1 3992 157 LONGITUDINAL EPIGENOME-WIDE ANALYSIS OF KIDNEY TRANSPLANT RECIPIENTS PRETRANSPLANT AND POSTTRANSPLANT. INTRODUCTION: KIDNEY TRANSPLANTATION REMAINS THE GOLD STANDARD OF TREATMENT FOR END-STAGE RENAL DISEASE (ESRD), WITH IMPROVED PATIENT OUTCOMES COMPARED WITH DIALYSIS. EPIGENOME-WIDE ASSOCIATION ANALYSIS (EWAS) OF DNA METHYLATION MAY IDENTIFY MARKERS THAT CONTRIBUTE TO AN INDIVIDUAL'S RISK OF ADVERSE TRANSPLANT OUTCOMES, YET ONLY A LIMITED NUMBER OF EWAS HAVE BEEN CONDUCTED IN KIDNEY TRANSPLANT RECIPIENTS. THIS EWAS AIMED TO INTERROGATE THE METHYLATION PROFILE OF A KIDNEY TRANSPLANT RECIPIENT COHORT WITH MINIMAL POSTTRANSPLANT COMPLICATIONS, EXPLORING DIFFERENCES IN SAMPLES PRETRANSPLANT AND POSTTRANSPLANT. METHODS: WE COMPARED DIFFERENTIALLY METHYLATED CYTOSINE-PHOSPHATE-GUANINE SITES (DMCPGS) IN SAMPLES DERIVED FROM PERIPHERAL BLOOD MONONUCLEAR CELLS OF THE SAME KIDNEY TRANSPLANT RECIPIENTS, COLLECTED BOTH PRETRANSPLANT AND POSTTRANSPLANT (N = 154), USING THE INFINIUM METHYLATIONEPIC MICROARRAY (ILLUMINA, SAN DIEGO, CA). RECIPIENTS RECEIVED KIDNEYS FROM DECEASED DONORS AND HAD A MEAN OF 17 YEARS OF FOLLOW-UP. RESULTS: FIVE TOP-RANKED DMCPGS WERE SIGNIFICANTLY DIFFERENT AT FALSE DISCOVERY RATE (FDR) ADJUSTED P </= 9 X 10(-8); CG23597162 WITHIN JAZF1, CG25187293 WITHIN BTNL8, CG17944885, LOCATED BETWEEN ZNF788P AND ZNF625-ZNF20, CG14655917 LOCATED BETWEEN ASB4 AND PDK4 AND CG09839120 LOCATED BETWEEN GIMAP6 AND EIF2AP3. CONCLUSION: FIVE DMCPGS WERE IDENTIFIED AT THE GENERALLY ACCEPTED EWAS CRITICAL SIGNIFICANCE LEVEL OF FDR ADJUSTED P (P (FDRADJ)) </= 9 X 10(-8), INCLUDING CG23597162 (WITHIN JAZF1) AND CG17944885, WHICH HAVE PRIOR ASSOCIATIONS WITH CHRONIC KIDNEY DISEASE (CKD). COMPARING INDIVIDUALS WITH NO EVIDENCE OF POSTTRANSPLANT COMPLICATIONS (N = 105) DEMONSTRATED THAT 693,555 CPGS (89.57%) DID NOT DISPLAY ANY SIGNIFICANT DIFFERENCE IN METHYLATION (P (FDRADJ) >/= 0.05), THEREBY THIS STUDY ESTABLISHES AN IMPORTANT REFERENCE FOR FUTURE EPIGENETIC STUDIES THAT SEEK TO IDENTIFY MARKERS OF POSTTRANSPLANT COMPLICATIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                   
2 2626  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                    
3 4740  42 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	
                                        
