1  552 139 AUTOINFLAMMATION IN SYNDROMIC HIDRADENITIS SUPPURATIVA: THE ROLE OF AIM2. BACKGROUND: AIM2 IS A KEY CYTOPLASMATIC PATHOGEN-SENSOR THAT DETECTS FOREIGN DNA FROM VIRUSES AND BACTERIA; IT CAN ALSO RECOGNIZE DAMAGED OR ANOMALOUS PRESENCE OF DNA, PROMOTING INFLAMMASOME ASSEMBLY AND ACTIVATION WITH THE SECRETION OF IL-1BETA, THUS SUSTAINING A CHRONIC INFLAMMATORY STATE, POTENTIALLY LEADING TO THE ONSET OF AUTOINFLAMMATORY SKIN DISEASES. GIVEN THE IMPLICATION OF THE IL-1BETA PATHWAY IN THE PATHOGENESIS OF SYNDROMIC HIDRADENITIS SUPPURATIVA (HS), AN AUTOINFLAMMATORY IMMUNE-MEDIATED SKIN CONDITION, THE POTENTIAL INVOLVEMENT OF AIM2 WAS INVESTIGATED. METHODS: SEQUENCING OF THE WHOLE CODING REGION OF THE AIM2 GENE, COMPRISING 5'- AND 3' UTR AND A REGION UPSTREAM OF THE FIRST EXON OF ~800 BP WAS PERFORMED IN TWELVE SYNDROMIC HS PATIENTS. RESULTS: SIX OUT OF TWELVE SYNDROMIC HS PATIENTS CARRIED A HETEROZYGOUS VARIANT C.-208 A >/= C (RS41264459), LOCATED ON THE PROMOTER REGION OF THE AIM2 GENE, WITH A MINOR ALLELE FREQUENCY OF 0.25, WHICH IS MUCH HIGHER THAN THAT REPORTED IN 1000 G AND GNOMAD (0.075 AND 0.094, RESPECTIVELY). THE SAME VARIANT WAS FOUND AT A LOWER ALLELIC FREQUENCY IN SPORADIC HS AND ISOLATED PYODERMA GANGRENOSUM (PG) (0.125 AND 0.065, RESPECTIVELY). CONCLUSION: OUR DATA SUGGEST THAT THIS VARIANT MIGHT PLAY A ROLE IN SUSCEPTIBILITY TO DEVELOP SYNDROMIC FORMS OF HS BUT NOT TO PROGRESS TO SPORADIC HS AND PG. FURTHERMORE, EPIGENETIC AND/OR SOMATIC VARIATIONS COULD AFFECT AIM2 EXPRESSION LEADING TO DIFFERENT, CONTEXT-DEPENDENT RESPONSES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 3284  36 HIDRADENITIS SUPPURATIVA PRESENTS A METHYLOME DYSREGULATION CAPABLE TO EXPLAIN THE PRO-INFLAMMATORY MICROENVIRONMENT: ARE THESE DNA METHYLATIONS POTENTIAL THERAPEUTIC TARGETS? BACKGROUND: HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC, SYSTEMIC, INFLAMMATORY SKIN CONDITION WITH ELUSIVE PATHOGENESIS THAT AFFECTS THERAPEUTIC INTERVENTION DIRECTLY. OBJECTIVE: TO CHARACTERIZE EPIGENETIC VARIATIONS IN CYTOKINES GENES CONTRIBUTING TO HS. METHODS: EPIGENOME-WIDE DNA METHYLATION PROFILING WITH THE ILLUMINA EPIC ARRAY WAS PERFORMED ON BLOOD DNA SAMPLES FROM 24 HS PATIENTS AND 24 AGE- AND SEX-MATCHED CONTROLS TO EXPLORE DNA METHYLATION CHANGES IN CYTOKINE GENES. RESULTS: WE IDENTIFIED 170 CYTOKINE GENES INCLUDING 27 HYPERMETHYLATED CPG SITES AND 143 GENES WITH HYPOMETHYLATED SITES RESPECTIVELY. HYPERMETHYLATED GENES, INCLUDING LIF, HLA-DRB1, HLA-G, MTOR, FADD, TGFB3, MALAT1 AND CCL28; HYPOMETHYLATED GENES, INCLUDING NCSTN, SMAD3, IGF1R, IL1F9, NOD2, NOD1, YY1, DLL1 AND BCL2 MAY CONTRIBUTE TO THE PATHOGENESIS OF HS. THESE GENES WERE ENRICHED IN THE 117 DIFFERENT PATHWAYS (FDR P-VALUES </= 0.05), INCLUDING IL-4/IL-13 PATHWAYS AND WNT/BETA-CATENIN SIGNALLING. CONCLUSIONS: THE LACK OF WOUND HEALING, MICROBIOME DYSBIOSIS AND INCREASED TUMOUR SUSCEPTIBILITY ARE ALL SUSTAINED BY THESE DYSFUNCTIONAL METHYLOMES, HOPEFULLY, CAPABLE TO BE TARGETED IN THE NEXT FUTURE. SINCE METHYLOME DESCRIBES AND SUMMARIZES GENETIC AND ENVIRONMENTAL CONTRIBUTIONS, THESE DATA MAY REPRESENT A FURTHER STEP TOWARDS A FEASIBLE PRECISION MEDICINE ALSO FOR HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 3285  39 HIDRADENITIS SUPPURATIVA: A PERSPECTIVE ON GENETIC FACTORS INVOLVED IN THE DISEASE. