1  1908 163 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH CHRONIC POSTSURGICAL PAIN AND ANXIETY IN CHILDREN: A PROSPECTIVE, PILOT STUDY. WE HAVE REPORTED CHILD ANXIETY SENSITIVITY (CHILD ANXIETY SENSITIVITY INDEX [CASI]) PREDICTS CHRONIC POSTSURGICAL PAIN (CPSP). HEREIN, WE EVALUATED DNA METHYLATION PROFILES TO UNDERSTAND THE GENE-ENVIRONMENT INTERACTIONS UNDERLYING CPSP AND CASI, TO IDENTIFY SHARED, ENRICHED, GENOMIC PATHWAYS. IN 73 PROSPECTIVELY RECRUITED ADOLESCENTS UNDERGOING SPINE FUSION, PREOPERATIVE CASI AND PAIN DATA OVER 12 MONTHS AFTER SURGERY WERE COLLECTED. DNA FROM THE PERIPHERAL BLOOD OF EVALUABLE SUBJECTS WITH (N = 16) AND WITHOUT CPSP (N = 40) WERE ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 637 AND 2,445 DIFFERENTIALLY DNA METHYLATED POSITIONS (DMPS) ASSOCIATED WITH CPSP AND CASI, RESPECTIVELY (P </= .05). INGENUITY PATHWAY ANALYSIS OF 39 GENES WITH DMPS FOR BOTH CPSP AND CASI REVEALED ENRICHMENT OF SEVERAL CANONICAL PATHWAYS, INCLUDING GABA RECEPTOR (P = .00016 FOR CPSP; P =.0008 FOR CASI) AND DOPAMINE-DARPP32 FEEDBACK IN CYCLIC ADENOSINE MONOPHOSPHATE (P = .004 FOR CPSP AND P =.00003 FOR CASI) SIGNALING. GENE-GENE INTERACTION NETWORK ENRICHMENT ANALYSIS REVEALED PARTICIPATION OF PATHWAYS IN CELL SIGNALING, MOLECULAR TRANSPORT, METABOLISM, AND NEUROLOGIC DISEASES (P < 10(-8)). BIOINFORMATIC APPROACHES TO IDENTIFY HISTONE MARKS AND TRANSCRIPTION FACTOR (TF) BINDING EVENTS UNDERLYING DMPS, SHOWED THEIR LOCATION IN ACTIVE REGULATORY REGIONS IN PAIN PATHWAY RELEVANT BRAIN CELLS. USING ENRICHR/PINET ENRICHMENT AND LIBRARY OF INTEGRATED NETWORK-BASED CELLULAR SIGNATURES KNOCKDOWN SIGNATURES, WE IDENTIFIED TFS REGULATING GENES WITH DMPS IN ASSOCIATION WITH CPSP AND CASI. IN CONCLUSION, WE IDENTIFIED EPIGENETICALLY ENRICHED PATHWAYS ASSOCIATED WITH CPSP AND ANXIETY SENSITIVITY IN CHILDREN UNDERGOING SURGERY. OUR FINDINGS SUPPORT GABA HYPOFUNCTION AND THE ROLES OF THE DOPAMINE-DARPP32 PATHWAY IN EMOTION/REWARD AND PAIN. THIS PILOT STUDY PROVIDES NEW EPIGENETIC INSIGHTS INTO THE PATHOPHYSIOLOGY OF CPSP AND A BASIS FOR FUTURE STUDIES IN BIOMARKER DEVELOPMENT AND TARGETABLE INTERVENTIONS. PERSPECTIVE: DIFFERENTIAL DNA METHYLATION IN REGULATORY GENOMIC REGIONS ENRICHING SHARED NEURAL PATHWAYS WERE ASSOCIATED WITH CPSP AND CASI IN ADOLESCENTS UNDERGOING SPINE SURGERY. OUR FINDINGS SUPPORT GABA HYPOFUNCTION AND THE ROLES OF THE DOPAMINE-DARPP32 PATHWAY IN EMOTION/REWARD CONTRIBUTING TO BEHAVIORAL MAINTENANCE OF PAIN 10 TO 12 MONTHS AFTER SURGERY.	2019	
                                                                                                                                                                                                                                                                                                                           
2  3075  33 GENOME-WIDE EPIGENETIC STUDY OF CHRONIC RHINOSINUSITIS TISSUES REVEALS DYSREGULATED INFLAMMATORY, IMMUNOLOGIC AND REMODELING PATHWAYS. BACKGROUND: EPIGENETICS STUDIES MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS, AND ALTERNATIVE POLYADENYLATION THAT CAN MODIFY GENE ACTIVITY WITHOUT CHANGING THE UNDERLYING DNA NUCLEOTIDE BASE-PAIR STRUCTURE. BECAUSE THESE CHANGES ARE REVERSIBLE, THEY HAVE POTENTIAL IN DEVELOPING NOVEL THERAPEUTICS. CURRENTLY, SEVEN PHARMACEUTICAL AGENTS TARGETING EPIGENETIC CHANGES ARE FDA APPROVED