1 4240 100 METHYLATION QUANTITATIVE TRAIT LOCUS ANALYSIS OF CHRONIC POSTSURGICAL PAIN UNCOVERS EPIGENETIC MEDIATORS OF GENETIC RISK. BACKGROUND: OVERLAP OF PATHWAYS ENRICHED BY SINGLE NUCLEOTIDE POLYMORPHISMS AND DNA-METHYLATION UNDERLYING CHRONIC POSTSURGICAL PAIN (CPSP), PROMPTED PILOT STUDY OF CPSP-ASSOCIATED METHYLATION QUANTITATIVE TRAIT LOCI (MEQTL). MATERIALS & METHODS: CHILDREN UNDERGOING SPINE-FUSION WERE RECRUITED PROSPECTIVELY. LOGISTIC-REGRESSION FOR GENOME- AND EPIGENOME-WIDE CPSP ASSOCIATION AND DNA-METHYLATION-SINGLE NUCLEOTIDE POLYMORPHISM ASSOCIATION/MEDIATION ANALYSES TO IDENTIFY MEQTLS WERE FOLLOWED BY FUNCTIONAL GENOMICS ANALYSES. RESULTS: CPSP (N = 20/58) AND NON-CPSP GROUPS DIFFERED IN PAIN-MEASURES. OF 2753 MEQTLS, DNA-METHYLATION AT 127 CYTOSINE-GUANINE DINUCLEOTIDES MEDIATED ASSOCIATION OF 470 MEQTLS WITH CPSP (P < 0.05). AT PARK16 LOCUS, CPSP RISK MEQTLS WERE ASSOCIATED WITH DECREASED DNA-METHYLATION AT RAB7L1 AND INCREASED DNA-METHYLATION AT PM20D1. CORRESPONDING RAB7L1/PM20D1 BLOOD EQTLS (GTEX) AND CYTOSINE-GUANINE DINUCLEOTIDE-LOCI ENRICHMENT FOR HISTONE MARKS, TRANSCRIPTION FACTOR BINDING SITES AND ATAC-SEQ PEAKS SUGGEST ALTERED TRANSCRIPTION FACTOR-BINDING. CONCLUSION: CPSP-ASSOCIATED MEQTLS INDICATE EPIGENETIC MECHANISMS MEDIATE GENETIC RISK. CLINICAL TRIAL REGISTRATION: NCT01839461, NCT01731873 (CLINICALTRIALS.GOV). 2021 2 2626 30 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 3753 25 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 4 6632 28 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 5 1422 20 DIFFERENTIAL CPG DNA METHYLATION OF PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES IN IGG4-RELATED DISEASE. OBJECTIVES: IMMUNOGLOBULIN-G4-RELATED DISEASE (IGG4-RD) IS A DISTINCT SYSTEMIC AUTOIMMUNE-MEDIATED DISEASE MANIFESTING AS CHRONIC INFLAMMATION AND TISSUE FIBROSIS. SINCE THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF IGG4-RD IS STILL UNCLEAR, WE CONDUCT THIS STUDY TO INVESTIGATE EPIGENETIC MODIFICATIONS IN IGG4-RD. METHODS: A GENOME-WIDE DNA METHYLATION STUDY WAS CONDUCTED WITH B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS AND MATCHED CONTROLS BY USING THE ILLUMINA HUMANMETHYLATION 850K BEADCHIP. WE FURTHER PERFORMED PYROSEQUENCING AND IMMUNOHISTOCHEMISTRY ASSAYS TO VALIDATE THE METHYLATION STATUS OF SOME TARGETS OF INTEREST. RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES INCLUDING 44 HYPOMETHYLATED AND 166 HYPERMETHYLATED DIFFERENTIALLY METHYLATED PROBES (DMPS) IN B CELLS AND 260 HYPOMETHYLATED AND 112 HYPERMETHYLATED DMPS IN CD4(+) T CELLS FROM 10 IGG4-RD PATIENTS COMPARED WITH 10 HEALTHY CONTROLS. WE ALSO IDENTIFIED 36945 HYPOMETHYLATED AND 78380 HYPERMETHYLATED DMPS IN SALIVARY GLAND TISSUES OF 4 IGG4-RD PATIENTS COMPARED WITH 4 CONTROLS. DPM2 (CG21181453), IQCK (CG10266221), AND ABCC13 (CG05699681, CG04985582) WERE HYPERMETHYLATED AND MBP (CG18455083) WAS HYPOMETHYLATED IN B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS. WE ALSO OBSERVED THE HYPOMETHYLATED HLA-DQB2 IN CD4(+) T CELLS FROM IGG4-RD PATIENTS. KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSIS OF DMPS IN SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS REVEALED ENRICHMENT OF PATHWAYS INVOLVED IN THE REGULATION OF IMMUNE CELL RESPONSES AND FIBROSIS. CONCLUSION: THIS IS THE FIRST DNA METHYLATION STUDY IN PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS. OUR FINDINGS HIGHLIGHTED THE ROLE OF EPIGENETIC MODIFICATION OF DNA METHYLATION AND IDENTIFIED SEVERAL GENES AND PATHWAYS POSSIBLY INVOLVED IN IGG4-RD PATHOGENESIS. 