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE OF THE PILOSEBACEOUS UNIT, CLINICALLY CONSISTING OF PAINFUL NODULES, ABSCESSES, AND SINUS TRACTS MOSTLY IN, BUT NOT LIMITED TO, INTERTRIGINOUS SKIN AREAS. HS CAN BE DEFINED AS A COMPLEX SKIN DISEASE WITH MULTIFACTORIAL ETIOLOGIES, INCLUDING-AMONG OTHERS-GENETIC, IMMUNOLOGIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. BASED ON GENETIC HETEROGENEITY AND COMPLEXITY, THREE DIFFERENT FORMS CAN BE RECOGNIZED AND CONSIDERED SEPARATELY AS SPORADIC, FAMILIAL, AND SYNDROMIC. TO DATE, SEVERAL GENETIC VARIANTS ASSOCIATED TO DISEASE SUSCEPTIBILITY, DISEASE-ONSET, AND/OR TREATMENT RESPONSE HAVE BEEN REPORTED; SOME OF THESE RESIDE IN GENES ENCODING THE GAMMA-SECRETASE SUBUNITS WHEREAS OTHERS INVOLVE AUTOINFLAMMATORY AND/OR KERATINIZATION GENES. THE AIM OF THIS PERSPECTIVE WORK IS TO PROVIDE AN OVERVIEW OF THE CONTRIBUTION OF SEVERAL GENETIC STUDIES ENCOMPASSING FAMILY LINKAGE ANALYSES, TARGET CANDIDATE GENE STUDIES, AND -OMIC STUDIES IN THIS FIELD. IN OUR VIEWPOINT, WE DISCUSS THE ROLE OF GENETICS IN HIDRADENITIS SUPPURATIVA CONSIDERING FINDINGS BASED ON SANGER SEQUENCING AS WELL AS THE MORE RECENT NEXT GENERATION SEQUENCING (I.E., EXOME SEQUENCING OR RNA SEQUENCING) WITH THE AIM OF BETTER UNDERSTANDING THE ETIO-PATHOGENESIS OF THE DISEASE AS WELL AS IDENTIFYING NOVEL THERAPEUTIC STRATEGIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4 3316  28 HISTIOCYTIC SARCOMA AS A SECONDARY MALIGNANCY: PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT. HISTIOCYTIC SARCOMA (HS) IS AN EXTREMELY RARE NON-LANGERHANS CELL DISORDER WITH AN AGGRESSIVE COURSE AND LIMITED TREATMENT OPTIONS. RECENT ADVANCES IN MOLECULAR/GENETIC SEQUENCING HAVE SUGGESTED A COMMON CLONAL ORIGIN BETWEEN VARIOUS HEMATOLYMPHOID DISORDERS AND CASES OF SECONDARY HS. DERIVING CONCLUSIONS FROM PREVIOUSLY REPORTED CASES OF HS ARISING SECONDARILY TO CERTAIN HEMATOLYMPHOID DISORDERS, HERE WE HAVE TRIED TO PROVIDE INSIGHT INTO THE MECHANISMS INFLUENCING THIS EVOLUTION. WE ALSO DISCUSS A CLINICAL CASE OF A 72-YEAR-OLD MAN WITH A DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), PRESENTING SUBSEQUENTLY WITH A HETEROGENEOUS LIVER MASS POSITIVE WITH A DIAGNOSIS OF HS. THE LIVER MASS SHOWED A RETAINED BCR-ABL1 TRANSLOCATION SUGGESTING CLONALITY BETWEEN THE CML AND HS. AS SEEN IN OUR CASE AND OTHER REPORTED CASES OF HS DERIVED SECONDARILY, THE CONCURRENT EXPRESSION OF IMMUNOGLOBULIN HEAVY (IGH)-/LIGHT-CHAIN REARRANGEMENTS OR CYTOGENETIC MARKERS COMMON TO THE PRIMARY MALIGNANCY SUGGESTS AN EVOLUTIONARY MECHANISM INVOLVING LINEAGE SWITCHING THAT COULD POTENTIALLY BE INFLUENCED BY GENETIC OR EPIGENETIC CUES WHICH MAY OCCUR AT THE LEVEL OF A PROGENITOR OR THE MALIGNANT CELL ITSELF.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5 1739  34 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT.	2022	
                                                                                                        
