1 3142 135 GLOBAL METHYLATION PROFILES IN BUCCAL CELLS OF LONG-TERM SMOKERS AND MOIST SNUFF CONSUMERS. PURPOSE: ALTERNATIONS IN GENE METHYLATION AND OTHER EPIGENETIC CHANGES REGULATE NORMAL DEVELOPMENT AS WELL AS DRIVE DISEASE PROGRESSION. THE AIM OF THIS STUDY IS TO INVESTIGATE GLOBAL METHYLATION CHANGES IN THE BUCCAL CELLS OF SMOKERS AND SMOKELESS TOBACCO USERS. MATERIALS AND METHODS: GENERALLY HEALTHY ADULT MALE SUBJECTS WERE RECRUITED INTO SMOKER (SMK), MOIST SNUFF CONSUMER (MSC) AND NON-TOBACCO CONSUMER (NTC) COHORTS (40 SUBJECTS/COHORT) (CLINICALTRIALS.GOV IDENTIFIER: NCT01923402). GLOBAL METHYLATION PROFILING WAS PERFORMED ON ILLUMINA 450 K METHYLATION ARRAYS USING BUCCAL CELL DNAS. RESULTS: THE SMK COHORT EXHIBITED LARGER QUALITATIVE AND QUANTITATIVE CHANGES RELATIVE TO MSC. APPROXIMATELY HALF OF THE DIFFERENTIALLY METHYLATED 1252 GENE LOCI WERE GROUPED AS COMBUSTIBLE TOBACCO-RELATED (CTR) SIGNATURES AND A THIRD OF THE CHANGES, TOBACCO-RELATED (TR) SIGNATURES, WERE ASSOCIATED WITH SMOKING. VERY FEW (41) DIFFERENTIALLY METHYLATED GENE LOCI WERE EXCLUSIVELY ASSOCIATED WITH MOIST SNUFF USE AND WERE DESIGNATED AS MOIST SNUFF-RELATED (MSR) SIGNATURE. PATHWAY ENRICHMENT ANALYSES REVEALED THAT DEVELOPMENTAL AND IMMUNE RESPONSE PATHWAYS, AMONG OTHERS, WERE IMPACTED DUE TO TOBACCO USE. CONCLUSIONS: CHRONIC CIGARETTE SMOKING CAUSES HYPER- AND HYPO-METHYLATION OF GENES THAT COULD CONTRIBUTE TO SMOKING-RELATED DISEASES. THESE RESULTS HELP PLACE COMBUSTIBLE AND NON-COMBUSTIBLE TOBACCO PRODUCTS ALONG A RISK CONTINUUM AND PROVIDE ADDITIONAL INSIGHTS INTO THE EFFECTS OF TOBACCO CONSUMPTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 1187  32 COPD GWAS VARIANT AT 19Q13.2 IN RELATION WITH DNA METHYLATION AND GENE EXPRESSION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AMONG THE MAJOR HEALTH BURDENS IN ADULTS. WHILE CIGARETTE SMOKING IS THE LEADING RISK FACTOR, A GROWING NUMBER OF GENETIC VARIATIONS HAVE BEEN DISCOVERED TO INFLUENCE DISEASE SUSCEPTIBILITY. EPIGENETIC MODIFICATIONS MAY MEDIATE THE RESPONSE OF THE GENOME TO SMOKING AND REGULATE GENE EXPRESSION. CHROMOSOME 19Q13.2 REGION IS ASSOCIATED WITH BOTH SMOKING AND COPD, YET ITS FUNCTIONAL ROLE IS UNCLEAR. OUR STUDY AIMED TO DETERMINE WHETHER RS7937 (RAB4B, EGLN2), A TOP GENETIC VARIANT IN 19Q13.2 REGION IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES OF COPD, IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD (N = 1490) AND GENE EXPRESSION IN BLOOD (N = 721) AND LUNGS (N = 1087). WE COMBINED GENETIC AND EPIGENETIC DATA FROM THE ROTTERDAM STUDY (RS) TO PERFORM THE EPIGENOME-WIDE ASSOCIATION ANALYSIS OF RS7937. FURTHER, WE USED GENETIC AND TRANSCRIPTOMIC DATA FROM BLOOD (RS) AND FROM LUNG TISSUE (LUNG EXPRESSION QUANTITATIVE TRAIT LOCI MAPPING STUDY), TO PERFORM THE TRANSCRIPTOME-WIDE ASSOCIATION STUDY OF RS7937. RS7937 WAS SIGNIFICANTLY (FDR < 0.05) AND CONSISTENTLY ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD AT 4 CPG SITES IN CIS, INDEPENDENT OF SMOKING. ONE METHYLATION SITE (CG11298343-EGLN2) WAS ALSO ASSOCIATED WITH COPD (P = 0.001). ADDITIONALLY, RS7937 WAS ASSOCIATED WITH GENE EXPRESSION LEVELS IN BLOOD IN CIS (EGLN2), 42% MEDIATED THROUGH CG11298343, AND IN LUNG TISSUE, IN CIS AND TRANS (NUMBL, EGLN2, DNMT3A, LOC101929709 AND PAK2). OUR RESULTS SUGGEST THAT CHANGES OF DNA METHYLATION AND GENE EXPRESSION MAY BE INTERMEDIATE STEPS BETWEEN GENETIC VARIANTS AND COPD, BUT FURTHER CAUSAL STUDIES IN LUNG TISSUE SHOULD CONFIRM THIS HYPOTHESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3   11  41 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 3050  27 GENOME-WIDE ASSOCIATION ANALYSES FOR LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE IDENTIFY NEW LOCI AND POTENTIAL DRUGGABLE TARGETS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY REDUCED LUNG FUNCTION AND IS THE THIRD LEADING CAUSE OF DEATH GLOBALLY. THROUGH GENOME-WIDE ASSOCIATION DISCOVERY IN 48,943 INDIVIDUALS, SELECTED FROM EXTREMES OF THE LUNG FUNCTION DISTRIBUTION IN UK BIOBANK, AND FOLLOW-UP IN 95,375 INDIVIDUALS, WE INCREASED THE YIELD OF INDEPENDENT SIGNALS FOR LUNG FUNCTION FROM 54 TO 97. A GENETIC RISK SCORE WAS ASSOCIATED WITH COPD SUSCEPTIBILITY (ODDS RATIO PER 1 S.D. OF THE RISK SCORE ( APPROXIMATELY 6 ALLELES) (95% CONFIDENCE INTERVAL) = 1.24 (1.20-1.27), P = 5.05 X 10(-49)), AND WE OBSERVED A 3.7-FOLD DIFFERENCE IN COPD RISK BETWEEN INDIVIDUALS IN THE HIGHEST AND LOWEST GENETIC RISK SCORE DECILES IN UK BIOBANK. THE 97 SIGNALS SHOW ENRICHMENT IN GENES FOR DEVELOPMENT, ELASTIC FIBERS AND EPIGENETIC REGULATION PATHWAYS. WE HIGHLIGHT TARGETS FOR DRUGS AND COMPOUNDS IN DEVELOPMENT FOR COPD AND ASTHMA (GENES IN THE INOSITOL PHOSPHATE METABOLISM PATHWAY AND CHRM3) AND DESCRIBE TARGETS FOR POTENTIAL DRUG REPOSITIONING FROM OTHER CLINICAL INDICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5 2626  34 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 6731  43 WATERPIPE SMOKING INDUCES EPIGENETIC CHANGES IN THE SMALL AIRWAY EPITHELIUM. WATERPIPE (ALSO CALLED HOOKAH, SHISHA, OR NARGHILE) SMOKING IS A COMMON FORM OF TOBACCO USE IN THE MIDDLE EAST. ITS USE IS BECOMING MORE PREVALENT IN WESTERN SOCIETIES, ESPECIALLY AMONG YOUNG ADULTS AS AN ALTERNATIVE FORM OF TOBACCO USE TO TRADITIONAL CIGARETTES. WHILE THE RISK TO CIGARETTE SMOKING IS WELL DOCUMENTED, THE RISK TO WATERPIPE SMOKING IS NOT WELL DEFINED WITH LIMITED INFORMATION ON ITS HEALTH IMPACT AT THE EPIDEMIOLOGIC, CLINICAL AND BIOLOGIC LEVELS WITH RESPECT TO LUNG DISEASE. BASED ON THE KNOWLEDGE THAT AIRWAY EPITHELIAL CELL DNA METHYLATION IS MODIFIED IN RESPONSE TO CIGARETTE SMOKE AND IN CIGARETTE SMOKING-RELATED LUNG DISEASES, WE ASSESSED THE IMPACT OF LIGHT-USE WATERPIPE SMOKING ON DNA METHYLATION OF THE SMALL AIRWAY EPITHELIUM (SAE) AND WHETHER CHANGES IN METHYLATION WERE LINKED TO THE TRANSCRIPTIONAL OUTPUT OF THE CELLS. SMALL AIRWAY EPITHELIUM WAS OBTAINED FROM 7 NONSMOKERS AND 7 LIGHT-USE (2.6 +/- 1.7 SESSIONS/WK) WATERPIPE-ONLY SMOKERS. GENOME-WIDE COMPARISON OF SAE DNA METHYLATION OF WATERPIPE SMOKERS TO NONSMOKERS IDENTIFIED 727 PROBESETS DIFFERENTIALLY METHYLATED (FOLD-CHANGE >1.5, P<0.05) REPRESENTING 673 UNIQUE GENES. DOMINANT PATHWAYS ASSOCIATED WITH THESE EPIGENETIC CHANGES INCLUDE THOSE LINKED TO G-PROTEIN COUPLED RECEPTOR SIGNALING, ARYL HYDROCARBON RECEPTOR SIGNALING AND XENOBIOTIC METABOLISM SIGNALING, ALL OF WHICH HAVE BEEN ASSOCIATED WITH CIGARETTE SMOKING AND LUNG DISEASE. OF THE GENES DIFFERENTIALLY METHYLATED, 11.3% EXHIBITED A CORRESPONDING SIGNIFICANT (P<0.05) CHANGE IN GENE EXPRESSION WITH ENRICHMENT IN PATHWAYS RELATED TO REGULATION OF MRNA TRANSLATION AND PROTEIN SYNTHESIS (EIF2 SIGNALING AND REGULATION OF EIF4 AND P70S6K SIGNALING). OVERALL, THESE DATA DEMONSTRATE THAT LIGHT-USE WATERPIPE SMOKING IS ASSOCIATED WITH EPIGENETIC CHANGES AND RELATED TRANSCRIPTIONAL MODIFICATIONS IN THE SAE, THE CELL POPULATION DEMONSTRATING THE EARLIEST PATHOLOGIC ABNORMALITIES ASSOCIATED WITH CHRONIC CIGARETTE SMOKING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 1990  31 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 6835  18 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 5092  33 PLACENTAL EPIGENETIC MARKS RELATED TO GESTATIONAL WEIGHT GAIN REVEAL POTENTIAL GENES ASSOCIATED WITH OFFSPRING OBESITY PARAMETERS. OBJECTIVE: OFFSPRING EXPOSED TO GESTATIONAL OBESITY HAVE AN INCREASED RISK FOR CHRONIC DISEASES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETICS MAY PLAY A MECHANISTIC ROLE IN METABOLIC PROGRAMMING. THIS STUDY AIMED TO IDENTIFY PLACENTAL DNA METHYLATION MARKS ASSOCIATED WITH GESTATIONAL WEIGHT GAIN (GWG) AND TO STUDY THEIR ASSOCIATION WITH OFFSPRING OBESITY PARAMETERS AT SCHOOL AGE. METHODS: A GLOBAL METHYLATION ARRAY WAS PERFORMED IN 24 PLACENTAS FROM MOTHERS WITH DIFFERENT DEGREES OF GWG (SCREENING SAMPLE). THE METHYLATION PERCENTAGE OF FOUR CYTOSINE-GUANINE (CPG) SITES AND THE RELATIVE EXPRESSION OF THE RESPECTIVE ANNOTATED GENES WERE STUDIED IN 90 ADDITIONAL PLACENTAS (VALIDATION SAMPLE). ASSOCIATIONS OF THESE EPIGENETIC MARKS WITH CLINICAL PARAMETERS IN THE OFFSPRING AT 6 YEARS OF AGE WERE EXAMINED. RESULTS: THE SCREENING ANALYSIS IDENTIFIED 104 CPG SITES (97 GENES) ASSOCIATED WITH GWG. THE VALIDATION ANALYSIS OF FOUR SELECTED CPG SITES (ANNOTATING FOR FRAT1, SNX5, AND KCNK3 GENES) SHOWED THAT THE UPREGULATION OF SNX5 METHYLATION, THE DOWNREGULATION OF FRAT1 METHYLATION, AND KCNK3 UNDEREXPRESSION ASSOCIATED WITH AN ADVERSE METABOLIC PHENOTYPE IN CHILDREN OF WOMEN WITH INCREASED GWG. CONCLUSIONS: THESE RESULTS SUGGEST THAT PLACENTAL REGULATION OF FRAT1, SNX5, AND KCNK3 RELATES TO OBESITY PARAMETERS IN OFFSPRING EXPOSED TO EXCESSIVE GWG AND THEREBY COULD CONDITION THE RISK FOR FUTURE METABOLIC DISORDERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10 2761  25 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11 5621  31 SCREENING METHYLATION OF DNA REPAIR GENES IN THE ORAL MUCOSA OF CHRONIC SMOKERS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EPIGENETIC CHANGES IN THE PROCESS OF ORAL CARCINOGENESIS BY SCREENING THE METHYLATION OF REPAIR GENES IN CHRONIC SMOKERS. DESIGN: TWO GROUPS WERE FORMED: GROUP 1: 16 SMOKERS WITH