1 1110 193 COMMON GENETIC POLYMORPHISMS INFLUENCE BLOOD BIOMARKER MEASUREMENTS IN COPD. IMPLEMENTING PRECISION MEDICINE FOR COMPLEX DISEASES SUCH AS CHRONIC OBSTRUCTIVE LUNG DISEASE (COPD) WILL REQUIRE EXTENSIVE USE OF BIOMARKERS AND AN IN-DEPTH UNDERSTANDING OF HOW GENETIC, EPIGENETIC, AND ENVIRONMENTAL VARIATIONS CONTRIBUTE TO PHENOTYPIC DIVERSITY AND DISEASE PROGRESSION. A META-ANALYSIS FROM TWO LARGE COHORTS OF CURRENT AND FORMER SMOKERS WITH AND WITHOUT COPD [SPIROMICS (N = 750); COPDGENE (N = 590)] WAS USED TO IDENTIFY SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) ASSOCIATED WITH MEASUREMENT OF 88 BLOOD PROTEINS (PROTEIN QUANTITATIVE TRAIT LOCI; PQTLS). PQTLS CONSISTENTLY REPLICATED BETWEEN THE TWO COHORTS. FEATURES OF PQTLS WERE COMPARED TO PREVIOUSLY REPORTED EXPRESSION QTLS (EQTLS). INFERENCE OF CAUSAL RELATIONS OF PQTL GENOTYPES, BIOMARKER MEASUREMENTS, AND FOUR CLINICAL COPD PHENOTYPES (AIRFLOW OBSTRUCTION, EMPHYSEMA, EXACERBATION HISTORY, AND CHRONIC BRONCHITIS) WERE EXPLORED USING CONDITIONAL INDEPENDENCE TESTS. WE IDENTIFIED 527 HIGHLY SIGNIFICANT (P < 8 X 10-10) PQTLS IN 38 (43%) OF BLOOD PROTEINS TESTED. MOST PQTL SNPS WERE NOVEL WITH LOW OVERLAP TO EQTL SNPS. THE PQTL SNPS EXPLAINED >10% OF MEASURED VARIATION IN 13 PROTEIN BIOMARKERS, WITH A SINGLE SNP (RS7041; P = 10-392) EXPLAINING 71%-75% OF THE MEASURED VARIATION IN VITAMIN D BINDING PROTEIN (GENE = GC). SOME OF THESE PQTLS [E.G., PQTLS FOR VDBP, SRAGE (GENE = AGER), SURFACTANT PROTEIN D (GENE = SFTPD), AND TNFRSF10C] HAVE BEEN PREVIOUSLY ASSOCIATED WITH COPD PHENOTYPES. MOST PQTLS WERE LOCAL (CIS), BUT DISTANT (TRANS) PQTL SNPS IN THE ABO BLOOD GROUP LOCUS WERE THE TOP PQTL SNPS FOR FIVE PROTEINS. THE INCLUSION OF PQTL SNPS IMPROVED THE CLINICAL PREDICTIVE VALUE FOR THE ESTABLISHED ASSOCIATION OF SRAGE AND EMPHYSEMA, AND THE EXPLANATION OF VARIANCE (R2) FOR EMPHYSEMA IMPROVED FROM 0.3 TO 0.4 WHEN THE PQTL SNP WAS INCLUDED IN THE MODEL ALONG WITH CLINICAL COVARIATES. CAUSAL MODELING PROVIDED INSIGHT INTO SPECIFIC PQTL-DISEASE RELATIONSHIPS FOR AIRFLOW OBSTRUCTION AND EMPHYSEMA. IN CONCLUSION, GIVEN THE FREQUENCY OF HIGHLY SIGNIFICANT LOCAL PQTLS, THE LARGE AMOUNT OF VARIANCE POTENTIALLY EXPLAINED BY PQTL, AND THE DIFFERENCES OBSERVED BETWEEN PQTLS AND EQTLS SNPS, WE RECOMMEND THAT PROTEIN BIOMARKER-DISEASE ASSOCIATION STUDIES TAKE INTO ACCOUNT THE POTENTIAL EFFECT OF COMMON LOCAL SNPS AND THAT PQTLS BE INTEGRATED ALONG WITH EQTLS TO UNCOVER DISEASE MECHANISMS. LARGE-SCALE BLOOD BIOMARKER STUDIES WOULD ALSO BENEFIT FROM CLOSE ATTENTION TO THE ABO BLOOD GROUP. 