6 1584  27 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7 5269  35 PROMOTER DNA METHYLATION CONTRIBUTES TO HUMAN BETA-DEFENSIN-1 DEFICIENCY IN ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY EPIDERMAL BARRIER DYSFUNCTION AND DYSREGULATION OF INNATE AND ADAPTIVE IMMUNITY. EPIGENETIC REGULATION OF HUMAN BETA-DEFENSIN-1 (HBD-1) MIGHT BE ASSOCIATED WITH A VARIETY OF DEFECTS IN THE INNATE IMMUNE SYSTEM DURING AD PATHOGENESIS. WE INVESTIGATED THE POSSIBLE MECHANISM OF DECREASED HBD-1 GENE EXPRESSION IN AD AND DEMONSTRATED THE RESTORATION OF HBD-1 TRANSCRIPTION IN UNDIFFERENTIATED NORMAL HUMAN EPIDERMAL KERATINOCYTE CELLS AFTER TREATMENT WITH A DNA METHYLTRANSFERASE INHIBITOR. WE ALSO CONDUCTED AN IN VITRO METHYLATED REPORTER ASSAY USING A REPORTER CONTAINING 14 CPG SITES. METHYLATION OF THE 14 CPG SITES WITHIN THE HBD-1 5' REGION RESULTED IN AN APPROXIMATELY 86% REDUCTION IN PROMOTER ACTIVITY AND AFFECTED HBD-1 TRANSCRIPTIONAL REGULATION. WE THEN COMPARED METHYLATION FREQUENCIES AT CPG 3 AND CPG 4 BETWEEN NON-LESIONAL AND LESIONAL EPIDERMIS SAMPLES OF PATIENTS WITH SEVERE AD AND BETWEEN THESE PAIRED TISSUES AND HEALTHY CONTROL EPIDERMIS FROM NORMAL VOLUNTEERS WITHOUT AD HISTORY. BISULFITE PYROSEQUENCING DATA SHOWED SIGNIFICANTLY HIGHER METHYLATION FREQUENCIES AT THE CPG 3 AND 4 SITES IN AD LESIONAL SAMPLES THAN IN NON-LESIONAL AD SKIN AND NORMAL SKIN SAMPLES (P < 0.05). THESE RESULTS SUGGEST THAT THE DNA METHYLATION SIGNATURE OF HBD-1 IS A NOVEL DIAGNOSTIC/PROGNOSTIC MARKER AND A PROMISING THERAPEUTIC TARGET FOR THE COMPROMISED STRATUM CORNEUM BARRIER ATTRIBUTED TO HBD-1 DEFICIENCY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8 1607  26 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9 5638  28 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                         
10 4235  29 METHYLATION OF THE AIM2 GENE: AN EPIGENETIC MEDIATOR OF PTSD-RELATED INFLAMMATION AND NEUROPATHOLOGY PLASMA BIOMARKERS. BACKGROUND: POSTTRAUMATIC STRESS DISORDER (PTSD) IS ASSOCIATED WITH INFLAMMATION AND VARIOUS FORMS OF CHRONIC DISEASE. THE ABSENT IN MELANOMA 2 (AIM2) GENE HAS BEEN IMPLICATED IN MECHANISMS OF INFLAMMATION AND ANXIETY, AND METHYLATION AT A PARTICULAR LOCUS IN THIS GENE (CG10636246) HAS PREVIOUSLY BEEN SHOWN TO INFLUENCE THE ASSOCIATION BETWEEN PTSD AND ELEVATED C-REACTIVE PROTEIN LEVELS IN BLOOD. METHOD: WE TESTED IF THIS ASSOCIATION MIGHT EXTEND TO OTHER INDICATORS OF INFLAMMATION AND TO PLASMA-BASED MEASURES OF NEUROPATHOLOGY IN A COHORT OF POST-9/11 US MILITARY VETERANS. USING A BAYESIAN APPROACH, MEDIATION MODELS WERE TESTED CROSS-SECTIONALLY (N = 478) AND LONGITUDINALLY (N = 298). PERIPHERAL