AND COMMERCIALLY AVAILABLE FOR TREATMENT OF CERTAIN CANCERS. HOWEVER, STUDIES INVESTIGATING EPIGENETICS IN CHRONIC RHINOSINUSITIS (CRS) HAVE NOT BEEN UNDERTAKEN PREVIOUSLY IN THE UNITED STATES. OBJECTIVES: THE GOAL OF THIS STUDY WAS TO INVESTIGATE SINONASAL DNA METHYLATION PATTERNS IN CRS VERSUS CONTROLS, TO DISCERN ENVIRONMENTALLY-INDUCED EPIGENETIC CHANGES IMPACTING CRS SUBJECTS. METHODS AND RESULTS: ETHMOIDAL SAMPLES FROM CRS AND INFERIOR TURBINATE MUCOSAL TISSUE SAMPLES FROM CONTROLS WITHOUT CRS WERE STUDIED. DNA METHYLATION WAS STUDIED BY REDUCED REPRESENTATION BISULFITE SEQUENCING. RADMETH(R) BIOSTATISTICAL PACKAGE WAS USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) BETWEEN CRS AND CONTROLS. INGENUITY PATHWAY ANALYSIS OF DMRS WAS PERFORMED TO IDENTIFY TOP UPSTREAM REGULATORS AND CANONICAL PATHWAYS. NINETY-THREE SAMPLES FROM 64 CRS SUBJECTS (36 CRSWNP; 28 CRSSNP) AND 29 CONTROLS WERE STUDIED. CRS AND CONTROL SAMPLES DIFFERED IN 13 662 CPGS SITES AND 1381 DMRS. TOP UPSTREAM REGULATORS IDENTIFIED INCLUDED: 1. CRS VERSUS CONTROLS: TGFB1, TNF, TP53, DGCR8, AND BETA-ESTRADIOL. 2. CRSWNP VERSUS CONTROLS: TGFB1, CTNNB1, LIPOPOLYSACCHARIDE, ID2, AND TCF7L2. 3. CRSSNP VERSUS CONTROLS: MYOD1, ACETONE, ID2, ST8SIA4, AND LEPR. CONCLUSIONS: DIFFERENTIAL PATTERNS OF METHYLATION WERE IDENTIFIED BETWEEN CONTROLS AND CRS, CRSWNP, AND CRSSNP. EPIGENETIC, ENVIRONMENTALLY-INDUCED CHANGES RELATED TO NOVEL, INFLAMMATORY, IMMUNOLOGIC, AND REMODELING PATHWAYS APPEAR TO AFFECT EPITHELIAL INTEGRITY, CELL PROLIFERATION, HOMEOSTASIS, VASCULAR PERMEABILITY, AND OTHER YET UNCHARACTERIZED PATHWAYS AND GENES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  1910  59 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH KNEE OSTEOARTHRITIS PAIN. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (I.E., GENOMIC REGION WHERE MULTIPLE ADJACENT CPG SITES SHOW DIFFERENTIAL METHYLATION) AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH KNEE OSTEOARTHRITIS PAIN (KOA). WE RECRUITED COGNITIVELY HEALTHY MIDDLE TO OLDER AGED (AGE 45-85) ADULTS WITH (N = 182) AND WITHOUT (N = 31) SELF-REPORTED KOA PAIN. WE ALSO EXTRACTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. THE R PACKAGE MINFI (ARYEE ET AL., 2014) WAS USED TO PERFORM METHYLATION DATA PREPROCESSING AND QUALITY CONTROL. TO INVESTIGATE BIOLOGICAL PATHWAYS IMPACTED BY DIFFERENTIAL METHYLATION, WE PERFORMED PATHWAY ENRICHMENT ANALYSIS USING INGENUITY PATHWAY ANALYSIS (IPA) TO IDENTIFY CANONICAL PATHWAYS AND UPSTREAM REGULATORS. ANNOTATED GENES WITHIN +/- 5 KB OF THE PUTATIVE DIFFERENTIALLY METHYLATED REGIONS (DMRS, P < 0.05) WERE SUBJECTED TO THE IPA ANALYSIS. THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE, SEX, STUDY SITE BETWEEN NO PAIN AND PAIN GROUP (P > 0.05). NON-HISPANIC BLACK INDIVIDUALS WERE OVERREPRESENTED IN THE PAIN GROUP (P = 0.003). AT RAW P < 0.05 CUTOFF, WE IDENTIFIED A TOTAL OF 19,710 CPG PROBES, INCLUDING 13,951 HYPERMETHYLATED CPG PROBES, FOR WHICH DNA METHYLATION LEVEL WAS HIGHER IN THE GROUPS WITH HIGHEST PAIN GRADES. WE ALSO IDENTIFIED 5,759 HYPOMETHYLATED CPG PROBES FOR WHICH DNA METHYLATION LEVEL WAS LOWER IN THE PAIN GROUPS WITH HIGHER PAIN GRADES. IPA REVEALED THAT PAIN-RELATED DMRS WERE ENRICHED ACROSS MULTIPLE PATHWAYS AND UPSTREAM REGULATORS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E., ANTIGEN PRESENTATION, PD-1, PD-L1 