2016 2 3050 30 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 3 57 48 A GENOME-WIDE ASSOCIATION STUDY OF QUANTITATIVE COMPUTED TOMOGRAPHIC EMPHYSEMA IN KOREAN POPULATIONS. EMPHYSEMA IS AN IMPORTANT FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). GENETIC FACTORS LIKELY AFFECT EMPHYSEMA PATHOGENESIS, BUT THIS QUESTION HAS PREDOMINANTLY BEEN STUDIED IN THOSE OF EUROPEAN ANCESTRY. IN THIS STUDY, WE SOUGHT TO DETERMINE GENETIC COMPONENTS OF EMPHYSEMA SEVERITY AND CHARACTERIZE THE POTENTIAL FUNCTION OF THE ASSOCIATED LOCI IN KOREAN POPULATION. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) ON QUANTITATIVE EMPHYSEMA IN SUBJECTS WITH OR WITHOUT COPD FROM TWO KOREAN COPD COHORTS. WE INVESTIGATED THE FUNCTIONAL CONSEQUENCES OF THE LOCI USING EPIGENETIC ANNOTATION AND GENE EXPRESSION DATA. WE ALSO COMPARED OUR GWAS RESULTS WITH AN EPIGENOME-WIDE ASSOCIATION STUDY AND PREVIOUS DIFFERENTIAL GENE EXPRESSION ANALYSIS. IN TOTAL, 548 SUBJECTS (476 [86.9%] MALE) INCLUDING 514 COPD PATIENTS WERE EVALUATED. WE IDENTIFIED ONE GENOME-WIDE SIGNIFICANT SNP (P < 5.0 X 10(-8)), RS117084279, NEAR PIBF1. WE IDENTIFIED AN ADDITIONAL 57 SNPS (P < 5.0 X 10(-6)) ASSOCIATED WITH EMPHYSEMA IN ALL SUBJECTS, AND 106 SNPS (P < 5.0 X 10(-6)) IN COPD PATIENTS. OF THESE CANDIDATE SNPS, 2 (RS12459249, RS11667314) NEAR CYP2A6 WERE EXPRESSION QUANTITATIVE TRAIT LOCI IN LUNG TISSUE AND A SNP (RS11214944) NEAR NNMT WAS AN EXPRESSION QUANTITATIVE TRAIT LOCUS IN WHOLE BLOOD. OF NOTE, RS11214944 WAS IN LINKAGE DISEQUILIBRIUM WITH VARIANTS IN ENHANCER HISTONE MARKS IN LUNG TISSUE. SEVERAL GENES NEAR ADDITIONAL SNPS WERE IDENTIFIED IN OUR PREVIOUS EWAS STUDY WITH NOMINAL LEVEL OF SIGNIFICANCE. WE IDENTIFIED A NOVEL SNP ASSOCIATED WITH QUANTITATIVE EMPHYSEMA ON CT. INCLUDING THE NOVEL SNP, SEVERAL CANDIDATE SNPS IN OUR STUDY MAY PROVIDE CLUES TO THE GENETIC ETIOLOGY OF EMPHYSEMA IN ASIAN POPULATIONS. FURTHER RESEARCH AND VALIDATION OF THE LOCI WILL HELP DETERMINE THE GENETIC FACTORS FOR THE DEVELOPMENT OF EMPHYSEMA. 2021 4 11 47 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 5 6190 48 THE IMPACT OF METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ON ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES. BACKGROUND: METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ARE THE GENETIC VARIANTS THAT MAY AFFECT THE DNA METHYLATION PATTERNS OF CPG SITES. HOWEVER, THEIR ROLES IN INFLUENCING THE DISTURBANCES OF SMOKING-RELATED EPIGENETIC CHANGES HAVE NOT BEEN WELL ESTABLISHED. THIS STUDY WAS CONDUCTED TO ADDRESS WHETHER MQTLS EXIST IN THE VICINITY OF SMOKING-RELATED CPG SITES (+/- 50 KB) AND TO EXAMINE THEIR ASSOCIATIONS WITH SMOKING EXPOSURE AND ALL-CAUSE MORTALITY IN OLDER ADULTS. RESULTS: WE OBTAINED DNA METHYLATION PROFILES IN WHOLE BLOOD SAMPLES BY ILLUMINA INFINIUM HUMAN METHYLATION 450 BEADCHIP ARRAY OF TWO INDEPENDENT SUBSAMPLES OF THE ESTHER STUDY (DISCOVERY SET, N = 581; VALIDATION SET, N = 368) AND THEIR CORRESPONDING GENOTYPING DATA USING THE ILLUMINA INFINIUM ONCOARRAY BEADCHIP. AFTER CORRECTION FOR MULTIPLE TESTING (FDR), WE SUCCESSFULLY IDENTIFIED THAT 70 OUT OF 151 PREVIOUSLY REPORTED SMOKING-RELATED CPG SITES WERE SIGNIFICANTLY ASSOCIATED WITH 192 SNPS WITHIN THE 50 KB SEARCH WINDOW OF EACH LOCUS. THE 192 MQTLS SIGNIFICANTLY INFLUENCED THE ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES, WITH PERCENTAGE CHANGES RANGING FROM 0.01 TO 18.96%, ESPECIALLY FOR THE WEAKLY/MODERATELY SMOKING-RELATED CPG SITES. HOWEVER, THESE IDENTIFIED MQTLS WERE NOT DIRECTLY ASSOCIATED WITH ACTIVE SMOKING EXPOSURE OR ALL-CAUSE MORTALITY. CONCLUSIONS: OUR FINDINGS CLEARLY DEMONSTRATED THAT IF NOT DEALT WITH PROPERLY, THE MQTLS MIGHT IMPAIR THE POWER OF EPIGENETIC-BASED MODELS OF SMOKING EXPOSURE TO A CERTAIN EXTENT. IN ADDITION, SUCH GENETIC VARIANTS COULD BE THE KEY FACTOR TO DISTINGUISH BETWEEN THE HERITABLE AND SMOKING-INDUCED IMPACT ON EPIGENOME DISPARITIES. THESE MQTLS ARE OF SPECIAL IMPORTANCE WHEN DNA METHYLATION MARKERS MEASURED BY ILLUMINA INFINIUM ASSAY ARE USED FOR ANY COMPARATIVE POPULATION STUDIES RELATED TO SMOKING-RELATED CANCERS AND CHRONIC DISEASES. 2017 6 1590 37 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 7 1187 46 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 3078 45 GENOME-WIDE METHYLATION ANALYSIS OF A LARGE POPULATION SAMPLE SHOWS NEUROLOGICAL PATHWAYS INVOLVEMENT IN CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN. CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN (CWP), HAS A CONSIDERABLE HERITABLE COMPONENT, WHICH REMAINS TO BE EXPLAINED. EPIGENETIC FACTORS MAY CONTRIBUTE TO AND ACCOUNT FOR SOME OF THE HERITABILITY ESTIMATE. WE ANALYSED EPIGENOME-WIDE METHYLATION USING MEDIPSEQ IN WHOLE BLOOD DNA FROM 1708 MONOZYGOTIC AND DIZYGOTIC CAUCASIAN TWINS HAVING CWP PREVALENCE OF 19.9%. LONGITUDINALLY STABLE METHYLATION BINS (LSBINS), WERE ESTABLISHED BY TESTING REPEATED MEASUREMENTS CONDUCTED >/=3 YEARS APART, N = 292. DNA METHYLATION VARIATION AT LSBINS WAS TESTED FOR ASSOCIATION WITH CWP IN A DISCOVERY SET OF 50 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR CWP, AND IN AN INDEPENDENT DATASET (N = 1608 TWINS), AND THE RESULTS FROM THE 2 SAMPLES WERE COMBINED USING