 ARE ASSOCIATED WITH HIGH RISK FOR AUTOANTIBODY-POSITIVE RA, WITH THE STRONGEST RISK CHARACTERIZED BY VALINE AT POSITION 11 OF THE PROTEIN SEQUENCE (HLA-DRB1*04 AND *10 ALLELES). THERE IS A STRONG PROTECTIVE EFFECT FOR THE RISK OF AUTOANTIBODY-POSITIVE RA ASSOCIATED WITH HLA-DRB1*13 ALLELES. ALTHOUGH MAJOR GENETIC ASSOCIATIONS HAVE BEEN KNOWN FOR SEVERAL YEARS, UNDERSTANDING OF THE SPECIFIC MECHANISMS IN THE DEVELOPMENT OF INCREASED RISK OF RA FOR THESE VARIATIONS IS WORK IN PROGRESS. CURRENT STUDIES FOCUS ON THE BINDING OF IMMUNE RECEPTORS INVOLVED IN RECOGNITION OF PUTATIVE PEPTIDES IN ACTIVATION OF T CELLS, AS WELL AS INVESTIGATION OF CELL SIGNALING MECHANISMS. AT LEAST A PART OF RA RISK COULD BE EXPLAINED BY GENE-GENE AND GENE-ENVIRONMENT INTERACTIONS. THERE ARE CURRENTLY MORE THAN 150 CANDIDATE LOCI WITH POLYMORPHISMS THAT ASSOCIATE WITH RA, MAINLY RELATED TO SEROPOSITIVE DISEASE, AND NEW DISCOVERIES ARE ANTICIPATED IN THE FUTURE FROM INVESTIGATION OF DIVERSE HUMAN POPULATIONS. THIS NEW RESEARCH WILL HELP CREATE A STRONG FOUNDATION FOR THE CONTINUING PROCESS OF INTEGRATING GENETIC, EPIGENETIC, TRANSCRIPTOMIC, AND PROTEOMIC DATA IN STUDIES OF RA. 2022 7 2588 43 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 8 5699 30 SIMULTANEOUS DETECTION OF DNA VARIATION AND METHYLATION AT HLA CLASS II LOCUS AND IMMUNE GENE PROMOTERS USING TARGETED SURESELECT METHYL-SEQUENCING. THE HUMAN LEUKOCYTE ANTIGEN (HLA) LOCUS ASSOCIATES WITH A VARIETY OF COMPLEX DISEASES, PARTICULARLY AUTOIMMUNE AND INFLAMMATORY CONDITIONS. THE HLA-DR15 HAPLOTYPE, FOR EXAMPLE, CONFERS THE MAJOR RISK FOR DEVELOPING MULTIPLE SCLEROSIS IN CAUCASIANS, PINPOINTING AN IMPORTANT ROLE IN THE ETIOLOGY OF THIS CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM. IN ADDITION TO THE PROTEIN-CODING VARIANTS THAT SHAPE THE FUNCTIONAL HLA-ANTIGEN-T CELL INTERACTION, RECENT STUDIES SUGGEST THAT THE LEVELS OF HLA MOLECULE EXPRESSION, THAT ARE EPIGENETICALLY CONTROLLED, ALSO PLAY A ROLE IN DISEASE DEVELOPMENT. HOWEVER, DECIPHERING THE EXACT MOLECULAR MECHANISMS OF THE HLA ASSOCIATION HAS BEEN HAMPERED BY THE TREMENDOUS GENETIC COMPLEXITY OF THE LOCUS AND A LACK OF ROBUST APPROACHES TO INVESTIGATE IT. HERE, WE DEVELOPED A METHOD TO SPECIFICALLY ENRICH THE GENOMIC DNA FROM THE HLA CLASS II LOCUS (CHR6:32,426,802-34,167,129) AND PROXIMAL PROMOTERS OF 2,157 IMMUNE-RELEVANT GENES, UTILIZING THE AGILENT RNA-BASED SURESELECT METHYL-SEQ CAPTURE RELATED METHOD, FOLLOWED BY SEQUENCING TO DETECT GENETIC AND EPIGENETIC VARIATION. WE DEMONSTRATED SUCCESSFUL SIMULTANEOUS DETECTION OF THE GENETIC VARIATION AND QUANTIFICATION OF DNA METHYLATION LEVELS IN HLA LOCUS. MOREOVER, BY THE DETECTION OF DIFFERENTIALLY METHYLATED POSITIONS IN PROMOTERS OF IMMUNE-RELATED GENES, WE IDENTIFIED RELEVANT PATHWAYS FOLLOWING STIMULATION OF CELLS. TAKEN TOGETHER, WE PRESENT A METHOD THAT CAN BE UTILIZED TO STUDY THE INTERPLAY BETWEEN GENETIC VARIANCE AND EPIGENETIC REGULATION IN THE HLA CLASS II REGION, POTENTIALLY, IN A WIDE DISEASE CONTEXT. 