CONSUMPTION OF 20 CIGARETTES/DAY FOR AT LEAST 10 YEARS; AND GROUP 2: 10 NON-SMOKING. EXFOLIATIVE CYTOLOGY OF THE TONGUE WAS PERFORMED, AND THE EXTRACTED DNA WAS TREATED BY ENZYMES. THE PCR ARRAY SYSTEM PERFORMED METHYLATION SCREENING TO EVALUATE 22 DNA REPAIR GENES, AND THE RESULTS WERE VALIDATED BY RT-QPCR FOR EACH GENE WITH METHYLATION LEVELS >/=10%. RESULTS: HIGHEST PERCENTAGES OF METHYLATION WERE OBSERVED FOR MLH3 AND XRCC1 GENES (11-20% METHYLATION) AND IN ONE CASE FOR MRE11A AND PMS2 (>50% METHYLATION). STATISTICAL ANALYSIS SHOWED SIGNIFICANT DIFFERENCES IN THE EXPRESSION OF THE GENES MRE11A (P = 0.0002), PMS2(P = 0.0068), XRCC1 (P = 0.0080) AND MLH3 (0.0057) BETWEEN THE TWO GROUPS. CONCLUSION: THE EFFECTS OF CHRONIC SMOKING ON ORAL MUCOSA LED TO THE METHYLATION OF GENES MRE11A PMS2, XRCC1 AND MLH3, BUT RESULTED IN A REDUCTION OF GENE EXPRESSION OF MRE11A AND PMS2, WHICH SHOWED >/=50% METHYLATION. THESE RESULTS PROVIDE EVIDENCE THAT SMOKING CAUSE METHYLATION AND REDUCED EXPRESSION OF REPAIR GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12 4740  40 NOVEL GENETIC VARIANTS ASSOCIATED WITH CHRONIC KIDNEY DISEASE PROGRESSION. SIGNIFICANCE STATEMENT: EGFR SLOPE HAS BEEN USED AS A SURROGATE OUTCOME FOR PROGRESSION OF CKD. HOWEVER, GENETIC MARKERS ASSOCIATED WITH EGFR SLOPE AMONG PATIENTS WITH CKD WERE UNKNOWN. WE AIMED TO IDENTIFY GENETIC SUSCEPTIBILITY LOCI ASSOCIATED WITH EGFR SLOPE. A TWO-PHASE GENOME-WIDE ASSOCIATION STUDY IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN TPPP AND FAT1-LINC02374 , AND 22 OF THEM WERE USED TO DERIVE POLYGENIC RISK SCORES THAT MARK THE DECLINE OF EGFR BY DISRUPTING BINDING OF NEARBY TRANSCRIPTION FACTORS. THIS WORK IS THE FIRST TO IDENTIFY THE IMPACT OF TPPP AND FAT1-LINC02374 ON CKD PROGRESSION, PROVIDING PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD. BACKGROUND: THE INCIDENCE OF CKD IS ASSOCIATED WITH GENETIC FACTORS. HOWEVER, GENETIC MARKERS ASSOCIATED WITH THE PROGRESSION OF CKD HAVE NOT BEEN FULLY ELUCIDATED. METHODS: WE CONDUCTED A GENOME-WIDE ASSOCIATION STUDY AMONG 1738 PATIENTS WITH CKD, MAINLY FROM THE KOREAN COHORT STUDY FOR OUTCOMES IN PATIENTS WITH CKD. THE OUTCOME WAS EGFR SLOPE. WE PERFORMED A REPLICATION STUDY FOR DISCOVERED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITH P <10 -6 IN 2498 PATIENTS WITH CKD FROM THE CHRONIC RENAL INSUFFICIENCY COHORT STUDY. SEVERAL EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL) STUDIES, PATHWAY ENRICHMENT ANALYSES, EXPLORATION OF EPIGENETIC ARCHITECTURE, AND PREDICTING DISRUPTION OF TRANSCRIPTION FACTOR (TF) BINDING SITES EXPLORED POTENTIAL BIOLOGICAL IMPLICATIONS OF THE LOCI. WE DEVELOPED AND EVALUATED THE EFFECT OF POLYGENIC RISK SCORES (PRS) ON INCIDENT CKD OUTCOMES. RESULTS: SNPS IN TWO NOVEL LOCI, TPPP AND FAT1-LINC02374 , WERE REPLICATED (RS59402340 IN TPPP , PDISCOVERY =7.11X10 -7 , PCRIC =8.13X10 -4 , PMETA =7.23X10 -8 ; RS28629773 IN FAT1-LINC02374 , PDISCOVERY =6.08X10 -7 , PCRIC =4.33X10 -2 , PMETA =1.87X10 -7 ). THE EQTL STUDIES REVEALED THAT THE REPLICATED SNPS