CANCER IMMUNOTHERAPY, B CELL DEVELOPMENT, IL-4 SIGNALING, TH1 AND TH2 ACTIVATION PATHWAY, AND PHAGOSOME MATURATION). MOREOVER, IN TERMS OF UPSTREAM REGULATORS, NDUFAF3 WAS THE MOST SIGNIFICANT (P = 8.6E-04) UPSTREAM REGULATOR. OUR FINDINGS SUPPORT PREVIOUS PRELIMINARY WORK SUGGESTING THE IMPORTANCE OF EPIGENETIC REGULATION OF THE IMMUNE SYSTEM IN KNEE PAIN AND THE NEED FOR FUTURE WORK TO UNDERSTAND THE EPIGENETIC CONTRIBUTIONS TO CHRONIC PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  6368  37 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  3460  30 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  1788  32 EFFECT OF CHRONIC ETHANOL CONSUMPTION IN RHESUS MACAQUES ON THE NUCLEUS ACCUMBENS CORE TRANSCRIPTOME. THE NUCLEUS ACCUMBENS CORE (NACC) HAS BEEN REPEATEDLY DEMONSTRATED TO BE A KEY COMPONENT OF THE CIRCUITRY ASSOCIATED WITH EXCESSIVE ETHANOL CONSUMPTION. PREVIOUS STUDIES HAVE ILLUSTRATED THAT IN A NONHUMAN PRIMATE (NHP) MODEL OF CHRONIC ETHANOL CONSUMPTION, THERE IS SIGNIFICANT EPIGENETIC REMODELING OF THE NACC. IN THE CURRENT STUDY, RNA-SEQ WAS USED TO EXAMINE GENOME-WIDE GENE EXPRESSION IN EIGHT EACH OF CONTROL, LOW/BINGE (LD*), AND HIGH/VERY HIGH (HD*) RHESUS MACAQUE DRINKERS. USING AN FDR < 0.05, ZERO GENES WERE SIGNIFICANTLY DIFFERENTIALLY EXPRESSED (DE) BETWEEN LD* AND CONTROLS, SIX GENES BETWEEN HD* AND LD*, AND 734 GENES BETWEEN HD* AND CONTROLS. FOCUSING ON HD* VERSUS CONTROL DE GENES, THE UPREGULATED GENES (N = 366) WERE ENRICHED IN GENES WITH ANNOTATIONS ASSOCIATED WITH SIGNAL RECOGNITION PARTICLE (SRP)-DEPENDENT CO-TRANSLATIONAL PROTEIN TARGETING TO MEMBRANE (FDR < 3 X 10(-59) ), STRUCTURAL CONSTITUENT OF RIBOSOME (FDR < 3 X 10(-47) ), AND RIBOSOMAL SUBUNIT (FDR < 5 X 10(-48) ). DOWNREGULATED GENES (N = 363) WERE ENRICHED IN ANNOTATIONS ASSOCIATED WITH BEHAVIOR (FDR < 2 X 10(-4) ), MEMBRANE ORGANIZATION (FDR < 1 X 10(-4) ), INORGANIC CATION TRANSMEMBRANE TRANSPORTER ACTIVITY (FDR < 2 X 10(-3) ), SYNAPSE PART (FDR < 4 X 10(-10) ), GLUTAMATERGIC SYNAPSE (FDR < 1 X 10(-6) ), AND GABAERGIC SYNAPSE (FDR < 6 X 10(-4) ). INGENUITY PATHWAY ANALYSIS (IPA) REVEALED THAT EIF2 SIGNALING AND MTOR PATHWAYS WERE SIGNIFICANTLY UPREGULATED IN HD* ANIMALS (FDR < 3 X 10(-33) AND <2 X 10(-16) , RESPECTIVELY). OVERALL, THE DATA SUPPORTED OUR WORKING HYPOTHESIS; EXCESSIVE CONSUMPTION WOULD BE ASSOCIATED WITH TRANSCRIPTIONAL DIFFERENCES IN GABA/GLUTAMATE-RELATED GENES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7   972  45 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  2406  36 EPIGENETIC RESPONSES TO RHINOVIRUS EXPOSURE IN AIRWAY EPITHELIAL CELLS ARE CORRELATED WITH KEY TRANSCRIPTIONAL PATHWAYS IN CHRONIC RHINOSINUSITIS. BACKGROUND: VIRUSES MAY DRIVE IMMUNE MECHANISMS RESPONSIBLE FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSWNP), BUT LITTLE IS KNOWN ABOUT THE UNDERLYING MOLECULAR MECHANISMS. OBJECTIVES: TO IDENTIFY EPIGENETIC AND TRANSCRIPTIONAL RESPONSES TO A COMMON UPPER RESPIRATORY PATHOGEN, RHINOVIRUS (RV), THAT ARE SPECIFIC TO PATIENTS WITH CRSWNP USING A PRIMARY SINONASAL EPITHELIAL CELL CULTURE MODEL. METHODS: AIRWAY EPITHELIAL CELLS WERE COLLECTED AT SURGERY FROM PATIENTS WITH CRSWNP (CASES) AND FROM CONTROLS WITHOUT SINUS DISEASE, CULTURED, AND THEN EXPOSED TO RV OR VEHICLE FOR 48 H. DIFFERENTIAL GENE EXPRESSION AND DNA METHYLATION (DNAM) BETWEEN CASES AND CONTROLS