2023 9 4676 37 NEW INSIGHTS TOWARD THE PATHOGENESIS OF ANKYLOSING SPONDYLITIS; GENETIC VARIATIONS AND EPIGENETIC MODIFICATIONS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE, CHARACTERIZED BY TYPICALLY AN AXIAL ARTHRITIS. AS IS THE PROTOTYPE OF A GROUP OF DISORDERS CALLED SPONDYLOARTHROPATHIES, WHICH IS BELIEVED TO HAVE COMMON CLINICAL MANIFESTATIONS AND GENETIC PREDISPOSITION. TO DATE, THE EXACT ETIOLOGY OF AS REMAINS UNCLEAR. OVER THE PAST FEW YEARS, HOWEVER, THE ROLE OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS CAUSED THROUGH ENVIRONMENTAL FACTORS HAVE BEEN EXTENSIVELY SURVEYED WITH RESPECT TO THE PATHOGENESIS OF AS, RESULTED IN IMPORTANT ADVANCES. THIS REVIEW ARTICLE FOCUSES ON THE RECENT ADVANCES IN THE FIELD OF AS RESEARCH, INCLUDING HLA AND NON-HLA SUSCEPTIBILITY GENES IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES (GWAS), AND ABERRANT EPIGENETIC MODIFICATIONS OF GENE LOCI ASSOCIATED WITH AS. HLA GENES MOST SIGNIFICANTLY LINKED WITH AS SUSCEPTIBILITY INCLUDE HLA-B27 AND ITS SUBTYPES. NUMEROUS NON-HLA GENES SUCH AS THOSE IN UBIQUITINATION, AMINOPEPTIDASES AND MHC CLASS I PRESENTATION MOLECULES LIKE ERAP-1 WERE ALSO REPORTED. MOREOVER, EPIGENETIC MODIFICATIONS OCCURRED IN AS HAS BEEN SUMMARIZED. TAKEN TOGETHER, THE FINDINGS PRESENTED IN THIS REVIEW ATTEMPT TO EXPLAIN THE CIRCUMSTANCE BY WHICH BOTH GENETIC VARIATIONS AND EPIGENETIC MODIFICATIONS ARE INVOLVED IN TRIGGERING AND DEVELOPMENT OF AS. NONETHELESS, SEVERAL UNANSWERED DARK SIDES CONTINUE TO CLOG OUR EXHAUSTIVE UNDERSTANDING OF AS. FUTURE RESEARCHES IN THE FIELD OF EPIGENETICS SHOULD BE CARRIED OUT TO EXTEND OUR VISION OF AS ETIOPATHOGENESIS. 2017 10 5506 45 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 11 6727 37 VITILIGO AND CHRONIC AUTOIMMUNE THYROIDITIS. VITILIGO, THE DISCOLORATION OF THE SKIN, HAS DIFFERENT AUTOIMMUNE MECHANISMS REFLECTED BY MANY BIOMARKERS AS SHOWN BY SKIN HISTOLOGY, STAINING FOR CD4 AND CD8 T LYMPHOCYTES, CHEMOKINE LIGAND 9 OR CIRCULATING CYTOKINES SUCH AS INTERLEUKIN (IL)-1 BETA, INTERFERON (IFN)-GAMMA, TRANSFORMING GROWTH FACTOR (TGF)-BETA, ANTIBODIES, MARKERS OF OXIDATIVE STRESS, CHEMOKINES, AND OTHERS. IN THIS NARRATIVE REVIEW, WE AIM TO OVERVIEW VITILIGO IN RELATIONSHIP WITH CHRONIC AUTOIMMUNE THYROIDITIS. REGARDING VITILIGO, MORE THAN 50 DIFFERENT GENETIC LOCI HAVE BEEN ASSOCIATED WITH THIS DISEASE, AND THE HERITABILITY IS HIGH. THERE IS A 20% RISK OF AN ENVIRONMENTAL CONNECTION WHICH MAY ALSO ACT AS A TRIGGER; MOREOVER, THE ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN (HLA) EXPRESSION IS WELL RECOGNIZED. THE SPECIFIC LESIONS DISPLAY CD8+ TISSUE-RESIDENT MEMORY T CELLS AS CONTINUOUS KEY ACTIVATORS OF MELANOCYTES. THE ASSOCIATION WITH CHRONIC THYROIDITIS IS BASED ON COMMON AUTOIMMUNE BACKGROUND AND EXCESSIVE REACTIVE OXYGEN SPECIES THAT DESTROY MELANOCYTES AND THYROCYTES (OXIDATIVE STRESS HYPOTHESIS) WITH THYROXINE AND MELANIN AS TARGET MOLECULES, THUS SHARING A COMMON ORIGIN: TYROSINE. MOREOVER, COMMON EPIGENETIC ANOMALIES OR MUTATIONS OF THE FORKHEAD TRANSCRIPTION FACTOR D3 (FOXD3) HAVE BEEN DESCRIBED. SINCE VITILIGO AFFECTS UP TO 1-2% OF THE POPULATION WORLDWIDE AND 34% OF PATIENTS HAVE POSITIVE THYROID ANTIBODIES, APART FROM COMMON AUTOIMMUNITY BACKGROUND AND OXIDATIVE STRESS TOXICITY, THE ASSOCIATION IS CLINICALLY RELEVANT FOR DIFFERENT PRACTITIONERS. 2021 12 2512 42 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 13 5220 37 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 14 5222 30 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 15 3507 19 IDENTIFICATION OF TARGET GENES AT JUVENILE IDIOPATHIC ARTHRITIS GWAS LOCI IN HUMAN NEUTROPHILS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATIC DISEASE AMONG CHILDREN WHICH COULD CAUSE SEVERE DISABILITY. GENOMIC STUDIES HAVE DISCOVERED SUBSTANTIAL NUMBER OF RISK LOCI FOR JIA, HOWEVER, THE MECHANISM OF HOW THESE LOCI AFFECT JIA DEVELOPMENT IS NOT FULLY UNDERSTOOD. NEUTROPHIL IS AN IMPORTANT CELL TYPE INVOLVED IN AUTOIMMUNE DISEASES. TO BETTER UNDERSTAND THE BIOLOGICAL FUNCTION OF GENETIC LOCI IN NEUTROPHILS DURING JIA DEVELOPMENT, WE TOOK AN INTEGRATED MULTI-OMICS APPROACH TO IDENTIFY TARGET GENES AT JIA RISK LOCI IN NEUTROPHILS AND CONSTRUCTED A PROTEIN-PROTEIN INTERACTION NETWORK VIA A MACHINE LEARNING APPROACH. WE IDENTIFIED GENES LIKELY TO BE JIA RISK LOCI TARGETED GENES IN NEUTROPHILS WHICH COULD CONTRIBUTE TO JIA DEVELOPMENT. 2019 16 6289 29 THE POTENTIAL ROLE OF GENETICS, ENVIRONMENTAL FACTORS, AND GUT DYSBIOSIS IN THE ABERRANT NON-CODING RNA EXPRESSION TO MEDIATE INFLAMMATION AND OSTEOCLASTOGENIC/OSTEOGENIC DIFFERENTIATION IN ANKYLOSING SPONDYLITIS. ANKYLOSING SPONDYLITIS (AS) OR RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS IS A CHRONIC IMMUNE-MEDIATED RHEUMATIC DISORDER CHARACTERIZED BY THE INFLAMMATION IN THE AXIAL SKELETON, PERIPHERAL JOINTS, AND SOFT TISSUES (ENTHESIS, FASCIA, AND LIGAMENT). IN ADDITION, THE EXTRA-SKELETAL COMPLICATIONS INCLUDING ANTERIOR UVEITIS, INTERSTITIAL LUNG DISEASES AND AORTITIS ARE FOUND. THE PATHOGENESIS OF AS IMPLICATES AN INTRICATE INTERACTION AMONG HLA (HLA-B27) AND NON-HLA LOCI [ENDOPLASMIC RETICULUM AMINOPEPTIDASE 1 (ERAP1), AND INTERLEUKIN-23 RECEPTOR (IL23R), GUT DYSBIOSIS, IMMUNE PLASTICITY, AND NUMEROUS ENVIRONMENTAL FACTORS (INFECTIONS, HEAVY METALS, STRESS, CIGARETTE SMOKING, ETC.) THE LATTER MULTIPLE NON-GENETIC FACTORS MAY EXERT A POWERFUL STRESS ON EPIGENETIC REGULATIONS. THESE EPIGENETIC