4 6036  40 THE CHARACTERISTICS OF EXTRACHROMOSOMAL CIRCULAR DNA IN PATIENTS WITH END-STAGE RENAL DISEASE. BACKGROUND: END-STAGE RENAL DISEASE (ESRD) IS THE FINAL STAGE OF CHRONIC KIDNEY DISEASE (CKD). IN ADDITION TO THE STRUCTURALLY INTACT CHROMOSOME GENOMIC DNA, THERE IS A DOUBLE-STRANDED CIRCULAR DNA CALLED EXTRACHROMOSOMAL CIRCULAR DNA (ECCDNA), WHICH IS THOUGHT TO BE INVOLVED IN THE EPIGENETIC REGULATION OF HUMAN DISEASE. HOWEVER, THE FEATURES OF ECCDNA IN ESRD PATIENTS ARE BARELY KNOWN. IN THIS STUDY, WE IDENTIFIED ECCDNA FROM ESRD PATIENTS AND HEALTHY PEOPLE, AS WELL AS REVEALED THE CHARACTERISTICS OF ECCDNA IN PATIENTS WITH ESRD. METHODS: USING THE HIGH-THROUGHPUT CIRCLE-SEQUENCING TECHNIQUE, WE EXAMINED THE ECCDNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY PEOPLE (NC) (N = 12) AND ESRD PATIENTS (N = 16). WE ANALYZED THE LENGTH DISTRIBUTION, GENOME ELEMENTS, AND MOTIFS FEATURE OF ECCDNA IN ESRD PATIENTS. THEN, AFTER IDENTIFYING THE SPECIFIC ECCDNA IN ESRD PATIENTS, WE EXPLORED THE POTENTIAL FUNCTIONS OF THE TARGET GENES OF THE SPECIFIC ECCDNA. FINALLY, WE INVESTIGATED THE PROBABLE HUB ECCDNA USING ALGORITHMS. RESULTS: IN TOTAL, 14,431 AND 11,324 ECCDNAS WERE FOUND IN THE ESRD AND NC GROUPS, RESPECTIVELY, WITH SIZES RANGING FROM 0.01 KB TO 60 KB AT MOST. ADDITIONALLY, THE ESRD GROUP HAD A GREATER DISTRIBUTION OF ECCDNA ON CHROMOSOMES 4, 11, 13, AND 20. IN TWO GROUPS, WE ALSO DISCOVERED SEVERAL MOTIFS OF SPECIFIC ECCDNAS. FURTHERMORE, WE IDENTIFIED 13,715 SPECIFIC ECCDNAS IN THE ESRD GROUP AND 10,585 SPECIFIC ECCDNAS IN THE NC GROUP, BOTH OF WHICH WERE LARGELY ANNOTATED AS MRNA CATALOG. PATHWAY STUDIES USING GENE ONTOLOGY (GO) AND THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) SHOWED THAT THE SPECIFIC ECCDNA IN ESRD WAS MARKEDLY ENRICHED IN CELL JUNCTION AND COMMUNICATION PATHWAYS. FURTHERMORE, WE IDENTIFIED POTENTIALLY 20 HUB ECCDNA-TARGETING GENES FROM ALL ESRD-SPECIFIC ECCDNA-TARGETING GENES. ALSO, WE FOUND THAT 39 ECCDNA-TARGETING GENES WERE ASSOCIATED WITH ESRD, AND SOME OF THESE ECCDNAS MAY BE RELATED TO THE PATHOGENESIS OF ESRD. CONCLUSIONS: OUR FINDINGS REVEALED THE CHARACTERISTICS OF ECCDNA IN ESRD PATIENTS AND DISCOVERED POTENTIALLY HUB AND ESRD-RELEVANT ECCDNA-TARGETING GENES, SUGGESTING A NOVEL PROBABLE MECHANISM OF ESRD.	2023	
                                                                                                                                                          
5 1187  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 6632  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 3907  39 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8 1990  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 2946  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 2390  33 EPIGENETIC REPRESSION OF CCDC37 AND MAP1B LINKS CHRONIC OBSTRUCTIVE PULMONARY DISEASE TO LUNG CANCER. INTRODUCTION: LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) SHARE ENVIRONMENTAL RISK FACTORS. COPD ALSO INCREASES THE RISK OF LUNG CANCER; HOWEVER, THE MOLECULAR MECHANISMS ARE UNCLEAR. METHODS: AN EPIGENOME-WIDE