MARKERS OF INFLAMMATION AND NEUROPATHOLOGY WERE MEASURED WITH ULTRA-SENSITIVE SINGLE MOLECULE ARRAY (SIMOA(R)) TECHNOLOGY. RESULTS: ANALYSES REVEALED INDIRECT EFFECTS OF PTSD SYMPTOM SEVERITY ON PERIPHERAL INDICES OF BOTH INFLAMMATION (INTERLEUKIN [IL]6, IL-10, TUMOR NECROSIS FACTOR-ALPHA; INDIRECT STANDARDIZED [STD.] SS RANGE = 0.018-0.023, ALL P-VALUES ADJUSTED FOR MULTIPLE TESTING [P(ADJ) ] < 0.05) AND NEUROPATHOLOGY (NEUROFILAMENT LIGHT [NFL]; INDIRECT STD. SS = -0.018, P(ADJ) = 0.02) VIA AIM2 METHYLATION. THIS INDIRECT EFFECT WAS ALSO EVIDENT WHEN PREDICTING IL-10 AT A FOLLOW-UP ASSESSMENT (INDIRECT STD. SS = -0.018, P(ADJ) = 0.04) CONTROLLING FOR BASELINE IL-10. CONCLUSIONS: GIVEN THAT AIM2 METHYLATION MEDIATED THE ASSOCIATION BETWEEN PTSD SYMPTOMS AND MULTIPLE INFLAMMATORY AND NEUROPATHOLOGY MARKERS, OUR RESULTS SUGGEST THAT AIM2 METHYLATION MAY OFFER CLINICAL UTILITY FOR INDEXING RISK FOR ADVERSE HEALTH OUTCOMES ASSOCIATED WITH THESE PERIPHERAL INDICES OF INFLAMMATION AND NEUROPATHOLOGY. RESULTS ALSO SUGGEST A POSSIBLE SHARED ETIOLOGY UNDERLYING THE FREQUENT CO-OCCURRENCE OF INFLAMMATION AND NEUROPATHOLOGY.	2022	
                                                                                                                                                                                                                                                                          
11 6488  37 TP53 R72P POLYMORPHISM MODULATES DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS CHARACTERIZED BY WIDESPREAD EPIDEMIOLOGICAL AND MOLECULAR HETEROGENEITY. PREVIOUS WORK SHOWED THAT IN THE WESTERN PART OF NORTH AFRICA, A REGION OF LOW INCIDENCE OF HCC, MUTATIONS ARE SCARCE FOR THIS TUMOR TYPE. AS EPIGENETIC CHANGES ARE CONSIDERED POSSIBLE SURROGATES TO MUTATIONS IN HUMAN CANCERS, WE DECIDED, THUS, TO CHARACTERIZE DNA METHYLATION IN HCC FROM NORTH-AFRICAN PATIENTS. METHODS: A SET OF 11 LOCI WAS INVESTIGATED IN A SERIES OF 45 TUMOR SPECIMENS USING METHYLATION-SPECIFIC AND COMBINED-BISULFITE RESTRICTION ASSAY PCR. RESULTS OBTAINED ON CLINICAL SAMPLES WERE SUBSEQUENTLY VALIDATED IN LIVER CANCER CELL LINES. RESULTS: DNA METHYLATION AT TUMOR SUPPRESSOR LOCI IS SIGNIFICANTLY HIGHER IN SAMPLES DISPLAYING CHROMOSOME INSTABILITY. MORE IMPORTANTLY, DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN ARG/ARG WHEN COMPARED TO PRO/PRO GENOTYPE CARRIERS AT CODON 72 RS1042522 OF TP53 (65% VS 20% METHYLATED LOCI, P = 0.0006), A POLYMORPHISM ALREADY KNOWN TO AFFECT SOMATIC MUTATION RATE IN HUMAN CARCINOMAS. IN VITRO EXPERIMENTS IN CELL LINES INDICATED THAT ENZYMES CONTROLLING DNA METHYLATION WERE DIFFERENTIALLY REGULATED BY CODON 72 ARG OR PRO ISOFORMS OF P53. FURTHERMORE, THE ARG72-CARRYING VERSION OF P53 WAS SHOWN TO RE-METHYLATE DNA MORE RAPIDLY THAN THE PRO-HARBORING ISOFORM. FINALLY, PRO-CARRYING CELL LINES WERE SHOWN TO BE SIGNIFICANTLY MORE RESISTANT TO DECITABINE TREATMENT (TWO-FOLD, P = 0.005). CONCLUSIONS: OUR DATA SUGGEST THAT ARG72PRO