IN RESPONSE TO RV WERE DETERMINED USING LINEAR MIXED MODELS. WEIGHTED GENE CO-EXPRESSION ANALYSIS (WGCNA) WAS USED TO IDENTIFY (A) CO-REGULATED GENE EXPRESSION AND DNAM SIGNATURES, AND (B) GENES, PATHWAYS, AND REGULATORY MECHANISMS SPECIFIC TO CRSWNP. RESULTS: WE IDENTIFIED 5585 DIFFERENTIAL TRANSCRIPTIONAL AND 261 DNAM RESPONSES (FDR <0.10) TO RV BETWEEN CRSWNP CASES AND CONTROLS. THESE DIFFERENTIAL RESPONSES FORMED THREE CO-EXPRESSION/CO-METHYLATION MODULES THAT WERE RELATED TO CRSWNP AND THREE THAT WERE RELATED TO RV (BONFERRONI CORRECTED P < .01). MOST (95%) OF THE DIFFERENTIALLY METHYLATED CPGS (DMCS) WERE IN MODULES RELATED TO CRSWNP, WHEREAS THE DIFFERENTIALLY EXPRESSED GENES (DEGS) WERE MORE EQUALLY DISTRIBUTED BETWEEN THE CRSWNP- AND RV-RELATED MODULES. GENES IN THE CRSWNP-RELATED MODULES WERE ENRICHED IN KNOWN CRS AND/OR VIRAL RESPONSE IMMUNE PATHWAYS. CONCLUSION: RV ACTIVATES SPECIFIC EPIGENETIC PROGRAMS AND CORRELATED TRANSCRIPTIONAL NETWORKS IN THE SINONASAL EPITHELIUM OF INDIVIDUALS WITH CRSWNP. THESE NOVEL OBSERVATIONS SUGGEST EPIGENETIC SIGNATURES SPECIFIC TO PATIENTS WITH CRSWNP MODULATE RESPONSE TO VIRAL PATHOGENS AT THE MUCOSAL ENVIRONMENTAL INTERFACE. DETERMINING HOW VIRAL RESPONSE PATHWAYS ARE INVOLVED IN EPITHELIAL INFLAMMATION IN CRSWNP COULD LEAD TO THERAPEUTIC TARGETS FOR THIS BURDENSOME AIRWAY DISORDER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  3070  39 GENOME-WIDE DNA METHYLATION PROFILING IN CD8 T-CELLS AND GAMMA DELTA T-CELLS OF ASIAN INDIAN PATIENTS WITH TAKAYASU ARTERITIS. BACKGROUND: TAKAYASU'S ARTERITIS (TA) IS A CHRONIC INFLAMMATORY DISEASE THAT AFFECTS AORTA AND ITS MAIN BRANCHES AT THEIR ORIGIN. GENETIC, PATHOLOGICAL AND FUNCTIONAL STUDIES HAVE SHOWN THAT CD8 AND GAMMA DELTA (GAMMA/DELTA) T-LYMPHOCYTES ARE INVOLVED IN INFLAMMATORY PROCESSES IN AFFECTED REGIONS OF ARTERIES CAUSING VASCULAR DAMAGE. THE MOLECULAR FUNCTION OF THESE LYMPHOCYTES REMAINS UNCLEAR AND CURRENTLY NO EPIGENETIC STUDIES ARE AVAILABLE IN TA. WE PRIMARILY PERFORMED GENOME WIDE METHYLATION ANALYSIS IN CD8 T CELLS AND GAMMADELTA T CELLS OF PATIENTS WITH TA AND COMPARED WITH HEALTHY CONTROLS. METHODS: WE RECRUITED 12 SUBJECTS IN EACH GROUP NAMELY TA PATIENT AND HEALTHY CONTROLS. BLOOD SAMPLES WERE COLLECTED AFTER OBTAINING INFORMED WRITTEN CONSENT. CD8 T CELLS AND GAMMADELTA T CELLS WERE SEPARATED FROM WHOLE BLOOD. DNA EXTRACTED FROM THESE CELLS AND WERE SUBJECTED TO BISULFITE TREATMENT. FINALLY, BISULFITE TREATED DNA WAS LOADED IN INFINIUM METHYLATION EPIC ARRAY. BIOINFORMATICS ANALYSIS WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS WHICH WERE THEN MAPPED TO GENES. RESULTS: INTERLEUKIN (IL)-32 AND LYMPHOTOXIN-A WERE GENES SIGNIFICANTLY HYPOMETHYLATED IN CD8 T-CELLS. ANTI-INFLAMMATORY CYTOKINE GENES, IL-10, IL-1RN AND IL-27 WERE HYPOMETHYLATED IN GAMMADELTA T CELLS OF TA PATIENTS AS COMPARED TO HEALTHY CONTROLS. GENE ENRICHMENT ANALYSIS USING GENE ONTOLOGY (GO) DATABASE AND KYOTO ENCYCLOPAEDIA OF GENES AND GENOMES (KEGG) IDENTIFIED THAT GENES INVOLVED IN T-CELL RECEPTOR SIGNALLING PATHWAYS WERE HYPOMETHYLATED IN CD8 T-CELLS AND HYPERMETHYLATED IN GAMMADELTA T CELLS OF TA PATIENTS. CONCLUSION: CD8 T-CELLS MIGHT PLAY A MAJOR ROLE IN IMMUNOPATHOGENESIS OF INFLAMMATION IN TA, WHEREAS GAMMADELTA T CELLS MAY PLAY A REGULATORY ROLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  3056  38 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                           