REGULATED THE EXPRESSION LEVEL OF NEARBY GENES ASSOCIATED WITH KIDNEY FUNCTION. FURTHERMORE, THESE SNPS WERE NEAR GENE ENHANCER REGIONS AND PREDICTED TO DISRUPT THE BINDING OF TFS. PRS BASED ON THE INDEPENDENTLY SIGNIFICANT TOP 22 SNPS WERE SIGNIFICANTLY ASSOCIATED WITH CKD OUTCOMES. CONCLUSIONS: THIS STUDY DEMONSTRATES THAT SNP MARKERS IN THE TPPP AND FAT1-LINC02374 LOCI COULD BE PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD.	2023	
                                                                                                                                                                                                                                                                
13 5887  33 SYSTEMIC STEROID EXPOSURE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. RATIONALE: SYSTEMIC GLUCOCORTICOIDS ARE USED THERAPEUTICALLY TO TREAT A VARIETY OF MEDICAL CONDITIONS. EPIGENETIC PROCESSES SUCH AS DNA METHYLATION MAY REFLECT EXPOSURE TO GLUCOCORTICOIDS AND MAY BE INVOLVED IN MEDIATING THE RESPONSES AND SIDE EFFECTS ASSOCIATED WITH THESE MEDICATIONS. OBJECTIVES: TO TEST THE HYPOTHESIS THAT DIFFERENCES IN DNA METHYLATION ARE ASSOCIATED WITH CURRENT SYSTEMIC STEROID USE. METHODS: WE OBTAINED DNA METHYLATION DATA AT 27,578 CPG SITES IN 14,475 GENES THROUGHOUT THE GENOME IN TWO LARGE, INDEPENDENT COHORTS: THE INTERNATIONAL COPD GENETICS NETWORK (N(DISCOVERY) = 1,085) AND THE BOSTON EARLY ONSET COPD STUDY (N(REPLICATION) = 369). SITES WERE TESTED FOR ASSOCIATION WITH CURRENT SYSTEMIC STEROID USE USING GENERALIZED LINEAR MIXED MODELS. MEASUREMENTS AND MAIN RESULTS: A TOTAL OF 511 SITES DEMONSTRATED SIGNIFICANT DIFFERENTIAL METHYLATION BY SYSTEMIC CORTICOSTEROID USE IN ALL THREE OF OUR PRIMARY MODELS. PYROSEQUENCING VALIDATION CONFIRMED ROBUST DIFFERENTIAL METHYLATION AT CPG SITES ANNOTATED TO GENES SUCH AS SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, AND RABGEF1. FUNCTIONAL ANNOTATION CLUSTERING DEMONSTRATED SIGNIFICANT ENRICHMENT IN INTRINSIC MEMBRANE COMPONENTS, HEMOSTASIS AND COAGULATION, CELLULAR ION HOMEOSTASIS, LEUKOCYTE AND LYMPHOCYTE ACTIVATION AND CHEMOTAXIS, PROTEIN TRANSPORT, AND RESPONSES TO NUTRIENTS. CONCLUSIONS: OUR ANALYSES SUGGEST THAT SYSTEMIC STEROID USE IS ASSOCIATED WITH SITE-SPECIFIC DIFFERENTIAL METHYLATION THROUGHOUT THE GENOME. DIFFERENTIALLY METHYLATED CPG SITES WERE FOUND IN BIOLOGICALLY PLAUSIBLE AND PREVIOUSLY UNSUSPECTED PATHWAYS; THESE GENES AND PATHWAYS MAY BE RELEVANT IN THE DEVELOPMENT OF NOVEL TARGETED THERAPIES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14 1598  29 DNA METHYLATION SIGNATURE IN MONONUCLEAR CELLS AND PROINFLAMMATORY CYTOKINES MAY DEFINE MOLECULAR SUBTYPES IN SPORADIC MENIERE DISEASE. MENIERE DISEASE (MD) IS A MULTIFACTORIAL DISORDER OF THE INNER EAR CHARACTERIZED BY VERTIGO ATTACKS ASSOCIATED WITH SENSORINEURAL HEARING LOSS AND TINNITUS WITH A SIGNIFICANT HERITABILITY. ALTHOUGH MD HAS BEEN ASSOCIATED WITH SEVERAL GENES, NO EPIGENETIC STUDIES HAVE BEEN PERFORMED ON MD. HERE WE PERFORMED WHOLE-GENOME BISULFITE SEQUENCING IN 14 MD