POLYMORPHISM IN A WT P53 CONTEXT MAY ACT AS A PRIMARY DRIVER OF EPIGENETIC CHANGES IN HCC. IT SUGGESTS, IN ADDITION, THAT RS1042522 GENOTYPE MAY PREDICT SENSITIVITY TO EPIGENETIC-TARGETED THERAPY. THIS MODEL OF LIVER TUMORIGENESIS THAT ASSOCIATES LOW PENETRANCE GENETIC PREDISPOSITION TO EPIGENETIC CHANGES EMERGES FROM A REGION OF LOW HCC INCIDENCE AND IT MAY, THEREFORE, APPLY ESSENTIALLY TO POPULATION LIVING IN SIMILAR AREAS. SURVEYS ON POPULATIONS SUBMITTED TO HIGHLY MUTAGENIC CONDITIONS AS PERINATALLY-ACQUIRED CHRONIC HEPATITIS B OR AFLATOXIN B1 EXPOSURE REMAINED TO BE CONDUCTED TO VALIDATE OUR OBSERVATIONS AS A GENERAL MODEL.	2015	

12 2820  24 FINE-MAPPING INFLAMMATORY BOWEL DISEASE LOCI TO SINGLE-VARIANT RESOLUTION. INFLAMMATORY BOWEL DISEASES ARE CHRONIC GASTROINTESTINAL INFLAMMATORY DISORDERS THAT AFFECT MILLIONS OF PEOPLE WORLDWIDE. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED 200 INFLAMMATORY BOWEL DISEASE-ASSOCIATED LOCI, BUT FEW HAVE BEEN CONCLUSIVELY RESOLVED TO SPECIFIC FUNCTIONAL VARIANTS. HERE WE REPORT FINE-MAPPING OF 94 INFLAMMATORY BOWEL DISEASE LOCI USING HIGH-DENSITY GENOTYPING IN 67,852 INDIVIDUALS. WE PINPOINT 18 ASSOCIATIONS TO A SINGLE CAUSAL VARIANT WITH GREATER THAN 95% CERTAINTY, AND AN ADDITIONAL 27 ASSOCIATIONS TO A SINGLE VARIANT WITH GREATER THAN 50% CERTAINTY. THESE 45 VARIANTS ARE SIGNIFICANTLY ENRICHED FOR PROTEIN-CODING CHANGES (N = 13), DIRECT DISRUPTION OF TRANSCRIPTION-FACTOR BINDING SITES (N = 3), AND TISSUE-SPECIFIC EPIGENETIC MARKS (N = 10), WITH THE LAST CATEGORY SHOWING ENRICHMENT IN SPECIFIC IMMUNE CELLS AMONG ASSOCIATIONS STRONGER IN CROHN'S DISEASE AND IN GUT MUCOSA AMONG ASSOCIATIONS STRONGER IN ULCERATIVE COLITIS. THE RESULTS OF THIS STUDY SUGGEST THAT HIGH-RESOLUTION FINE-MAPPING IN LARGE SAMPLES CAN CONVERT MANY DISCOVERIES FROM GENOME-WIDE ASSOCIATION STUDIES INTO STATISTICALLY CONVINCING CAUSAL VARIANTS, PROVIDING A POWERFUL SUBSTRATE FOR EXPERIMENTAL ELUCIDATION OF DISEASE MECHANISMS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  546  41 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                     
14 2908  25 GENE EXPRESSION PROFILE OF NORMAL BREAST TISSUE AND BODY MASS INDEX. BACKGROUND: IN HUMAN BREAST, ADIPOSE TISSUE REPRESENTS UP TO 80% OF THE TOTAL VOLUME AND PLAYS A CRITICAL ROLE IN MAMMARY GLAND REMODELING. GIVEN THE EMERGING ROLE OF OBESITY IN BREAST CANCER GROWTH AND DEVELOPMENT, WE EXPLORED THE RELATIONSHIP BETWEEN BODY MASS INDEX (BMI), AS A PROXY OF WOMAN'S OBESITY STATUS, AND THE EXPRESSION IN NORMAL BREAST TISSUE FROM HEALTHY WOMEN OF A SELECTED PANEL OF GENES, KNOWN TO BE INVOLVED IN MAMMARY GLAND HOMEOSTASIS. METHODS: TWO INDEPENDENT PUBLICLY AVAILABLE DATASETS, COMPOSED OF 180 SPECIMENS OF NORMAL BREAST TISSUE FROM REDUCTION MAMMOPLASTY WERE INTERROGATED. DIFFERENTIAL GENE EXPRESSION AMONG BMI CLASSES WAS EVALUATED BY ANOVA, AND PARTIAL CORRELATION COEFFICIENT WAS USED TO ASSAY THE CORRELATION BETWEEN GENES CONTROLLING FOR BMI. RESULTS: DESPITE THE DIFFERENCES IN MICROARRAY PLATFORMS AND ANALYTICAL PROCEDURES, THE TWO DATASETS SHARED A CORE OF 9 GENES DIFFERENTIALLY EXPRESSED IN BMI CLASSES AND SIGNIFICANTLY CORRELATED WITH BMI. FOUR (44%) OF THESE GENES BELONG TO THE FUNCTIONAL CLASS OF CYTOKINES AND CYTOKINE RECEPTORS (IL1R1, IL2RA, IL12A, AND IL12RB2). THE OTHERS BELONG TO THE FUNCTIONAL CLASS OF THE EPIGENETIC REGULATION (MEDAG AND SETD7), SIGNAL TRANSDUCTION (STAT1), CELL ADHESION (ITGAV), AND ENZYMATIC ACTIVITY (STS). CONCLUSIONS: ALTHOUGH EXPLORATORY, PRESENT FINDINGS ARE IN AGREEMENT WITH THE ROLE OF INFLAMMATION MODULATORS IN THE HOMEOSTASIS OF NORMAL BREAST TISSUE AND THE BELIEVE THAT AN INCREASE IN BODY ADIPOSE TISSUE MAY HAVE A POTENTIALLY DANGEROUS LOCAL EFFECT, THROUGH THE INCREASED EXPRESSION OF INFLAMMATION-RELATED GENES AND THE ESTABLISHMENT OF A LOW-GRADE CHRONIC INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 1587  36 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 2620  40 EPIGENOME-WIDE ASSOCIATION DATA IMPLICATES DNA METHYLATION-MEDIATED GENETIC RISK IN PSORIASIS. BACKGROUND: PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPROLIFERATION AND ALTERED KERATINOCYTE DIFFERENTIATION AND INFLAMMATION AND IS CAUSED BY THE INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. PREVIOUS STUDIES HAVE REVEALED THAT DNA METHYLATION (DNAM) AND GENETIC MAKERS ARE CLOSELY ASSOCIATED WITH PSORIASIS, AND STRONG EVIDENCES HAVE SHOWN THAT DNAM CAN BE CONTROLLED BY GENETIC FACTORS, WHICH ATTRACTED US TO EVALUATE THE RELATIONSHIP AMONG DNAM, GENETIC MAKERS, AND DISEASE STATUS. METHODS: WE UTILIZED THE GENOME-WIDE METHYLATION DATA OF PSORIATIC SKIN (PP, N = 114) AND UNAFFECTED CONTROL SKIN (NN, N = 62) TISSUE SAMPLES IN OUR PREVIOUS STUDY, AND WE PERFORMED WHOLE-GENOME GENOTYPING WITH PERIPHERAL BLOOD OF THE SAME SAMPLES TO EVALUATE THE UNDERLYING GENETIC EFFECT ON SKIN DNA METHYLATION. CAUSAL INFERENCE TEST (CIT) WAS USED TO ASSESS WHETHER DNAM REGULATE GENETIC VARIATION AND GAIN A BETTER UNDERSTANDING OF THE EPIGENETIC BASIS OF PSORIASIS SUSCEPTIBILITY. RESULTS: WE IDENTIFIED 129 SNP-CPG PAIRS ACHIEVING THE SIGNIFICANT ASSOCIATION THRESHOLD, WHICH CONSTITUTED 28 UNIQUE METHYLATION QUANTITATIVE TRAIT LOCI (METHQTL) AND 34 UNIQUE CPGS. THERE ARE 18 SNPS WERE ASSOCIATED WITH PSORIASIS AT A BONFERONI-CORRECTED P < 0.05, AND THESE 18 SNPS FORMED 93 SNP-CPG PAIRS WITH 17 UNIQUE CPG SITES. WE FOUND THAT 11 OF 93 SNP-CPG PAIRS, COMPOSED OF 5 UNIQUE SNPS AND 3 CPG SITES, PRESENTED A METHYLATION-MEDIATED RELATIONSHIP BETWEEN SNPS AND PSORIASIS. THE 3 CPG SITES WERE LOCATED ON THE BODY OF C1ORF106, THE TSS1500 PROMOTER REGION OF DMBX1 AND THE BODY OF SIK3. CONCLUSIONS: THIS STUDY REVEALED THAT DNAM OF SOME GENES CAN BE CONTROLLED BY GENETIC FACTORS AND ALSO MEDIATE RISK VARIATION FOR PSORIASIS IN CHINESE HAN POPULATION AND PROVIDED NOVEL MOLECULAR INSIGHTS INTO THE PATHOGENESIS OF PSORIASIS.	2016	
                                                                                                                                                                                                                                                                                
