1 3050 105 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2   11  34 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	
            
3 6835  17 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4 1187  34 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	
                                                                                                                                                                                                                                                                     
5 1990  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6 3764  31 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY.	2015	
                                                                                                                                                                                                                               
7  546  23 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	
                                                                                                                                                                                                      
8 5887  26 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	
                                                                                                                                                                                                                             
9 6731  25 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	
        
10 6358  24 THE ROLE OF IL?16 GENE POLYMORPHISMS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS ONE OF THE MOST COMMON GYNECOLOGICAL DISEASES AFFECTING UP TO 10% OF THE FEMALE POPULATION OF CHILDBEARING AGE AND A MAJOR CAUSE OF PAIN AND INFERTILITY. IT IS INFLUENCED BY MULTIPLE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. INTERLEUKIN?16 (IL?16) IS A PROINFLAMMATORY CYTOKINE PLAYING A PIVOTAL ROLE IN MANY INFLAMMATORY AND AUTOIMMUNE DISEASES AS WELL AS IN THE PATHOGENESIS OF ENDOMETRIOSIS. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE ASSOCIATION OF TWO IL?16 GENE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), RS4072111 AND RS11556218, WITH THE RISK OF ENDOMETRIOSIS IN WOMEN FROM GREECE AS WELL AS TO GAIN INSIGHT ABOUT THE STRUCTURAL CONSEQUENCES OF THESE TWO EXONIC SNPS REGARDING DEVELOPMENT OF THE DISEASE. A TOTAL OF 159 WOMEN WITH ENDOMETRIOSIS (STAGES I?IV) HOSPITALIZED FOR ENDOMETRIOSIS, DIAGNOSED BY LAPAROSCOPIC INTERVENTION AND HISTOLOGICALLY CONFIRMED, AND 146 NORMAL CONTROLS WERE RECRUITED AND GENOTYPED. SUBJECTS WERE GENOTYPED USING A POLYMERASE CHAIN REACTION RESTRICTION FRAGMENT LENGTH POLYMORPHISM (PCR?RFLP) STRATEGY. A SIGNIFICANT ASSOCIATION WAS DETECTED REGARDING THE GG AND GT GENOTYPE AS WELL AS 'G' ALLELE OF RS11556218 IN PATIENTS WITH ENDOMETRIOSIS. THE RS4072111 SNP OF THE IL?16 GENE WAS NOT FOUND TO BE ASSOCIATED WITH AN INCREASED SUSCEPTIBILITY TO ENDOMETRIOSIS EITHER FOR ALL PATIENTS (STAGES I?IV) OR FOR STAGE III AND IV OF THE DISEASE ONLY. OUR RESULTS DEMONSTRATED THAT RS11556218 IS ASSOCIATED WITH ENDOMETRIOSIS IN GREEK WOMEN, PROBABLY BY RESULTING IN THE ABERRANT EXPRESSION OF IL?16, AS SUGGESTED BY THE BIOINFORMATICS ANALYSIS CONDUCTED ON THE SNP?DERIVED PROTEIN SEQUENCES, WHICH INDICATED A POSSIBLE ASSOCIATION BETWEEN MUTATION AND FUNCTIONAL MODIFICATION OF PRO?IL?16.	2018	
                                                                                                                                                                                                                                                                        
11 1590  36 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12 1598  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13 2967  21 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES.	2022	