ASSOCIATION STUDY OF LUNG TUMORS AND CANCER-FREE LUNG TISSUE (CFLT) PAIRS FROM NON-SMALL-CELL LUNG CANCER CASES WITH (N = 18) OR WITHOUT (N = 17) COPD WAS CONDUCTED USING THE HUMANMETHYLATION450 BEADCHIP (HM450K). COPD-ASSOCIATED METHYLATION OF TOP-RANKED GENES WAS CONFIRMED IN A LARGER SAMPLE SET, INDEPENDENTLY VALIDATED, AND THEIR POTENTIAL AS SPUTUM-BASED BIOMARKERS WAS INVESTIGATED. RESULTS: METHYLATION OF CCDC37 AND MAP1B WAS MORE PREVALENT IN LUNG TUMORS FROM COPD THAN NON-COPD CASES [54 OF 71 (76%) VERSUS 20 OF 46 (43%), P = 0.0013] AND [48 OF 71 (68%) VERSUS 17 OF 46 (37%), P = 0.0035], RESPECTIVELY, AFTER ADJUSTMENT FOR AGE, SEX, SMOKING STATUS, AND TUMOR HISTOLOGY. HM450K PROBES ACROSS CCDC37 AND MAP1B PROMOTERS SHOWED HIGHER METHYLATION IN TUMORS THAN CFLT WITH THE HIGHEST METHYLATION SEEN IN TUMORS FROM COPD CASES (P < 0.05). THESE RESULTS WERE INDEPENDENTLY VALIDATED USING THE CANCER GENOME ATLAS DATA. CCDC37 METHYLATION WAS MORE PREVALENT IN SPUTUM FROM COPD THAN NON-COPD SMOKERS (P < 0.005) FROM TWO COHORTS. CCDC37 AND MAP1B EXPRESSION WAS DRAMATICALLY REPRESSED IN TUMORS AND CFLT FROM COPD THAN NON-COPD CASES, P LESS THAN 0.02. CONCLUSIONS: THE REDUCED EXPRESSION OF CCDC37 AND MAP1B ASSOCIATED WITH COPD LIKELY PREDISPOSES THESE GENES TO METHYLATION THAT IN TURN, MAY CONTRIBUTE TO LUNG CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 6835  25 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12 3956  32 LONG NON-CODING RNA GENES POLYMORPHISMS H19 (RS2251375) AND MALAT1 (RS3200401) ASSOCIATION WITH RHEUMATOID ARTHRITIS AND THEIR CORRELATION WITH DISEASE ACTIVITY IN A COHORT OF EGYPTIAN PATIENTS: A PILOT STUDY. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, PROGRESSIVE, INFLAMMATORY, AUTOIMMUNE DISEASE THAT COULD BE DISABLING THROUGHOUT ITS COURSE. IT AFFECTS PEOPLE IN THEIR MOST REPRODUCTIVE YEARS WITH RELATIVELY HIGH MORBIDITY AND MORTALITY. LONG NON-CODING RNAS BECAME ONE OF THE EPIGENETIC MECHANISMS TO PROVE A LINK TO RA PATHOGENESIS AND DEVELOPMENT, INCLUDING H19 AND MALAT1 GENES. THESE TWO GENES' EXPRESSIONS HAD PROVED TO INCREASE IN MULTIPLE DISEASES, ATTRACTING ATTENTION TO THEIR POLYMORPHISMS AND THEIR POSSIBLE RISK ROLE. ASSESS THE ASSOCIATION BETWEEN H19 SNP (RS2251375) AND MALAT1 SNP (RS3200401) AND THE SUSCEPTIBILITY OF RA AND ITS DISEASE ACTIVITY. IN THIS PILOT STUDY, 200 HUNDRED SUBJECTS (100 RA PATIENTS AND 100 HEALTHY CONTROLS) WERE INVESTIGATED FOR A POSSIBLE LINK BETWEEN THE POLYMORPHISMS H19 SNP (RS2251375) AND MALAT1 SNP (3200401) AND RA SUSCEPTIBILITY AND DISEASE ACTIVITY. RA-RELATED INVESTIGATIONS AND CLINICAL ASSESSMENT WERE DONE. REAL-TIME PCR GENOTYPING OF BOTH SNPS WAS DONE USING TAQMAN(R) MGB PROBES. THERE WAS NO