2023 6 4740 33 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 7 1187 33 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 8 2946 22 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 9 3907 21 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 10 1496 18 DNA IS HYPOMETHYLATED IN CIRCADIAN MANIFESTATIONS OF BRUXISM. OBJECTIVE: THE AIM OF THIS STUDY WAS TO COMPARE THE GLOBAL DNA METHYLATION LEVELS IN PATIENTS UNDER BRUXISM TREATMENT AND A CONTROL GROUP. METHODS: SUBJECTS UNDERGOING BRUXISM TREATMENT WERE CLASSIFIED IN AWAKE BRUXISM (42 PATIENTS), SLEEP BRUXISM (32 PATIENTS) AND BOTH CONDITIONS (42 PATIENTS). THE CONTROL GROUP INCLUDED 42 INDIVIDUALS. A COLORIMETRIC ASSAY (METHYLFLASH METHYLATED DNA 5-MC QUANTIFICATION KIT, EPIGENETIC GROUP INC., NY, USA) WAS USED TO DETERMINE THE GLOBAL DNA METHYLATION LEVELS. RESULTS: STATISTICALLY SIGNIFICANT DIFFERENCES WERE FOUND IN AMOUNTS OF METHYLATED DNA IN ALL CIRCADIAN MANIFESTATIONS OF BRUXISM COMPARED WITH A CONTROL GROUP (SLEEP BRUXISM = 0.95% +/- 2.02%; AWAKE BRUXISM = 0.87% +/- 2.1%; SLEEP AND AWAKE BRUXISM = 0.17% +/- 0.25%; CONTROL = 1.69% +/- 1.6%; KRUSKAL-WALLIS TEST [P = .0001] FOLLOWED BY DUNN'S TEST [P < .05]). CONCLUSION: PATIENTS UNDERGOING BRUXISM TREATMENT EXHIBITED HYPOMETHYLATED DNA LEVELS WHEN COMPARED TO CONTROL GROUP. OUR RESULTS SUGGEST THAT DNA HYPOMETHYLATION MIGHT BE A NOVEL AETIOLOGIC FACTOR IN BRUXISM AETIOLOGY. FURTHER RESEARCHES MUST BE PERFORMED EXPLORING THE ROLE OF EPIGENETICS MODIFICATIONS IN CIRCADIAN MANIFESTATIONS OF BRUXISM. 2018 11 2125 20 EPIGENETIC INACTIVATION OF DLX4 IS ASSOCIATED WITH DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION OF VARIOUS GENES HAS BEEN IDENTIFIED TO BE ASSOCIATED WITH DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA (CML). OUR STUDY WAS INTENDED TO INVESTIGATE DLX4 METHYLATION PATTERN IN DIFFERENT CLINICAL STAGES OF CML AND FURTHER DETERMINE ITS ROLE IN REGULATING DLX4 EXPRESSION. REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC PCR AND BISULFITE SEQUENCING PCR WERE APPLIED TO DETECT DLX4 METHYLATION. 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) WAS USED FOR DEMETHYLATION STUDIES. DLX4 WAS SIGNIFICANTLY HYPERMETHYLATED IN CML PATIENTS (P = 0.002) ESPECIALLY IN BLASTIC PHASE (BC) STAGE (P < 0.001) AS COMPARED WITH CONTROLS. MOREOVER, DLX4 METHYLATION LEVEL IN BC STAGE WAS SIGNIFICANTLY HIGHER THAN IN CHRONIC PHASE (CP) STAGE (P < 0.001). DLX4 METHYLATION DENSITY WAS SIGNIFICANTLY INCREASED DURING THE PROGRESSION OF CML AMONG THE TESTED TWO PATIENTS (P < 0.001). DLX4 HYPERMETHYLATION OCCURRED WITH THE HIGHEST INCIDENCE IN BC STAGE (83%), LOWER INCIDENCE IN ACUTE PHASE (AP) STAGE (43%), AND