REGULATIONS OF GENE EXPRESSION CONTAIN DNA METHYLATION/DEMETHYLATION, HISTONE MODIFICATIONS AND ABERRANT NON-CODING RNAS (NCRNAS) EXPRESSION, LEADING TO INFLAMMATION AND IMMUNE DYSFUNCTIONS. IN THE PRESENT REVIEW, WE SHALL DISCUSS THESE CONTRIBUTORY FACTORS THAT ARE INVOLVED IN AS PATHOGENESIS, ESPECIALLY THE ABERRANT NCRNA EXPRESSION AND ITS EFFECTS ON THE PROINFLAMMATORY CYTOKINE PRODUCTIONS (TNF-ALPHA, IL-17 AND IL-23), T CELL SKEWING TO TH1/TH17, AND OSTEOCLASTOGENIC/OSTEOGENIC DIFFERENTIATION. FINALLY, SOME POTENTIAL INVESTIGATORY APPROACHES ARE RAISED FOR SOLVING THE PUZZLES IN AS PATHOGENESIS. 2021 17 3057 29 GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIES HLA-B*27 DEPENDENT AND INDEPENDENT DNA METHYLATION CHANGES IN WHOLE BLOOD. BACKGROUND AND OBJECTIVE: ANKYLOSING SPONDYLITIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY INFLAMMATION OF THE SACROILIAC JOINTS AND THE SPINE THAT CAN LEAD TO SIGNIFICANT PAIN, IMMOBILITY, AND DISABILITY. THE ETIOLOGY AND PATHOGENESIS OF ANKYLOSING SPONDYLITIS ARE INCOMPLETELY UNDERSTOOD, THOUGH MOST PATIENTS CARRY THE HLA-B*27 ALLELE. THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE DNA METHYLATION CHANGES IN ANKYLOSING SPONDYLITIS WITH THE GOAL OF REVEALING NOVEL MECHANISTIC INSIGHTS INTO THIS DISEASE. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED IN WHOLE BLOOD DNA SAMPLES USING THE INFINIUM METHYLATIONEPIC ARRAY IN PATIENTS WITH ANKYLOSING SPONDYLITIS COMPARED TO AGE, SEX, AND RACE MATCHED PATIENTS WITH OSTEOARTHRITIS AS A NON-INFLAMMATORY DISEASE CONTROL. WE STUDIED 24 PATIENTS WITH ANKYLOSING SPONDYLITIS, INCLUDING 12 PATIENTS WHO CARRY HLA-B*27 AND 12 PATIENTS WHO ARE HLA-B*27 NEGATIVE. DNA METHYLATION ANALYSIS WAS PERFORMED WITH ADJUSTMENT FOR BLOOD CELL COMPOSITION IN EACH SAMPLE. RESULTS: WE IDENTIFIED A TOTAL OF 67 DIFFERENTIALLY METHYLATED SITES BETWEEN ANKYLOSING SPONDYLITIS PATIENTS AND OSTEOARTHRITIS CONTROLS. HYPERMETHYLATED GENES FOUND INCLUDED GTPASE-RELATED GENES, WHILE HYPOMETHYLATED GENES INCLUDED HCP5, WHICH ENCODES A LNCRNA WITHIN THE MHC REGION, PREVIOUSLY ASSOCIATED WITH GENETIC RISK FOR PSORIASIS AND TOXIC EPIDERMAL NECROLYSIS. CARRYING HLA-B*27 WAS ASSOCIATED WITH ROBUST HYPOMETHYLATION OF HCP5, TUBULIN FOLDING COFACTOR A (TBCA) AND PHOSPHOLIPASE D FAMILY MEMBER 6 (PLD6) IN ANKYLOSING SPONDYLITIS PATIENTS. HYPOMETHYLATION WITHIN HCP5 INVOLVES A CPG SITE THAT CONTAINS A SINGLE NUCLEOTIDE POLYMORPHISM IN LINKAGE DISEQUILIBRIUM WITH HLA-B*27 AND THAT CONTROLS DNA METHYLATION AT THIS LOCUS IN AN ALLELE-SPECIFIC MANNER. CONCLUSIONS: A GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIED DNA METHYLATION PATTERNS THAT COULD PROVIDE POTENTIAL NOVEL INSIGHTS INTO THIS DISEASE. OUR FINDINGS SUGGEST THAT HLA-B*27 MIGHT PLAY A ROLE IN ANKYLOSING SPONDYLITIS IN PART THROUGH INDUCING EPIGENETIC DYSREGULATION. 