14  686  31 BRAIN-SPECIFIC GENES CONTRIBUTE TO CHRONIC BUT NOT TO ACUTE BACK PAIN. INTRODUCTION: BACK PAIN IS THE LEADING CAUSE OF DISABILITY WORLDWIDE. ALTHOUGH MOST BACK PAIN CASES ARE ACUTE, 20% OF ACUTE PAIN PATIENTS EXPERIENCE CHRONIC BACK PAIN SYMPTOMS. IT IS UNCLEAR WHETHER ACUTE PAIN AND CHRONIC PAIN HAVE SIMILAR OR DISTINCT UNDERLYING GENETIC MECHANISMS. OBJECTIVES: TO CHARACTERIZE THE MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO ACUTE AND CHRONIC PAIN STATES. METHODS: CROSS-SECTIONAL OBSERVATIONAL GENOME-WIDE ASSOCIATION STUDY. RESULTS: A TOTAL OF 375,158 INDIVIDUALS FROM THE UK BIOBANK COHORT WERE INCLUDED IN THE DISCOVERY OF GENOME-WIDE ASSOCIATION STUDY. OF THOSE, 70,633 (19%) AND 32,209 (9%) INDIVIDUALS MET THE DEFINITION OF CHRONIC AND ACUTE BACK PAIN, RESPECTIVELY. A TOTAL OF 355 SINGLE NUCLEOTIDE POLYMORPHISM GROUPED INTO 13 LOCI REACHED THE GENOME-WIDE SIGNIFICANCE THRESHOLD (5X10(-8)) FOR CHRONIC BACK PAIN, BUT NONE FOR ACUTE. OF THESE, 7 LOCI WERE REPLICATED IN THE NORD-TRONDELAG HEALTH STUDY (HUNT) COHORT (19,760 CHRONIC LOW BACK PAIN CASES AND 28,674 PAIN-FREE CONTROLS). SINGLE NUCLEOTIDE POLYMORPHISM HERITABILITY WAS 4.6% (P=1.4X10(-78)) FOR CHRONIC BACK PAIN AND 0.81% (P=1.4X10-8) FOR ACUTE BACK PAIN. SIMILAR DIFFERENCES IN HERITABILITY ESTIMATES BETWEEN ACUTE AND CHRONIC BACK PAIN WERE FOUND IN THE HUNT COHORT: 3.4% (P=0.0011) AND 0.6% (P=0.851), RESPECTIVELY. PATHWAY ANALYSES, TISSUE-SPECIFIC HERITABILITY ENRICHMENT ANALYSES, AND EPIGENETIC CHARACTERIZATION SUGGEST A SUBSTANTIAL GENETIC CONTRIBUTION TO CHRONIC BUT NOT ACUTE BACK PAIN FROM THE LOCI PREDOMINANTLY EXPRESSED IN THE CENTRAL NERVOUS SYSTEM. CONCLUSION: CHRONIC BACK PAIN IS SUBSTANTIALLY MORE HERITABLE THAN ACUTE BACK PAIN. THIS HERITABILITY IS MOSTLY ATTRIBUTED TO GENES EXPRESSED IN THE BRAIN.	2022	
                                                                                                                                                                                                                                                                       