THE LOWEST INCIDENCE IN CP STAGE (26%) (P = 0.001). MOREOVER, T(9; 22) WITH ADDITIONAL ALTERATION CASES HAD SIGNIFICANTLY HIGHER FREQUENCY OF DLX4 HYPERMETHYLATION COMPARED WITH THE OTHER CYTOGENETICS (P = 0.010). SIGNIFICANTLY NEGATIVE CORRELATION WAS OBSERVED BETWEEN DLX4 METHYLATION AND DLX4-TV2 (THE SHORTER DLX4 ISOFORM) EXPRESSION (R = -0.382, P = 0.001, N = 78) BUT NOT BETWEEN DLX4 METHYLATION AND BP1 (THE LONGER DLX4 ISOFORM) EXPRESSION (R = 0.134, P = 0.244, N = 78) IN CML PATIENTS. BOTH DLX4-TV2 AND BP1 MRNA WERE SIGNIFICANTLY INCREASED AFTER 5-AZA-DC TREATMENT IN K562 CELL LINE (P < 0.001). OUR STUDY INDICATED THAT HYPERMETHYLATION OF DLX4 CORRELATED WITH DISEASE PROGRESSION OF CML. MOREOVER, DLX4 EXPRESSION WAS REGULATED BY ITS METHYLATION IN CML. 2015 12 2978 31 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 13 1622 23 DNA METHYLTRANSFERASES IN MALAR MELASMA AND THEIR MODIFICATION BY SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. BACKGROUND: MALAR MELASMA HAS A CHRONIC AND RECURRENT CHARACTER THAT MAY BE RELATED TO EPIGENETIC CHANGES. OBJECTIVE: TO RECOGNIZE THE EXPRESSION AND DNA METHYLATION OF DNA METHYLTRANSFERASES (DNMTS) IN MALAR MELASMA AND PERILESIONAL SKIN, AS WELL AS THE CHANGES IN DNMTS AFTER THEIR TREATMENT WITH SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. METHODS: THIRTY FEMALE PATIENTS WERE CLINICALLY EVALUATED FOR THE EXPRESSION OF DNMT1 AND DNMT3B USING REAL-TIME PCR AND IMMUNOFLUORESCENCE. THESE INITIAL RESULTS WERE COMPARED TO RESULTS AFTER EIGHT WEEKS OF TREATMENT WITH SUNSCREEN IN COMBINATION WITH NIACINAMIDE, RETINOIC ACID, OR PLACEBO. RESULTS: THE RELATIVE EXPRESSION OF DNMT1 WAS SIGNIFICANTLY ELEVATED IN MELASMA COMPARED WITH UNAFFECTED SKIN IN ALL SUBJECTS, INDICATING DNA HYPERMETHYLATION. AFTER TREATMENT, IT WAS DECREASED IN ALL GROUPS: NIACINAMIDE (7 VERSUS 1; P<0.01), RETINOIC ACID (7 VERSUS 2; P<0.05), AND PLACEBO (7 VERSUS 3; P<0.05), WHICH CORRELATES WITH CLINICAL IMPROVEMENT. DNMT3B WAS NOT OVEREXPRESSED IN LESIONAL SKIN BUT REDUCED IN ALL GROUPS. CONCLUSIONS: WE FOUND DNA HYPERMETHYLATION IN MELASMA LESIONS. ENVIRONMENTAL FACTORS SUCH AS SOLAR RADIATION MAY INDUCE CELLULAR CHANGES THAT TRIGGER HYPERPIGMENTATION THROUGH THE ACTIVATION OF PATHWAYS REGULATED BY EPIGENETIC MODIFICATIONS. HOWEVER, LIMITING OR DECREASING DNA METHYLATION THROUGH SUNSCREEN, NIACINAMIDE, AND RETINOIC ACID TREATMENTS THAT PROVIDE PHOTOPROTECTION AND GENETIC TRANSCRIPTION CAN COUNTERACT THIS. 2019 14 5621 18 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 15 154 18 ABERRANT METHYLATION OF NUCLEOTIDE EXCISION REPAIR GENES IS ASSOCIATED WITH CHRONIC ARSENIC POISONING. OBJECTIVE: TO DEFINE WHETHER ABERRANT METHYLATION OF DNA REPAIR GENES IS ASSOCIATED WITH CHRONIC ARSENIC POISONING. METHODS: HUNDRED AND TWO ENDEMIC ARSENICOSIS PATIENTS AND 36 HEALTHY SUBJECTS WERE RECRUITED. METHYLIGHT AND BISULFITE SEQUENCING (BSP) ASSAYS WERE USED TO EXAMINE THE METHYLATION STATUS OF ERCC1, ERCC2 AND XPC GENES IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) AND SKIN LESIONS OF ARSENICOSIS PATIENTS AND NAASO(2)-TREATED HACAT