11   812  45 CHANGES IN DNA METHYLATION PROFILES OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME PATIENTS REFLECT SYSTEMIC DYSFUNCTIONS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A LIFELONG DEBILITATING DISEASE WITH A COMPLEX PATHOLOGY NOT YET CLEARLY DEFINED. SUSCEPTIBILITY TO ME/CFS INVOLVES GENETIC PREDISPOSITION AND EXPOSURE TO ENVIRONMENTAL FACTORS, SUGGESTING AN EPIGENETIC ASSOCIATION. EPIGENETIC STUDIES WITH OTHER ME/CFS COHORTS HAVE USED ARRAY-BASED TECHNOLOGY TO IDENTIFY DIFFERENTIALLY METHYLATED INDIVIDUAL SITES. CHANGES IN RNA QUANTITIES AND PROTEIN ABUNDANCE HAVE BEEN DOCUMENTED IN OUR PREVIOUS INVESTIGATIONS WITH THE SAME ME/CFS COHORT USED FOR THIS STUDY. RESULTS: DNA FROM A WELL-CHARACTERISED NEW ZEALAND COHORT OF 10 ME/CFS PATIENTS AND 10 AGE-/SEX-MATCHED HEALTHY CONTROLS WAS ISOLATED FROM PERIPHERAL BLOOD MONONUCLEAR (PBMC) CELLS, AND USED TO GENERATE REDUCED GENOME-SCALE DNA METHYLATION MAPS USING REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS). THE SEQUENCING DATA WERE ANALYSED UTILISING THE DMAP ANALYSIS PIPELINE TO IDENTIFY DIFFERENTIALLY METHYLATED FRAGMENTS, AND THE METHYLKIT PIPELINE WAS USED TO QUANTIFY METHYLATION DIFFERENCES AT INDIVIDUAL CPG SITES. DMAP IDENTIFIED 76 DIFFERENTIALLY METHYLATED FRAGMENTS AND METHYLKIT IDENTIFIED 394 DIFFERENTIALLY METHYLATED CYTOSINES THAT INCLUDED BOTH HYPER- AND HYPO-METHYLATION. FOUR CLUSTERS WERE IDENTIFIED WHERE DIFFERENTIALLY METHYLATED DNA FRAGMENTS OVERLAPPED WITH OR WERE WITHIN CLOSE PROXIMITY TO MULTIPLE DIFFERENTIALLY METHYLATED INDIVIDUAL CYTOSINES. THESE CLUSTERS IDENTIFIED REGULATORY REGIONS FOR 17 PROTEIN ENCODING GENES RELATED TO METABOLIC AND IMMUNE ACTIVITY. ANALYSIS OF DIFFERENTIALLY METHYLATED GENE BODIES (EXONS/INTRONS) IDENTIFIED 122 UNIQUE GENES. COMPARISON WITH OTHER STUDIES ON PBMCS FROM ME/CFS PATIENTS AND CONTROLS WITH ARRAY TECHNOLOGY SHOWED 59% OF THE GENES IDENTIFIED IN THIS STUDY WERE ALSO FOUND IN ONE OR MORE OF THESE STUDIES. FUNCTIONAL PATHWAY ENRICHMENT ANALYSIS IDENTIFIED 30 ASSOCIATED PATHWAYS. THESE INCLUDED IMMUNE, METABOLIC AND NEUROLOGICAL-RELATED FUNCTIONS DIFFERENTIALLY REGULATED IN ME/CFS PATIENTS COMPARED TO THE MATCHED HEALTHY CONTROLS. CONCLUSIONS: MAJOR DIFFERENCES WERE IDENTIFIED IN THE DNA METHYLATION PATTERNS OF ME/CFS PATIENTS THAT CLEARLY DISTINGUISHED THEM FROM THE HEALTHY CONTROLS. OVER HALF FOUND IN GENE BODIES WITH RRBS IN THIS STUDY HAD BEEN IDENTIFIED IN OTHER ME/CFS STUDIES USING THE SAME CELLS BUT WITH ARRAY TECHNOLOGY. WITHIN THE ENRICHED FUNCTIONAL IMMUNE, METABOLIC AND NEUROLOGICAL PATHWAYS, A NUMBER OF ENRICHED NEUROTRANSMITTER AND NEUROPEPTIDE REACTOME PATHWAYS HIGHLIGHTED A DISTURBED NEUROLOGICAL PATHOPHYSIOLOGY WITHIN THE PATIENT GROUP.	2020	
                                                                                                       