ASSOCIATION BETWEEN THE SNPS AND RISK OF DEVELOPING RA. HOWEVER, BOTH SNPS HAD A SIGNIFICANT ASSOCIATION WITH HIGH DISEASE ACTIVITY. H19 SNP (RS2251375) HETEROZYGOUS GENOTYPE CA HAD AN ASSOCIATION WITH ELEVATED LEVELS OF ESR (P = 0.04) AND HIGHER DAS28-ESR SCORE (P = 0.03). MALAT1 (RS3200401) C ALLELE HAD AN ASSOCIATION WITH ELEVATED ESR (P = 0.001), DAS28-ESR (P = 0.03), AND DAS28-CRP (P = 0.007), WHILE CC GENOTYPE HAD AN ASSOCIATION WITH DAS28-CRP (P = 0.015). LINKAGE DISEQUILIBRIUM AND HAPLOTYPING OF THE ALLELES OF BOTH SNPS WERE ANALYZED AS BOTH GENES ARE PRESENT ON CHROMOSOME 11, BUT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN ANY OF THE COMBINATIONS OF THE ALLELES (P > 0.05), DENOTING THAT (RS2251375) AND (RS3200401) ARE NOT IN LINKAGE DISEQUILIBRIUM. THERE IS NO ASSOCIATION BETWEEN H19 SNP (RS2251375) AND MALAT1 SNP (RS3200401) AND THE SUSCEPTIBILITY OF RA. HOWEVER, THERE IS AN ASSOCIATION BETWEEN H19 SNP (RS2251375) GENOTYPE CA AND MALAT1 SNP (RS3200401) GENOTYPE CC WITH RA HIGH DISEASE ACTIVITY.	2023	
                                                                                                                                                                       
13 5070  44 PHYSICAL ACTIVITY, TELEVISION VIEWING TIME, AND DNA METHYLATION IN PERIPHERAL BLOOD. INTRODUCTION: PHYSICAL ACTIVITY MAY AFFECT HEALTH VIA DNA METHYLATION. THE EPIGENETIC INFLUENCES OF SEDENTARY BEHAVIORS SUCH AS TELEVISION VIEWING ARE UNKNOWN. WE PERFORMED A GENOMEWIDE STUDY OF DNA METHYLATION IN PERIPHERAL BLOOD IN RELATION TO PHYSICAL ACTIVITY AND TELEVISION VIEWING TIME. METHODS: DNA METHYLATION WAS MEASURED USING THE ILLUMINA INFINIUM HUMANMETHYLATION450K BEADCHIP ARRAY IN BLOOD SAMPLES COLLECTED AT BASELINE (N = 5513) AND FOLLOW-UP (N = 1249) FROM PARTICIPANTS IN THE MELBOURNE COLLABORATIVE COHORT STUDY. AT BASELINE, TIMES PER WEEK OF LEISURE-TIME PHYSICAL ACTIVITY WERE SELF-REPORTED. AT FOLLOW-UP, THE INTERNATIONAL PHYSICAL ACTIVITY QUESTIONNAIRE WAS USED TO ASSESS MET-HOURS PER WEEK OF TOTAL AND LEISURE-TIME PHYSICAL ACTIVITY AND HOURS PER DAY OF TELEVISION VIEWING TIME. LINEAR MIXED MODELS WERE USED TO ASSESS ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY AND TELEVISION VIEWING MEASURES AND DNA METHYLATION AT INDIVIDUAL CPG SITES, ADJUSTED FOR POTENTIAL CONFOUNDERS AND BATCH EFFECTS. RESULTS: AT FOLLOW-UP, TOTAL PHYSICAL ACTIVITY WAS ASSOCIATED WITH DNA METHYLATION AT CG10266336 (P = 6.0 X 10), ANNOTATED TO THE SAA2 GENE. WEAKER EVIDENCE OF ASSOCIATIONS (P < 1.0 X 10) WERE OBSERVED FOR AN ADDITIONAL 14 CPG SITES WITH TOTAL PHYSICAL ACTIVITY, FOR 7 CPG SITES WITH LEISURE-TIME PHYSICAL ACTIVITY, AND FOR 9 CPG SITES WITH TELEVISION VIEWING TIME. CHANGES IN