17 2957  30 GENETIC AND EPIGENETIC IMPACT OF CHRONIC INFLAMMATION ON COLON MUCOSA CELLS. CHRONIC INFLAMMATION INCREASES CANCER RISK, AND CANCER DEVELOPMENT IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. DURING CHRONIC INFLAMMATION, INFECTIOUS AGENTS AND INTRINSIC MEDIATORS OF INFLAMMATORY RESPONSES CAN INDUCE GENETIC AND EPIGENETIC CHANGES. THIS STUDY TRIED TO EVALUATE BOTH THE GENETIC AND EPIGENETIC INFLUENCE OF CHRONIC INFLAMMATION ON COLON MUCOSA CELLS. REPETITIVE DEXTRAN SULFATE SODIUM (DSS) TREATMENT INDUCED CHRONIC COLITIS MODEL. WHOLE-EXOME SEQUENCING (WES) (200X COVERAGE) WAS PERFORMED TO DETECT SOMATIC VARIATIONS IN COLON MUCOSA CELLS. WITH THE USE OF WHOLE-GENOME BISULFITE SEQUENCING (BS) AT 34-FOLD COVERAGE (17-FOLD PER STRAND), THE METHYLOME OF BOTH THE COLITIS AND CONTROL TISSUE WAS COMPARATIVELY ANALYZED. BIOINFORMATICS ASSAY SHOWED THAT THERE WAS NO SIGNIFICANT SINGLE-NUCLEOTIDE POLYMORPHISM/INSERTION OR DELETION (SNP/INDEL) MUTATION ACCUMULATION IN COLITIS TISSUE, WHILE IT ACCUMULATED IN AGED MICE. FORTY-EIGHT GENES WITH SNP/INDEL MUTATION WERE OVERLAPPED IN THE THREE COLITIS TISSUES, TWO (WNT3A AND LAMA2) OF WHICH ARE IN THE CANCER DEVELOPMENT-RELATED SIGNALING PATHWAY. DIFFERENTIALLY METHYLATED REGION (DMR) ASSAY SHOWED THAT MANY GENES IN THE COLITIS TISSUE ARE ENRICHED IN THE CANCER DEVELOPMENT-RELATED SIGNALING PATHWAY, SUCH AS PI3K-AKT, RAS, WNT, TGF-BETA, AND MAPK SIGNALING PATHWAY. TOGETHER, THESE DATA SUGGESTED THAT EVEN THOUGH CHRONIC INFLAMMATION DID NOT OBVIOUSLY INCREASE GENETIC MUTATION ACCUMULATION, IT COULD BOTH GENETICALLY AND EPIGENETICALLY ALTER SOME GENES RELATED TO CANCER DEVELOPMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18 2024  31 EPIGENETIC CHANGES CAUSED BY DIABETES AND THEIR POTENTIAL ROLE IN THE DEVELOPMENT OF PERIODONTITIS. AIMS/INTRODUCTION: PERIODONTAL DISEASE, A CHRONIC INFLAMMATION INDUCED BY BACTERIA, IS CLOSELY LINKED WITH DIABETES MELLITUS. MANY COMPLICATIONS ASSOCIATED WITH DIABETES ARE RELATED TO EPIGENETIC CHANGES. HOWEVER, THE EXACT EPIGENETIC CHANGES WHEREBY DIABETES AFFECTS PERIODONTAL DISEASE REMAIN LARGELY UNKNOWN. THUS, WE SOUGHT TO INVESTIGATE THE ROLE OF DIABETES-DEPENDENT EPIGENETIC CHANGES OF GINGIVAL TISSUE IN THE SUSCEPTIBILITY TO PERIODONTAL DISEASE. MATERIALS AND METHODS: WE STUDIED THE EFFECT OF STREPTOZOTOCIN-INDUCED DIABETES IN MINIPIGS ON GINGIVAL MORPHOLOGICAL AND EPIGENETIC TISSUE CHANGES. ACCORDINGLY, WE RANDOMLY DIVIDED SIX MINIPIGS INTO TWO GROUPS: STREPTOZOTOCIN-INDUCED DIABETES GROUP, N = 3; AND NON-DIABETES HEALTHY CONTROL GROUP, N = 3. AFTER 85 DAYS, ALL ANIMALS WERE KILLED, AND GINGIVAL TISSUE WAS COLLECTED FOR HISTOLOGY, DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS AND IMMUNOHISTOCHEMISTRY. RESULTS: A DIABETES