12  3496  44 IDENTIFICATION OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME-ASSOCIATED DNA METHYLATION PATTERNS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX CONDITION INVOLVING MULTIPLE ORGAN SYSTEMS AND CHARACTERIZED BY PERSISTENT/RELAPSING DEBILITATING FATIGUE, IMMUNE DYSFUNCTION, NEUROLOGICAL PROBLEMS, AND OTHER SYMPTOMS NOT CURABLE FOR AT LEAST 6 MONTHS. DISRUPTION OF DNA METHYLATION PATTERNS HAS BEEN TIED TO VARIOUS IMMUNE AND NEUROLOGICAL DISEASES; HOWEVER, ITS STATUS IN ME/CFS REMAINS UNCERTAIN. OUR STUDY AIMED AT IDENTIFYING CHANGES IN THE DNA METHYLATION PATTERNS THAT ASSOCIATE WITH ME/CFS. METHODS: WE EXTRACTED GENOMIC DNA FROM PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 13 ME/CFS STUDY SUBJECTS AND 12 HEALTHY CONTROLS AND MEASURED GLOBAL DNA METHYLATION BY ELISA-LIKE METHOD AND SITE-SPECIFIC METHYLATION STATUS USING ILLUMINA METHYLATIONEPIC MICROARRAYS. PYROSEQUENCING VALIDATION INCLUDED 33 ME/CFS CASES AND 31 CONTROLS FROM TWO GEOGRAPHICALLY DISTANT COHORTS. RESULTS: GLOBAL DNA METHYLATION LEVELS OF ME/CFS CASES WERE SIMILAR TO THOSE OF CONTROLS. HOWEVER, MICROARRAY-BASED APPROACH ALLOWED DETECTION OF 17,296 DIFFERENTIALLY METHYLATED CPG SITES IN 6,368 GENES ACROSS REGULATORY ELEMENTS AND WITHIN CODING REGIONS OF GENES. ANALYSIS OF DNA METHYLATION IN PROMOTER REGIONS REVEALED 307 DIFFERENTIALLY METHYLATED PROMOTERS. INGENUITY PATHWAY ANALYSIS INDICATED THAT GENES ASSOCIATED WITH DIFFERENTIALLY METHYLATED PROMOTERS PARTICIPATED IN AT LEAST 15 DIFFERENT PATHWAYS MOSTLY RELATED TO CELL SIGNALING WITH A STRONG IMMUNE COMPONENT. CONCLUSIONS: THIS IS THE FIRST STUDY THAT HAS EXPLORED GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH ME/CFS USING THE ADVANCED ILLUMINA METHYLATIONEPIC MICROARRAYS COVERING ABOUT 850,000 CPG SITES IN TWO GEOGRAPHICALLY DISTANT COHORTS OF ME/CFS CASES AND MATCHED CONTROLS. OUR RESULTS ARE ALIGNED WITH PREVIOUS STUDIES THAT INDICATE A DYSREGULATION OF THE IMMUNE SYSTEM IN ME/CFS. THEY ALSO SUGGEST A POTENTIAL ROLE OF EPIGENETIC DE-REGULATION IN THE PATHOBIOLOGY OF ME/CFS. WE PROPOSE SCREENING OF LARGER COHORTS OF ME/CFS CASES TO DETERMINE THE EXTERNAL VALIDITY OF THESE EPIGENETIC CHANGES IN ORDER TO IMPLEMENT THEM AS POSSIBLE DIAGNOSTIC MARKERS IN CLINICAL SETTING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  1571  50 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT.	2021	

14  2418  36 EPIGENETIC SIGNATURE OF CHRONIC LOW BACK PAIN IN HUMAN T CELLS. OBJECTIVE: DETERMINE IF CHRONIC LOW BACK PAIN (LBP) IS ASSOCIATED WITH DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT WILL REVEAL NOVEL MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS AND EXPLORE THE FEASIBILITY OF EPIGENETIC DIAGNOSTIC MARKERS FOR PAIN-RELATED PATHOPHYSIOLOGY. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS OF 850,000 CPG SITES IN WOMEN AND MEN WITH CHRONIC LBP AND PAIN-FREE CONTROLS WAS PERFORMED. T CELLS WERE ISOLATED (DISCOVERY COHORT, N = 32) AND USED TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES, AND GENE ONTOLOGIES AND MOLECULAR PATHWAYS WERE IDENTIFIED. A POLYGENIC DNA METHYLATION SCORE FOR LBP WAS GENERATED IN BOTH WOMEN AND MEN. VALIDATION WAS PERFORMED IN AN INDEPENDENT COHORT (VALIDATION COHORT, N = 63) OF CHRONIC LBP AND HEALTHY CONTROLS. RESULTS: ANALYSIS WITH THE DISCOVERY COHORT REVEALED A TOTAL OF 2,496 AND 419 DIFFERENTIALLY METHYLATED CPGS IN WOMEN AND MEN, RESPECTIVELY. IN WOMEN, MOST OF THESE SITES WERE HYPOMETHYLATED AND ENRICHED IN GENES WITH FUNCTIONS IN THE EXTRACELLULAR MATRIX, IN THE IMMUNE SYSTEM (IE, CYTOKINES), OR IN EPIGENETIC PROCESSES. IN MEN, A UNIQUE CHRONIC LBP DNA METHYLATION SIGNATURE WAS IDENTIFIED CHARACTERIZED BY SIGNIFICANT ENRICHMENT FOR GENES FROM THE MAJOR HISTOCOMPATIBILITY COMPLEX. SEX-SPECIFIC POLYGENIC DNA METHYLATION SCORES WERE