LEISURE-TIME PHYSICAL ACTIVITY BETWEEN BASELINE AND FOLLOW-UP WERE ASSOCIATED WITH METHYLATION CHANGES (P < 0.05) AT FOUR OF THE SEVEN CPG SITES WITH WEAKER EVIDENCE OF CROSS-SECTIONAL ASSOCIATIONS WITH LEISURE-TIME PHYSICAL ACTIVITY. CONCLUSION: PHYSICAL ACTIVITY AND TELEVISION VIEWING MAY BE ASSOCIATED WITH BLOOD DNA METHYLATION, A POTENTIAL PATHWAY TO CHRONIC DISEASE DEVELOPMENT. FURTHER RESEARCH USING ACCELEROMETER DATA AND LARGER SAMPLE SIZES IS WARRANTED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 3505  36 IDENTIFICATION OF SEX-SPECIFIC DNA METHYLATION CHANGES DRIVEN BY SPECIFIC CHEMICALS IN CORD BLOOD IN A FAROESE BIRTH COHORT. FAROE ISLANDERS CONSUME MARINE FOODS CONTAMINATED WITH METHYLMERCURY (MEHG), POLYCHLORINATED BIPHENYLS (PCBS), AND OTHER TOXICANTS ASSOCIATED WITH CHRONIC DISEASE RISKS. DIFFERENTIAL DNA METHYLATION AT SPECIFIC CPG SITES IN CORD BLOOD MAY SERVE AS A SURROGATE BIOMARKER OF HEALTH IMPACTS FROM CHEMICAL EXPOSURES. WE AIMED TO IDENTIFY KEY ENVIRONMENTAL CHEMICALS IN CORD BLOOD ASSOCIATED WITH DNA METHYLATION CHANGES IN A POPULATION WITH ELEVATED EXPOSURE TO CHEMICAL MIXTURES. WE STUDIED 72 PARTICIPANTS OF A FAROESE BIRTH COHORT RECRUITED BETWEEN 1986 AND 1987 AND FOLLOWED UNTIL ADULTHOOD. THE CORD BLOOD DNA METHYLOME WAS PROFILED USING INFINIUM HUMANMETHYLATION450 BEADCHIPS. WE DETERMINED THE ASSOCIATIONS OF CPG SITE CHANGES WITH CONCENTRATIONS OF MEHG, MAJOR PCBS, OTHER ORGANOCHLORINE COMPOUNDS [HEXACHLOROBENZENE (HCB), P,P'-DICHLORODIPHENYLDICHLOROETHYLENE (P,P'-DDE) AND P,P'-DICHLORODIPHENYLTRICHLOROETHANE], AND PERFLUOROALKYL SUBSTANCES. IN A COMBINED SEX ANALYSIS, AMONG THE 16 CHEMICALS STUDIED, PCB CONGENER 105 (CB-105) EXPOSURE WAS ASSOCIATED WITH THE MAJORITY OF DIFFERENTIALLY METHYLATED CPG SITES (214 OUT OF A TOTAL OF 250). IN FEMALE-ONLY ANALYSIS, ONLY 73 CB-105 ASSOCIATED CPG SITES WERE DETECTED, 44 OF WHICH WERE MAPPED TO GENES IN THE ELAV1-ASSOCIATED CANCER NETWORK. IN MALES-ONLY, METHYLATION CHANGES WERE SEEN FOR PERFLUOROOCTANE SULFONATE, HCB, AND P,P'-DDE IN 10,598, 1,238, AND 1,473 CPG SITES, RESPECTIVELY, 15% OF WHICH WERE ENRICHED IN CYTOBANDS OF THE X-CHROMOSOME ASSOCIATED WITH NEUROLOGICAL DISORDERS. IN THIS MULTIPLE-POLLUTANT AND GENOME-WIDE STUDY, WE IDENTIFIED KEY EPIGENETIC TOXICANTS. THE SIGNIFICANT ENRICHMENT OF SPECIFIC X-CHROMOSOME SITES IN MALES IMPLIES POTENTIAL SEX-SPECIFIC EPIGENOME RESPONSES TO PRENATAL CHEMICAL EXPOSURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 2621  32 EPIGENOME-WIDE ASSOCIATION STUDIES IDENTIFY DNA METHYLATION ASSOCIATED WITH KIDNEY FUNCTION. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). PREVIOUS GENETIC STUDIES HAVE IMPLICATED REGULATORY MECHANISMS CONTRIBUTING TO CKD. HERE WE PRESENT EPIGENOME-WIDE ASSOCIATION STUDIES OF EGFR AND CKD USING WHOLE-BLOOD DNA METHYLATION OF 2264 ARIC STUDY AND 2595 FRAMINGHAM HEART STUDY PARTICIPANTS TO IDENTIFY EPIGENETIC SIGNATURES OF KIDNEY FUNCTION. OF 19 CPG SITES SIGNIFICANTLY ASSOCIATED (P < 1E-07) WITH EGFR/CKD AND REPLICATED, FIVE ALSO ASSOCIATE WITH RENAL FIBROSIS IN BIOPSIES FROM CKD PATIENTS AND SHOW CONCORDANT DNA METHYLATION CHANGES IN KIDNEY CORTEX. LEAD CPGS AT PTPN6/PHB2, ANKRD11, AND TNRC18 MAP TO ACTIVE ENHANCERS IN KIDNEY CORTEX. AT PTPN6/PHB2 CG19942083, METHYLATION IN KIDNEY CORTEX ASSOCIATES WITH LOWER RENAL PTPN6 EXPRESSION, HIGHER EGFR, AND LESS RENAL FIBROSIS. THE REGIONS CONTAINING THE 243 EGFR-ASSOCIATED (P < 1E-05) CPGS ARE SIGNIFICANTLY ENRICHED FOR TRANSCRIPTION FACTOR BINDING SITES OF EBF1, EP300, AND CEBPB (P < 5E-6). OUR FINDINGS HIGHLIGHT KIDNEY FUNCTION ASSOCIATED EPIGENETIC VARIATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16   11  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                   
17 3050  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 2978  38 GENETIC ASSOCIATION AND EXPRESSION ANALYSES OF THE PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE (PIP5K1C) GENE IN ALCOHOL USE DISORDER-RELEVANCE FOR PAIN SIGNALING AND ALCOHOL USE. BACKGROUND: THE GENE ENCODING PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE (PIP5K1C) HAS BEEN RECENTLY IMPLICATED IN PAIN REGULATION. INTERESTINGLY, A RECENT CROSS-TISSUE AND CROSS-PHENOTYPIC EPIGENETIC ANALYSIS IDENTIFIED THE SAME GENE IN ALCOHOL USE DISORDER (AUD). GIVEN THE HIGH COMORBIDITY BETWEEN AUD AND CHRONIC PAIN, WE HYPOTHESIZED THAT GENETIC VARIATION IN PIP5K1C MIGHT CONTRIBUTE TO SUSCEPTIBILITY TO AUD. METHODS: WE CONDUCTED A CASE-CONTROL ASSOCIATION STUDY OF GENETIC VARIANTS IN PIP5K1C. ASSOCIATION ANALYSES OF 16 COMMON PIP5K1C SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WERE CONDUCTED IN CASES AND CONTROLS OF AFRICAN (427 CASES AND 137 CONTROLS) AND EUROPEAN ANCESTRY (488 CASES AND 324 CONTROLS) USING STANDARD METHODS. IN ADDITION, GIVEN THE PROMINENT ROLE OF THE OPIOID SYSTEM IN PAIN SIGNALING, WE INVESTIGATED THE EFFECTS OF ACUTE ALCOHOL EXPOSURE ON PIP5K1C EXPRESSION IN HUMANIZED TRANSGENIC MICE FOR THE MU-OPIOID RECEPTOR THAT INCLUDED THE OPRM1 A118G POLYMORPHISM, A WIDELY USED MOUSE MODEL TO STUDY ANALGESIC RESPONSE TO OPIOIDS IN PAIN. PIP5K1C EXPRESSION WAS MEASURED IN THE THALAMUS AND BASOLATERAL AMYGDALA (BLA) IN MICE AFTER SHORT-TERM ADMINISTRATION (SINGLE 2 G/KG DOSE) OF ALCOHOL OR SALINE USING IMMUNOHISTOCHEMISTRY AND ANALYZED BY 2-WAY ANALYSIS OF VARIANCE. RESULTS: IN THE CASE-CONTROL ASSOCIATION STUDY USING AN NIAAA DISCOVERY SAMPLE, 8 