PATIENTS AND SIX HEALTHY CONTROLS, WITH THE AIM OF IDENTIFYING AN MD METHYLATION SIGNATURE AND POTENTIAL DISEASE MECHANISMS. WE OBSERVED A HIGH NUMBER OF DIFFERENTIALLY METHYLATED CPGS (DMC) WHEN COMPARING MD PATIENTS TO CONTROLS (N= 9545), SEVERAL OF THEM IN HEARING LOSS GENES, SUCH AS PCDH15,&NBSP;ADGRV1 AND CDH23. BIOINFORMATIC ANALYSES OF DMCS AND CIS-REGULATORY REGIONS PREDICTED PHENOTYPES RELATED TO ABNORMAL EXCITATORY POSTSYNAPTIC CURRENTS, ABNORMAL NMDA-MEDIATED RECEPTOR CURRENTS AND ABNORMAL GLUTAMATE-MEDIATED RECEPTOR CURRENTS WHEN COMPARING MD TO CONTROLS. MOREOVER, WE IDENTIFIED VARIOUS DMCS IN GENES PREVIOUSLY ASSOCIATED WITH COCHLEOVESTIBULAR PHENOTYPES IN MICE. WE HAVE ALSO FOUND 12 UNDERMETHYLATED REGIONS (UMR) THAT WERE EXCLUSIVE TO MD, INCLUDING TWO UMR IN AN INTER CPG ISLAND IN THE PHB GENE. WE SUGGEST THAT THE DNA METHYLATION SIGNATURE ALLOWS DISTINGUISHING BETWEEN MD PATIENTS AND CONTROLS. THE ENRICHMENT ANALYSIS CONFIRMS PREVIOUS FINDINGS OF A CHRONIC INFLAMMATORY PROCESS UNDERLYING MD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 3073  41 GENOME-WIDE DNA METHYLATION STATUS OF MONGOLIANS EXHIBITS SIGNS OF CELLULAR STRESS RESPONSE RELATED TO THEIR NOMADIC LIFESTYLE. BACKGROUND: EPIGENETICS IS CRUCIAL FOR CONNECTING ENVIRONMENTAL STRESSES WITH PHYSIOLOGICAL RESPONSES IN HUMANS. MONGOLIA, WHERE NOMADIC LIVESTOCK PASTORALISM HAS BEEN THE PRIMAL LIVELIHOOD, HAS A HIGHER PREVALENCE OF VARIOUS CHRONIC DISEASES THAN THE SURROUNDING EAST ASIAN REGIONS, WHICH ARE MORE SUITABLE FOR CROP FARMING. THE GENES RELATED TO DIETARY STRESS AND PATHOGENESIS OF RELATED DISORDERS MAY HAVE VARYING EPIGENETIC STATUSES AMONG THE HUMAN POPULATIONS WITH DIVERSE DIETARY CULTURES. HENCE, TO UNDERSTAND SUCH EPIGENETIC DIFFERENCES, WE CONDUCTED A COMPARATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION OF MONGOLIANS AND CROP-FARMING EAST ASIANS. METHODS: GENOME-WIDE DNA METHYLATION STATUS OF PERIPHERAL BLOOD CELLS (PBCS) FROM 23 MONGOLIAN ADULTS AND 24 THAI ADULTS WAS DETERMINED USING THE INFINIUM HUMAN METHYLATION 450K ARRAYS AND ANALYZED IN COMBINATION WITH PREVIOUSLY PUBLISHED 450K DATA OF 20 JAPANESE AND 8 CHINESE ADULTS. CPG SITES/REGIONS DIFFERENTIALLY METHYLATED BETWEEN MONGOLIANS AND CROP-FARMING EAST ASIANS WERE DETECTED USING A LINEAR MODEL ADJUSTED FOR SEX, AGE, ETHNICITY, AND IMMUNE CELL HETEROGENEITY ON RNBEADS SOFTWARE. RESULTS: OF THE QUALITY-CONTROLLED 389,454 AUTOSOMAL CPG SITES, 223 CPG SITES WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED AMONG MONGOLIANS AND THE FOUR CROP FARMING EAST ASIAN POPULATIONS (FALSE DISCOVERY RATE < 0.05). ANALYSES FOCUSED ON GENE PROMOTER REGIONS REVEALED THAT PM20D1 (PEPTIDASE M20 DOMAIN CONTAINING 1), WHICH IS INVOLVED IN MITOCHONDRIAL UNCOUPLING AND VARIOUS PROCESSES, INCLUDING CELLULAR PROTECTION FROM REACTIVE OXYGEN SPECIES (ROS) AND THERMOGENESIS, WAS THE TOP DIFFERENTIALLY METHYLATED GENE. MOREOVER, GENE ONTOLOGY ENRICHMENT ANALYSIS REVEALED THAT BIOLOGICAL PROCESSES RELATED TO ROS METABOLISM WERE OVERREPRESENTED AMONG THE TOP 