GENERATED TO ESTIMATE THE PAIN STATUS OF EACH INDIVIDUAL AND CONFIRMED IN THE VALIDATION COHORT USING PYROSEQUENCING. CONCLUSION: THIS STUDY REVEALS SEX-SPECIFIC DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT DISCRIMINATES CHRONIC LBP PARTICIPANTS FROM HEALTHY CONTROLS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15   401  33 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  3501  45 IDENTIFICATION OF POTENTIAL BIOMARKERS FOR SYSTEMIC LUPUS ERYTHEMATOSUS BY INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA. INTRODUCTION: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS AND CHRONIC AUTOIMMUNE DISEASE. ABERRANT DNA METHYLATION OCCURS DURING VARIOUS PROCESSES OF SLE DEVELOPMENT REGULATING THE MRNA EXPRESSION OF INTERRELATED GENES. THIS STUDY AIMS TO SCREEN POTENTIAL DNA METHYLATION MARKERS FOR SLE. METHODS: GENE EXPRESSION AND METHYLATION DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN SLE PATIENTS AND HEALTHY CONTROLS WERE SCREENED USING THE LIMMA R PACKAGE, AND DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND REGIONS (DMRS) WERE IDENTIFIED USING DMPFINDER AND BUMPHUNTER (MINFI). ADDITIONALLY, THE DNA METHYLATION MARKERS TO DISTINGUISH SLE PATIENTS FROM HEALTHY CONTROLS WERE EXPLORED THROUGH RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES AND LOGISTIC REGRESSION ANALYSES. FINALLY, WE VALIDATED THE RESULTS OF THE BIOINFORMATIC ANALYSIS BY PYROSEQUENCING. RESULTS: IN TOTAL, 91 DEGS, 90,092 DMPS, 15 DMRS, AND 13 DMR-ASSOCIATED GENES WERE IDENTIFIED. THROUGH THE INTEGRATIVE ANALYSIS OF DEG- AND DMR-ASSOCIATED GENES, WE IDENTIFIED FIVE TYPE I INTERFERON (IFN)-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE. GO ENRICHMENT ANALYSIS SHOWED THAT THE FIVE SLE-ASSOCIATED EPIGENETIC-DRIVEN GENES WERE MAINLY ENRICHED IN THE TYPE I IFN SIGNALING PATHWAY INVOLVED IN IMMUNE RESPONSE AND DEFENSE RESPONSE TO VIRUS. MOREOVER, WE IDENTIFIED TWO SLE-SPECIFIC DNA METHYLATION MARKERS, THREE SLE WITHOUT LUPUS NEPHRITIS (SLE-LN(-))-SPECIFIC DNA METHYLATION MARKERS, AND TWO SLE WITH LUPUS NEPHRITIS (SLE-LN(+))-SPECIFIC DNA METHYLATION MARKERS BY STEPWISE LOGISTIC REGRESSION. CONCLUSIONS: OVERALL, OUR STUDY DEMONSTRATES POTENTIAL DNA METHYLATION MARKERS OF SLE, SLE-LN(-), AND SLE-LN(+), WHICH MAY HELP THE DIAGNOSIS, BOOST THE DEVELOPMENT OF NEW EPIGENETIC THERAPY, AND CONTRIBUTE TO INDIVIDUALIZED TREATMENT. KEY POINTS * THIS STUDY IDENTIFIED FIVE TYPE I IFN-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE, WHICH SUPPORT THE IMPORTANCE OF THE TYPE I IFN PATHWAY IN THE PATHOGENESIS OF SLE * WE IDENTIFIED NOVEL DNA METHYLATION BIOMARKERS IN SLE, SLE-LN-, AND SLE-LN+ BY A COMPREHENSIVE ANALYSIS OF BIOINFORMATICS METHODS AND EXECUTED EXPERIMENTAL VALIDATION, AND BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT THEY HAVE EXCELLENT POTENTIAL * THESE RESULTS MAY PROVIDE NEW INSIGHTS INTO THE BIOLOGICAL MECHANISMS OF SLE, AND IDENTIFY RELIABLE BIOMARKERS FOR SLE, SLE-LN-, AND SLE-LN+, WHICH MAY CONTRIBUTE TO DIAGNOSIS AND INDIVIDUALIZED TREATMENT.	2023	
                                                                                                                                                                                 