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	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 6911  20 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17 3125  20 GHSR DNA HYPERMETHYLATION IS A COMMON EPIGENETIC ALTERATION OF HIGH DIAGNOSTIC VALUE IN A BROAD SPECTRUM OF CANCERS. IDENTIFICATION OF A SINGLE MOLECULAR TRAIT THAT IS DETERMINANT OF COMMON MALIGNANCIES MAY SERVE AS A POWERFUL DIAGNOSTIC SUPPLEMENT TO CANCER TYPE-SPECIFIC MARKERS. HERE, WE REPORT A DNA METHYLATION MARK THAT IS CHARACTERISTIC OF SEVEN STUDIED MALIGNANCIES, NAMELY CANCERS OF LUNG, BREAST, PROSTATE, PANCREAS, COLORECTUM, GLIOBLASTOMA AND B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) (N = 137). THIS MARK WAS DEFINED BY SUBSTANTIAL HYPERMETHYLATION AT THE PROMOTER AND FIRST EXON OF GROWTH HORMONE SECRETAGOUGE RECEPTOR (GHSR) THROUGH BISULFITE PYROSEQUENCING. THE DEGREE OF ABERRANT METHYLATION WAS CAPABLE OF ACCURATE DISCRIMINATION BETWEEN CANCER AND CONTROL SAMPLES. THE HIGHEST SENSITIVITY AND SPECIFICITY OF CANCER DETECTION WAS ACHIEVED FOR CANCERS OF PANCREAS, LUNG, BREAST AND CLL YIELDING THE AREA UNDER THE CURVE (AUC) VALUES OF 1.0000, 0.9952, 0.9800 AND 0.9400, RESPECTIVELY. NARROWING TO A SINGLE CPG SITE WITHIN THE GENE'S PROMOTER OR FOUR CONSECUTIVE CPG UNITS OF THE HIGHEST METHYLATION LEVELS WITHIN THE FIRST EXON IMPROVED THE DETECTION POWER. GHSR HYPERMETHYLATION WAS DETECTED ALREADY AT THE EARLY STAGE TUMORS. THE ACCURATE PERFORMANCE OF THIS MARKER WAS FURTHER REPLICATED IN AN INDEPENDENT SET OF PANCREATIC CANCER AND CONTROL SAMPLES (N = 78). THESE FINDINGS SUPPORT THE CANDIDATURE OF GHSR METHYLATION AS A HIGHLY ACCURATE PAN-CANCER MARKER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18 3296  26 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 5464  20 RESILIENCE IN LONG-TERM VIRAL INFECTION: GENETIC DETERMINANTS AND INTERACTIONS. VIRUS-INDUCED NEUROLOGICAL SEQUELAE RESULTING FROM INFECTION BY THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) ARE USED FOR STUDYING HUMAN CONDITIONS RANGING FROM EPILEPTIC SEIZURES TO DEMYELINATING DISEASE. MOUSE STRAINS ARE TYPICALLY CONSIDERED SUSCEPTIBLE OR RESISTANT TO TMEV INFECTION BASED ON VIRAL PERSISTENCE AND EXTREME PHENOTYPES, SUCH AS DEMYELINATION. WE HAVE IDENTIFIED A BROADER SPECTRUM OF PHENOTYPIC OUTCOMES BY INFECTING STRAINS OF THE GENETICALLY DIVERSE COLLABORATIVE CROSS (CC) MOUSE RESOURCE. WE EVALUATED THE CHRONIC-INFECTION GENE EXPRESSION PROFILES OF HIPPOCAMPI AND THORACIC SPINAL CORDS FOR 19 CC STRAINS IN RELATION TO PHENOTYPIC SEVERITY AND TMEV PERSISTENCE. STRAINS WERE CLUSTERED BASED ON SIMILAR PHENOTYPIC PROFILES AND TMEV LEVELS AT 90 DAYS POST-INFECTION, AND WE CATEGORIZED DISTINCT TMEV RESPONSE PROFILES. THE THREE MOST COMMON PROFILES INCLUDED "RESISTANT" AND "SUSCEPTIBLE," AS BEFORE, AS WELL AS A "RESILIENT" TMEV RESPONSE GROUP WHICH EXPERIENCED BOTH TMEV PERSISTENCE AND MILD NEUROLOGICAL PHENOTYPES EVEN AT 90 DAYS POST-INFECTION. EACH PROFILE HAD A DISTINCT GENE EXPRESSION SIGNATURE, ALLOWING THE IDENTIFICATION OF PATHWAYS AND NETWORKS SPECIFIC TO EACH TMEV RESPONSE GROUP. CC FOUNDER HAPLOTYPES FOR GENES INVOLVED IN THESE PATHWAYS/NETWORKS REVEALED CANDIDATE RESPONSE-SPECIFIC ALLELES. THESE ALLELES DEMONSTRATED PLEIOTROPY AND EPIGENETIC (MIRNA) REGULATION IN LONG-TERM TMEV INFECTION, WITH PARTICULAR RELEVANCE FOR RESILIENT MOUSE STRAINS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20 2761  17 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