1% DIFFERENTIALLY METHYLATED GENES. THE PROMOTER REGIONS OF THESE GENES WERE GENERALLY HYPERMETHYLATED IN MONGOLIANS, SUGGESTING THAT THE METABOLIC PATHWAY DETOXIFYING ROS MIGHT BE GLOBALLY SUPPRESSED IN MONGOLIANS, RESULTING IN THE HIGH SUSCEPTIBILITY OF THIS POPULATION TO VARIOUS CHRONIC DISEASES. CONCLUSIONS: THIS STUDY SHOWED A SIGNIFICANTLY DIVERSE DNA METHYLATION STATUS AMONG MONGOLIANS AND CROP-FARMING EAST ASIANS. FURTHER, WE FOUND AN ASSOCIATION BETWEEN THE DIFFERENTIALLY METHYLATED GENES AND VARIOUS METABOLIC AND NEURODEGENERATIVE DISEASES. KNOWLEDGE OF THE EPIGENETIC REGULATORS MIGHT HELP IN PROPER UNDERSTANDING, TREATMENT, AND CONTROL OF SUCH DISORDERS, AND PHYSIOLOGICAL ADAPTATION IN THE FUTURE.	2022	

16  546  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17 6632  30 UNDERSTANDING THE ROLE OF THE CHROMOSOME 15Q25.1 IN COPD THROUGH EPIGENETICS AND TRANSCRIPTOMICS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A MAJOR HEALTH BURDEN IN ADULTS AND CIGARETTE SMOKING IS CONSIDERED THE MOST IMPORTANT ENVIRONMENTAL RISK FACTOR OF COPD. CHROMOSOME 15Q25.1 LOCUS IS ASSOCIATED WITH BOTH COPD AND SMOKING. OUR STUDY AIMS AT UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION OF CHROMOSOME 15Q25.1 WITH COPD THROUGH EPIGENETIC AND TRANSCRIPTIONAL VARIATION IN A POPULATION-BASED SETTING. TO ASSESS IF COPD-ASSOCIATED VARIANTS IN 15Q25.1 ARE METHYLATION QUANTITATIVE TRAIT LOCI, EPIGENOME-WIDE ASSOCIATION ANALYSIS OF FOUR GENETIC VARIANTS, PREVIOUSLY ASSOCIATED WITH COPD (P < 5 X 10(-8)) IN THE 15Q25.1 LOCUS (RS12914385:C>T-CHRNA3, RS8034191:T>C-HYKK, RS13180:C>T-IREB2 AND RS8042238:C>T-IREB2), WAS PERFORMED IN THE ROTTERDAM STUDY (N = 1489). ALL FOUR VARIANTS WERE SIGNIFICANTLY ASSOCIATED (P < 1.4 X 10(-6)) WITH BLOOD DNA METHYLATION OF IREB2, CHRNA3 AND PSMA4, OF WHICH TWO, INCLUDING IREB2 AND PSMA4, WERE ALSO DIFFERENTIALLY METHYLATED IN COPD CASES AND CONTROLS (P < 0.04). FURTHER ADDITIVE AND MULTIPLICATIVE EFFECTS OF SMOKING WERE EVALUATED AND NO SIGNIFICANT EFFECT WAS OBSERVED. TO EVALUATE IF THESE FOUR GENETIC VARIANTS ARE EXPRESSION QUANTITATIVE TRAIT LOCI, TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS WAS PERFORMED IN 1087 LUNG SAMPLES. ALL FOUR VARIANTS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH DIFFERENTIAL EXPRESSION OF THE IREB2 3'UTR IN LUNG TISSUES (P < 5.4 X 10(-95)). WE CONCLUDE THAT REGULATORY MECHANISMS AFFECTING THE EXPRESSION OF IREB2 GENE, SUCH AS DNA METHYLATION, MAY EXPLAIN THE ASSOCIATION BETWEEN GENETIC VARIANTS IN CHROMOSOME 15Q25.1 AND COPD, LARGELY INDEPENDENT OF SMOKING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18 3296  35 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19 2946  29 GENETIC AND EPIGENETIC CHANGES IN THE EUTOPIC ENDOMETRIUM OF WOMEN WITH ENDOMETRIOSIS: ASSOCIATION WITH DECREASED ENDOMETRIAL ALPHAVBETA3 INTEGRIN EXPRESSION. ABOUT 40% OF WOMEN WITH INFERTILITY AND 70% OF WOMEN WITH PELVIC PAIN SUFFER FROM ENDOMETRIOSIS. THE PREGNANCY RATE IN WOMEN UNDERGOING IVF WITH LOW ENDOMETRIAL INTEGRIN ALPHAVBETA3 (LEI) EXPRESSION