17  3063  44 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  5744  28 SMOKING-INDUCED EXPRESSION OF THE GPR15 GENE INDICATES ITS POTENTIAL ROLE IN CHRONIC INFLAMMATORY PATHOLOGIES. DESPITE THE DESCRIBED CLEAR EPIGENETIC EFFECTS OF SMOKING, THE EFFECT OF SMOKING ON GENOME-WIDE GENE EXPRESSION IN THE BLOOD IS OBSCURE. WE THEREFORE STUDIED THE SMOKING-INDUCED CHANGES IN THE GENE-EXPRESSION PROFILE OF THE PERIPHERAL BLOOD. RNA WAS EXTRACTED FROM THE WHOLE BLOOD OF 48 INDIVIDUALS WITH A DETAILED SMOKING HISTORY (24 NEVER-SMOKERS, 16 SMOKERS, AND 8 EX-SMOKERS). GENE-EXPRESSION PROFILES WERE EVALUATED WITH RNA SEQUENCING, AND RESULTS WERE ANALYZED SEPARATELY IN 24 MEN AND 24 WOMEN. IN THE MALE SMOKERS, 13 GENES WERE STATISTICALLY SIGNIFICANTLY (FALSE-DISCOVERY RATE <0.1) DIFFERENTIALLY EXPRESSED; IN FEMALE SMOKERS, 5 GENES. ALTHOUGH MOST OF THE DIFFERENTIALLY EXPRESSED GENES WERE DIFFERENT BETWEEN THE MALE AND FEMALE SMOKERS, THE G-PROTEIN-COUPLED RECEPTOR 15 GENE (GPR15) WAS DIFFERENTIALLY EXPRESSED IN BOTH MALE AND FEMALE SMOKERS COMPARED WITH NEVER-SMOKERS. ANALYSIS OF GPR15 METHYLATION IDENTIFIED SIGNIFICANTLY GREATER HYPOMETHYLATION IN SMOKERS COMPARED WITH THAT IN NEVER-SMOKERS. GPR15 IS THE CHEMOATTRACTANT RECEPTOR THAT REGULATES T-CELL MIGRATION AND IMMUNITY. UP-REGULATION OF GPR15 COULD EXPLAIN TO SOME EXTENT THE HEALTH HAZARDS OF SMOKING WITH REGARD TO CHRONIC INFLAMMATORY DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  2633  38 EPIGENOME-WIDE DNA METHYLATION PATTERNS ASSOCIATED WITH FATIGUE IN PRIMARY SJOGREN'S SYNDROME. OBJECTIVE: CHRONIC FATIGUE IS A COMMON, DISABLING AND POORLY UNDERSTOOD PHENOMENON. RECENT STUDIES INDICATE THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN THE EXPRESSION OF FATIGUE, A PROMINENT FEATURE OF PRIMARY SS (PSS). THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER DNA METHYLATION PROFILES OF WHOLE BLOOD ARE ASSOCIATED WITH FATIGUE IN PATIENTS WITH PSS. METHODS: FORTY-EIGHT PSS PATIENTS WITH HIGH (N = 24) OR LOW (N = 24) FATIGUE AS MEASURED BY A VISUAL ANALOGUE SCALE WERE INCLUDED. GENOME-WIDE DNA METHYLATION WAS INVESTIGATED USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY. AFTER QUALITY CONTROL, A TOTAL OF 383 358 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES REMAINED FOR FURTHER ANALYSIS. AGE, SEX AND DIFFERENTIAL CELL COUNT ESTIMATES WERE INCLUDED AS COVARIATES IN THE ASSOCIATION MODEL. A FALSE DISCOVERY RATE-CORRECTED P < 0.05 WAS CONSIDERED SIGNIFICANT, AND A CUT-OFF OF 3% AVERAGE DIFFERENCE IN METHYLATION LEVELS BETWEEN HIGH- AND LOW-FATIGUE PATIENTS WAS APPLIED. RESULTS: A TOTAL OF 251 DIFFERENTIALLY METHYLATED CPG SITES WERE ASSOCIATED WITH FATIGUE. THE CPG SITE WITH THE MOST PRONOUNCED HYPOMETHYLATION IN PSS HIGH FATIGUE ANNOTATED TO THE SBF2-ANTISENSE RNA1 GENE. THE MOST DISTINCT HYPERMETHYLATION WAS OBSERVED AT A CPG SITE ANNOTATED TO THE LYMPHOTOXIN ALPHA GENE. FUNCTIONAL PATHWAY ANALYSIS OF GENES WITH DIFFERENTLY METHYLATED CPG SITES IN SUBJECTS WITH HIGH VS LOW FATIGUE REVEALED ENRICHMENT IN SEVERAL PATHWAYS ASSOCIATED WITH INNATE AND ADAPTIVE IMMUNITY. CONCLUSION: SOME GENES INVOLVED IN REGULATION OF THE IMMUNE SYSTEM AND IN INFLAMMATION ARE DIFFERENTLY METHYLATED IN PSS PATIENTS WITH HIGH VS LOW FATIGUE. THESE FINDINGS POINT TO FUNCTIONAL NETWORKS THAT MAY UNDERLIE FATIGUE. EPIGENETIC CHANGES COULD CONSTITUTE A FATIGUE-REGULATING MECHANISM IN PSS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  3046  38 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR.	2020