FISHER METHOD. FUNCTIONAL INTERPRETATION OF THE MOST ASSOCIATED SIGNALS WAS BASED ON FUNCTIONAL GENOMIC ANNOTATIONS, GENE ONTOLOGY, AND PATHWAY ANALYSES. OF 723,029 SIGNALS IDENTIFIED AS LSBINS, 26,399 LSBINS DEMONSTRATED THE SAME DIRECTION OF ASSOCIATION IN BOTH DISCOVERY AND REPLICATION DATASETS AT NOMINAL SIGNIFICANCE (P 65 WITH CURRENT SMOKING STATUS AND CUMULATIVE SMOKING >20 PACK-YEARS, HAD ABSOLUTE 10-YEAR RISKS VARYING FROM 4% TO 16% BY AHRR(CG05575921) METHYLATION. CONCLUSION: A SIMPLE RISK CHART INCLUDING AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION, IDENTIFIES INDIVIDUALS WITH 10-YEAR LUNG CANCER RISK FROM BELOW 1% TO 16%. INCLUDING AHRR(CG05575921) METHYLATION IN THE ELIGIBILITY CRITERIA FOR SCREENING IDENTIFIES SMOKERS WHO WOULD BENEFIT THE MOST FROM SCREENING. 2023 11 5883 29 SYSTEMIC AND AIRWAY EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH HEALTH STATUS IN COPD. EPIGENETIC MODIFICATIONS ARE COMMON IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD); HOWEVER, THEIR CLINICAL RELEVANCE IS LARGELY UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH SYMPTOMS AND HEALTH STATUS IN COPD. WE PROFILED THE BLOOD (N = 57) AND AIRWAYS (N = 62) OF COPD PATIENTS FOR DNA METHYLATION (N = 55 PAIRED). THE PATIENTS' HEALTH STATUS WAS ASSESSED USING THE ST. GEORGE'S RESPIRATORY QUESTIONNAIRE (SGRQ). WE CONDUCTED DIFFERENTIAL METHYLATION ANALYSES AND IDENTIFIED PATHWAYS CHARACTERIZED BY EPIGENETIC DISRUPTIONS ASSOCIATED WITH SGRQ SCORES AND ITS INDIVIDUAL DOMAINS. 29,211 AND 5044 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE ASSOCIATED WITH TOTAL SGRQ SCORES IN BLOOD AND AIRWAY SAMPLES, RESPECTIVELY. THE ACTIVITY, IMPACT, AND SYMPTOM DOMAINS WERE ASSOCIATED WITH 9161, 25,689 AND 17,293 DMPS IN BLOOD, RESPECTIVELY; AND 4674, 3730 AND 5063 DMPS IN AIRWAYS, RESPECTIVELY. THERE WAS A SUBSTANTIAL OVERLAP OF DMPS BETWEEN AIRWAY AND BLOOD. DMPS WERE ENRICHED FOR PATHWAYS RELATED TO COMMON CO-MORBIDITIES OF COPD (E.G., AGEING, CANCER AND NEUROLOGICAL) IN BOTH TISSUES. HEALTH STATUS IN COPD IS ASSOCIATED WITH AIRWAY AND SYSTEMIC EPIGENETIC CHANGES ESPECIALLY IN PATHWAYS RELATED TO CO-MORBIDITIES OF COPD. THERE ARE MORE BLOOD DMPS THAN IN THE AIRWAYS SUGGESTING THAT BLOOD EPIGENOME IS A PROMISING SOURCE TO DISCOVER BIOMARKERS FOR CLINICAL OUTCOMES IN COPD. 2023 12 2390 39 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 13 4750 38 NOVEL REGIONAL AGE-ASSOCIATED DNA METHYLATION CHANGES WITHIN HUMAN COMMON DISEASE-ASSOCIATED LOCI. BACKGROUND: ADVANCING AGE PROGRESSIVELY IMPACTS ON RISK AND SEVERITY OF CHRONIC DISEASE. IT