IS SIGNIFICANTLY LOWER COMPARED TO THE WOMEN WITH HIGH ENDOMETRIAL INTEGRIN ALPHAVBETA3 (HEI). MID-SECRETORY EUTOPIC ENDOMETRIAL BIOPSIES WERE OBTAINED FROM HEALTHY CONTROLS (C; N=3), AND WOMEN WITH HEI (N=4) AND LEI (N=4) AND ENDOMETRIOSIS. CHANGES IN GENE EXPRESSION WERE ASSESSED USING HUMAN GENE ARRAYS AND DNA METHYLATION DATA WERE DERIVED USING 385 K TWO-ARRAY PROMOTER ARRAYS. TRANSCRIPTIONAL ANALYSIS REVEALED THAT LEI AND C GROUPS CLUSTERED SEPARATELY WITH 396 DIFFERENTIALLY EXPRESSED GENES (DEGS) (P<0.01: 275 UP AND 121 DOWN) DEMONSTRATING THAT TRANSCRIPTIONAL AND EPIGENETIC CHANGES ARE DISTINCT IN THE LEI EUTOPIC ENDOMETRIUM COMPARED TO THE C AND HEI GROUP. IN CONTRAST, HEI VS C AND HEI VS LEI COMPARISONS ONLY IDENTIFIED 83 AND 45 DEGS, RESPECTIVELY. THE METHYLATION PROMOTER ARRAY IDENTIFIED 1304 DIFFERENTIALLY METHYLATED REGIONS IN THE LEI VS C COMPARISON. THE OVERLAP OF GENE AND METHYLATION ARRAY DATA IDENTIFIED 14 EPIGENETICALLY DYSREGULATED GENES AND QUANTITATIVE RT-PCR ANALYSIS VALIDATED THE TRANSCRIPTOMIC FINDINGS. THE ANALYSIS ALSO REVEALED THAT ARYL HYDROCARBON RECEPTOR (AHR) WAS HYPOMETHYLATED AND SIGNIFICANTLY OVEREXPRESSED IN LEI SAMPLES COMPARED TO C. FURTHER ANALYSIS VALIDATED THAT AHR TRANSCRIPT AND PROTEIN EXPRESSION ARE SIGNIFICANTLY (P<0.05) INCREASED IN LEI WOMEN COMPARED TO C. THE INCREASE IN AHR, TOGETHER WITH THE ALTERED METHYLATION STATUS OF THE 14 ADDITIONAL GENES, MAY PROVIDE A DIAGNOSTIC TOOL TO IDENTIFY THE SUBSET OF WOMEN WHO HAVE ENDOMETRIOSIS-ASSOCIATED INFERTILITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20 1541  31 DNA METHYLATION IN GENES OF LONGEVITY-REGULATING PATHWAYS: ASSOCIATION WITH OBESITY AND METABOLIC COMPLICATIONS. AGING IS THE MAIN RISK FACTOR FOR MOST CHRONIC DISEASES. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION (DNAM) PLAYS A PIVOTAL ROLE IN THE REGULATION OF PHYSIOLOGICAL RESPONSES THAT CAN VARY ALONG LIFESPAN. THE AIM OF THIS RESEARCH WAS TO ANALYZE THE ASSOCIATION BETWEEN LEUKOCYTE DNAM IN GENES INVOLVED IN LONGEVITY AND THE OCCURRENCE OF OBESITY AND RELATED METABOLIC ALTERATIONS IN AN ADULT POPULATION. SUBJECTS FROM THE MENA COHORT (N=474) WERE CATEGORIZED ACCORDING TO AGE (<45 VS 45>) AND THE PRESENCE OF METABOLIC ALTERATIONS: INCREASED WAIST CIRCUMFERENCE, HYPERCHOLESTEROLEMIA, INSULIN RESISTANCE, AND METABOLIC SYNDROME. THE METHYLATION LEVELS OF 58 CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE STRONGLY CORRELATED (FDR-ADJUSTED< 0.0001) WITH BMI. FIFTEEN OF THEM WERE DIFFERENTIALLY METHYLATED (P<0.05) BETWEEN YOUNGER AND OLDER SUBJECTS THAT EXHIBITED AT LEAST ONE METABOLIC ALTERATION. SIX OF THESE CPG SITES, LOCATED AT MTOR (CG08862778), ULK1 (CG07199894), ADCY6 (CG11658986), IGF1R (CG01284192), CREB5 (CG11301281), AND RELA (CG08128650), WERE COMMON TO THE METABOLIC TRAITS, AND CREB5, RELA, AND ULK1 WERE STATISTICALLY ASSOCIATED WITH AGE. IN SUMMARY, LEUKOCYTE DNAM LEVELS OF SEVERAL CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME TRAITS, SUGGESTING A ROLE OF DNAM IN AGING-RELATED METABOLIC ALTERATIONS.	2019