SNPS IN PIP5K1C WERE SIGNIFICANTLY ASSOCIATED WITH AUD IN THE AFRICAN ANCESTRY (AA) GROUP (P < 0.05 AFTER CORRECTION; RS4807493, RS10405681, RS2074957, RS10432303, RS8109485, RS1476592, RS10419980, AND RS4432372). HOWEVER, A REPLICATION ANALYSIS USING AN INDEPENDENT SAMPLE (N = 3,801) FOUND NO SIGNIFICANT ASSOCIATIONS AFTER CORRECTION FOR MULTIPLE TESTING. IN THE HUMANIZED TRANSGENIC MOUSE MODEL WITH THE OPRM1 POLYMORPHISM, PIP5K1C EXPRESSION WAS SIGNIFICANTLY DIFFERENT BETWEEN ALCOHOL AND SALINE-TREATED MICE, REGARDLESS OF GENOTYPE, IN BOTH THE THALAMUS (P < 0.05) AND BLA (P < 0.01). CONCLUSIONS: OUR DISCOVERY SAMPLE SHOWS THAT GENETIC VARIANTS IN PIP5K1C ARE ASSOCIATED WITH AUD IN THE AA GROUP, AND ACUTE ALCOHOL EXPOSURE LEADS TO UP-REGULATION OF PIP5K1C, POTENTIALLY EXPLAINING A MECHANISM UNDERLYING THE INCREASED RISK FOR CHRONIC PAIN CONDITIONS IN INDIVIDUALS WITH AUD.	2018	

19 3753  34 INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA TO IDENTIFY POTENTIAL BIOMARKERS RELATED TO ATHEROSCLEROSIS ONSET. ATHEROSCLEROSIS IS A KIND OF CHRONIC INFLAMMATORY CARDIOVASCULAR DISEASE. EPIGENETIC REGULATION PLAYS A CRUCIAL ROLE IN ATHEROSCLEROSIS. OUR STUDY WAS AIMED AT FINDING POTENTIAL BIOMARKERS ASSOCIATED WITH THE OCCURRENCE OF ATHEROSCLEROSIS. TWO DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. THE EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ANALYSIS WAS PERFORMED ON METHYLATION DATA USING CPGASSOC PACKAGE. THE DIFFERENTIAL EXPRESSION ANALYSIS WAS CONDUCTED ON MRNA DATA USING LIMMA PACKAGE. THE GO (GENE ONTOLOGY) AND KEGG (KYOTO ENCYCLOPEDIA OF GENES AND GENOMES) FUNCTIONAL ENRICHMENT WAS DONE IN CLUSTERPROFILER PACKAGE. FINALLY, THE LOGISTIC REGRESSION MODEL WAS CONSTRUCTED USING GENERALIZED LINEAR MODEL (GLM) FUNCTION. BETWEEN ATHEROSCLEROTIC VS. NONATHEROSCLEROTIC SAMPLES, TOTALLY 4980 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES (ANNOTATED TO 2860 GENES) AND 132 DIFFERENTIALLY EXPRESSED GENES (DEGS) RELATED TO ATHEROSCLEROSIS WERE IDENTIFIED. THE ANNOTATED 2860 GENES AND 132 DEGS WERE SIGNIFICANTLY ENRICHED IN 9 AND 4 KEGG PATHWAYS AND 289 AND 132 GO TERMS, RESPECTIVELY. AFTER CROSS-ANALYSIS, 6 CRUCIAL CPG SITES WERE SCREENED TO BUILD THE MODEL, INCLUDING CG01187920, CG03422911, CG08018825, CG10967350, CG14473924, AND CG25313204. THE DIAGNOSTIC MODEL COULD RELIABLY SEPARATE THE ATHEROSCLEROSIS SAMPLES FROM NONATHEROSCLEROTIC SAMPLES. IN CONCLUSION, THE 6 CPG SITES ARE PROBABLY POTENTIAL DIAGNOSTIC BIOMARKERS FOR ATHEROSCLEROSIS, INCLUDING CG01187920, CG03422911, CG08018825, CG10967350, CG14473924, AND CG25313204.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20 5621  27 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