2019 18 5371 33 RECENT ADVANCES IN UNDERSTANDING THE GENETIC BASIS OF SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A POLYGENIC CHRONIC AUTOIMMUNE DISEASE LEADING TO MULTIPLE ORGAN DAMAGE. A LARGE HERITABILITY OF UP TO 66% IS ESTIMATED IN SLE, WITH ROUGHLY 180 REPORTED SUSCEPTIBILITY LOCI THAT HAVE BEEN IDENTIFIED MOSTLY BY GENOME-WIDE ASSOCIATION STUDIES (GWASS) AND ACCOUNT FOR APPROXIMATELY 30% OF GENETIC HERITABILITY. A VAST MAJORITY OF RISK VARIANTS RESIDE IN NON-CODING REGIONS, WHICH MAKES IT QUITE CHALLENGING TO INTERPRET THEIR FUNCTIONAL IMPLICATIONS IN THE SLE-AFFECTED IMMUNE SYSTEM, SUGGESTING THE IMPORTANCE OF UNDERSTANDING CELL TYPE-SPECIFIC EPIGENETIC REGULATION AROUND SLE GWAS VARIANTS. THE LATEST GENETIC STUDIES HAVE BEEN HIGHLY FRUITFUL AS SEVERAL DOZENS OF SLE LOCI WERE NEWLY DISCOVERED IN THE LAST FEW YEARS AND MANY LOCI HAVE COME TO BE UNDERSTOOD IN SYSTEMIC APPROACHES INTEGRATING GWAS SIGNALS WITH OTHER BIOLOGICAL RESOURCES. IN THIS REVIEW, WE SUMMARIZE SLE-ASSOCIATED GENETIC VARIANTS IN BOTH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) AND NON-MHC LOCI, EXAMINING POLYGENETIC RISK SCORES FOR SLE AND THEIR ASSOCIATIONS WITH CLINICAL FEATURES. FINALLY, VARIANT-DRIVEN PATHOGENETIC FUNCTIONS UNDERLYING GENETIC ASSOCIATIONS ARE DESCRIBED, COUPLED WITH DISCUSSION ABOUT CHALLENGES AND FUTURE DIRECTIONS IN GENETIC STUDIES ON SLE. 2022 19 3564 43 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 20 406 24 ANALYSIS OF FIVE CHRONIC INFLAMMATORY DISEASES IDENTIFIES 27 NEW ASSOCIATIONS AND HIGHLIGHTS DISEASE-SPECIFIC PATTERNS AT SHARED LOCI. WE SIMULTANEOUSLY INVESTIGATED THE GENETIC LANDSCAPE OF ANKYLOSING SPONDYLITIS, CROHN'S DISEASE, PSORIASIS, PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS TO INVESTIGATE PLEIOTROPY AND THE RELATIONSHIP BETWEEN THESE CLINICALLY RELATED DISEASES. USING HIGH-DENSITY GENOTYPE DATA FROM MORE THAN 86,000 INDIVIDUALS OF EUROPEAN ANCESTRY, WE IDENTIFIED 244 INDEPENDENT MULTIDISEASE SIGNALS, INCLUDING 27 NEW GENOME-WIDE SIGNIFICANT SUSCEPTIBILITY LOCI AND 3 UNREPORTED SHARED RISK LOCI. COMPLEX PLEIOTROPY WAS SUPPORTED WHEN CONTRASTING MULTIDISEASE SIGNALS WITH EXPRESSION DATA SETS FROM HUMAN, RAT AND MOUSE TOGETHER WITH EPIGENETIC AND EXPRESSED ENHANCER PROFILES. THE COMORBIDITIES AMONG THE FIVE IMMUNE DISEASES WERE BEST EXPLAINED BY BIOLOGICAL PLEIOTROPY RATHER THAN HETEROGENEITY (A SUBGROUP OF CASES GENETICALLY IDENTICAL TO THOSE WITH ANOTHER DISEASE, POSSIBLY OWING TO DIAGNOSTIC MISCLASSIFICATION, MOLECULAR SUBTYPES OR EXCESSIVE COMORBIDITY). IN PARTICULAR, THE STRONG COMORBIDITY BETWEEN PRIMARY SCLEROSING CHOLANGITIS AND INFLAMMATORY BOWEL DISEASE IS LIKELY THE RESULT OF A UNIQUE DISEASE, WHICH IS GENETICALLY DISTINCT FROM CLASSICAL INFLAMMATORY BOWEL DISEASE PHENOTYPES. 2016