CELLS. RESULTS: HYPERMETHYLATION OF ERCC1 AND ERCC2 AND SUPPRESSED GENE EXPRESSION WERE FOUND IN PBLS AND SKIN LESIONS OF ARSENICOSIS PATIENTS AND WAS CORRELATED WITH THE LEVEL OF ARSENIC EXPOSURE. PARTICULARLY, THE EXPRESSION OF ERCC1 AND ERCC2 WAS ASSOCIATED WITH THE SEVERITY OF SKIN LESIONS. IN VITRO STUDIES REVEALED AN INDUCTION OF ERCC2 HYPERMETHYLATION AND DECREASED MRNA EXPRESSION IN RESPONSE TO NAASO(2) TREATMENT. CONCLUSION: HYPERMETHYLATION OF ERCC1 AND ERCC2 AND CONCOMITANT SUPPRESSION OF GENE EXPRESSION MIGHT BE SERVED AS THE EPIGENETIC MARKS ASSOCIATED WITH ARSENIC EXPOSURE AND ADVERSE HEALTH EFFECTS. 2017 16 6036 24 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 17 3992 27 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 /= 0.05), THEREBY THIS STUDY ESTABLISHES AN IMPORTANT REFERENCE FOR FUTURE EPIGENETIC STUDIES THAT SEEK TO IDENTIFY MARKERS OF POSTTRANSPLANT COMPLICATIONS. 2023 18 3956 18 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 19 145 23 ABERRANT DNA METHYLATION STATUS AND MRNA EXPRESSION LEVEL OF SMG1 GENE IN CHRONIC MYELOID LEUKEMIA: A CASE-CONTROL STUDY. OOBJECTIVE: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE MALIGNANCY WITH DIFFERENT STAGES. ABERRANT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HAVE BEEN INTRODUCED AS A SIGNATURE FOR DIVERSE CANCERS WHICH ALSO PLAYS A CRUCIAL ROLE IN CML PATHOGENESIS AND DEVELOPMENT. SUPPRESSOR WITH MORPHOGENETIC EFFECT ON GENITALIA (SMG1) GENE RECENTLY HAS BEEN BROUGHT TO THE SPOTLIGHT AS A POTENT TUMOR SUPPRESSOR GENE THAT CAN BE SUPPRESSED BY TUMORS FOR FURTHER PROGRESS. THE PRESENT STUDY AIMS TO INVESTIGATE SMG1 STATUS IN CML PATIENTS. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, PERIPHERAL BLOOD FROM 30 PATIENTS WITH DIFFERENT PHASES OF CML [NEW CASE (N)=10, COMPLETE MOLECULAR REMISSION (CMR)=10, BLASTIC PHASE (BP)=10] AND 10 HEALTHY SUBJECTS WERE COLLECTED. METHYLATION STATUS AND EXPRESSION LEVEL OF SMG1 GENE PROMOTER WAS ASSESSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND QUANTITATIVE REVERSE-TRANSCRIPTION PCR, RESPECTIVELY. RESULTS: MSP RESULTS OF SMG1 GENE PROMOTOR IN THE NEW CASE GROUP WERE METHYLATED (60% METHYLATED, 30% HEMIMETHYLATED AND 10% UNMETHYLATED). ALL CMR AND CONTROL GROUP PATIENTS WERE UNMETHYLATED IN THE SMG1 GENE PROMOTER. IN THE BP GROUP, METHYLATED SMG1 PROMOTER WAS SEEN (50% OF PATIENTS HAD A METHYLATED STATUS AND 50% HAD HEMIMETHYLATED STATUS). IN COMPARISON WITH THE HEALTHY SUBJECTS, EXPRESSION LEVEL OF SMG1 IN THE NEW CASE GROUP WAS DECREASED (P<0.01); IN THE CMR GROUP AND BP-CML GROUPS, IT WAS INCREASED (P<0.05). NO SIGNIFICANT CORRELATION BETWEEN PATIENTS' HEMATOLOGICAL FEATURES AND SMG1 METHYLATION WAS SEEN. CONCLUSION: OUR RESULTS DEMONSTRATED THAT ABERRANT METHYLATION OF SMG1 OCCURRED IN CML PATIENTS AND IT HAD A SIGNIFICANT ASSOCIATION WITH SMG1 EXPRESSION. SMG1 GENE PROMOTER SHOWED DIVERSE METHYLATED STATUS AND SUBSEQUENT EXPRESSION LEVELS IN DIFFERENT PHASES OF CML. THESE FINDINGS SUGGESTED POSSIBLE PARTICIPATION OF SMG1 SUPPRESSION IN THE CML PATHOGENESIS. 2022 20 3505 24 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