MELLITUS MODEL WAS SUCCESSFULLY CREATED, AS EVIDENCED BY SIGNIFICANTLY INCREASED BLOOD GLUCOSE LEVELS, REDUCTION OF PANCREATIC INSULIN-PRODUCING BETA-CELLS AND HISTOPATHOLOGICAL CHANGES IN THE KIDNEYS. THE GINGIVAL TISSUES IN THE DIABETES GROUP PRESENTED ACANTHOSIS OF BOTH GINGIVAL SQUAMOUS EPITHELIUM AND SULCULAR/JUNCTIONAL EPITHELIUM, AND A SIGNIFICANT REDUCTION IN THE NUMBER AND LENGTH OF RETE PEGS. DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS SHOWED A TOTAL OF 1,163 AFFECTED GENES, OF WHICH 599 AND 564 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY. IMMUNOHISTOCHEMISTRY STAINING SHOWED THAT THE HYPOMETHYLATED GENES - TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-6 - WERE POSITIVELY EXPRESSED UNDER THE JUNCTIONAL EPITHELIUM AREA IN THE DIABETES GROUP. CONCLUSIONS: DIABETES MELLITUS INDUCES MORPHOLOGICAL AND EPIGENETIC CHANGES IN PERIODONTAL TISSUE, WHICH MIGHT CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PERIODONTAL DISEASES IN PATIENTS WITH DIABETES.	2021	
                                                                                                                                                                                                     
19 3069  28 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC CHANGES IN CD4+ AND CD14+ CELLS OF MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE AND DEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, WHICH DEVELOPS IN GENETICALLY PREDISPOSED INDIVIDUALS UPON EXPOSURE TO ENVIRONMENTAL INFLUENCES. ENVIRONMENTAL TRIGGERS OF MS, SUCH AS VIRAL INFECTIONS OR SMOKING, WERE DEMONSTRATED TO AFFECT DNA METHYLATION, AND THUS TO INVOLVE THIS IMPORTANT EPIGENETIC MECHANISM IN THE DEVELOPMENT OF PATHOLOGICAL PROCESS. TO IDENTIFY MS-ASSOCIATED DNA METHYLATION HALLMARKS, WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING OF TWO CELL POPULATIONS (CD4+ T-LYMPHOCYTES AND CD14+ MONOCYTES), COLLECTED FROM THE SAME TREATMENT-NAIVE RELAPSING-REMITTING MS PATIENTS AND HEALTHY SUBJECTS, USING ILLUMINA 450 K METHYLATION ARRAYS. WE REVEALED SIGNIFICANT CHANGES IN DNA METHYLATION FOR BOTH CELL POPULATIONS IN MS. IN CD4+ CELLS OF MS PATIENTS THE MAJORITY OF DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE SHOWN TO BE HYPOMETHYLATED, WHILE IN CD14+ CELLS - HYPERMETHYLATED. DIFFERENTIAL METHYLATION OF HLA-DRB1 GENE IN CD4+ AND CD14+ CELLS WAS ASSOCIATED WITH CARRIAGE OF DRB1*15 ALLELE INDEPENDENTLY FROM THE DISEASE STATUS. BESIDES, ABOUT 20% OF IDENTIFIED DMPS WERE SHARED BETWEEN TWO CELL POPULATIONS AND HAD THE SAME DIRECTION OF METHYLATION CHANGES; THEY MAY BE INVOLVED IN BASIC EPIGENETIC PROCESSES OCCURING IN MS. THESE FINDINGS SUGGEST THAT THE EPIGENETIC MECHANISM OF DNA METHYLATION IN IMMUNE CELLS CONTRIBUTES TO MS; FURTHER STUDIES ARE NOW REQUIRED TO VALIDATE THESE RESULTS AND UNDERSTAND THEIR FUNCTIONAL SIGNIFICANCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20 3954  25 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES.	2021