ALSO MODIFIES THE EPIGENOME, WITH CHANGES IN DNA METHYLATION, DUE TO BOTH RANDOM DRIFT AND VARIATION WITHIN SPECIFIC FUNCTIONAL LOCI. RESULTS: IN A DISCOVERY SET OF 2238 PERIPHERAL-BLOOD GENOME-WIDE DNA METHYLOMES AGED 19-82 YEARS, WE IDENTIFY 71 AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS WITHIN THE LINKAGE DISEQUILIBRIUM BLOCKS OF THE SINGLE NUCLEOTIDE POLYMORPHISMS FROM THE NIH GENOME-WIDE ASSOCIATION STUDY CATALOGUE. THIS INCLUDED 52 NOVEL REGIONS, 29 WITHIN LOCI NOT COVERED BY 450 K OR 27 K ILLUMINA ARRAY, AND WITH ENRICHMENT FOR DNASE-I HYPERSENSITIVITY SITES ACROSS THE FULL RANGE OF TISSUES. THESE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS ALSO SHOW MARKED ENRICHMENT FOR ENHANCERS AND POISED PROMOTERS ACROSS MULTIPLE CELL TYPES. IN A REPLICATION SET OF 2084 DNA METHYLOMES, 95.7 % OF THE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS SHOWED THE SAME DIRECTION OF AGEING EFFECT, WITH 80.3 % AND 53.5 % REPLICATED TO P < 0.05 AND P < 1.85 X 10(-8), RESPECTIVELY. CONCLUSION: BY ANALYSING THE FUNCTIONALLY ENRICHED DISEASE AND TRAIT-ASSOCIATED REGIONS OF THE HUMAN GENOME, WE IDENTIFY NOVEL EPIGENETIC AGEING CHANGES, WHICH COULD BE USEFUL BIOMARKERS OR PROVIDE MECHANISTIC INSIGHTS INTO AGE-RELATED COMMON DISEASES. 2016 14 3956 36 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 15 3687 36 INFLAMMATION-RELATED GENES ARE ASSOCIATED WITH EPIGENETIC AGING IN HIV. CHRONIC INFLAMMATION IS CHARACTERISTIC OF BOTH HIV AND AGING ("INFLAMMAGING") AND MAY CONTRIBUTE TO THE ACCELERATED AGING OBSERVED IN PEOPLE LIVING WITH HIV (PLWH). WE EXAMINED WHETHER THREE INFLAMMATION-RELATED SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS) WERE RISK FACTORS FOR ACCELERATED AGING AND HIV-ASSOCIATED, NON-AIDS (HANA) CONDITIONS AMONG PLWH. WE EXAMINED 155 POSTMORTEM CASES WITH HIV (MEAN AGE = 47.3, 81% MALE, 68% SELF-REPORTED WHITE) FROM THE NATIONAL NEUROAIDS TISSUE CONSORTIUM WHO HAD PRE-MORTEM NEUROBEHAVIORAL/MEDICAL/VIROLOGIC DATA AND EPIGENOMIC DATA FROM OCCIPITAL CORTEX TISSUE. ACCELERATED AGING WAS MEASURED ACCORDING TO THE EPIGENETIC CLOCK; AN AGING BIOMARKER BASED ON DNA METHYLATION LEVELS. PAST OR CURRENT AGE-ASSOCIATED HANA CONDITIONS INCLUDING CEREBROVASCULAR, LIVER AND KIDNEY DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CANCER, AND DIABETES WERE DETERMINED VIA SELF-REPORT. EPIGENETIC AGING Z-SCORES AND LIKELIHOOD OF PAST/CURRENT HANA CONDITIONS WERE COMPARED BETWEEN MAJOR ALLELE HOMOZYGOTES AND MINOR ALLELE CARRIERS FOR EACH SNP (IL-6 - 174G>C, IL-10 - 592C>A, TNF-ALPHA - 308 G>A) SEPARATELY. ANALYSES WERE ADJUSTED FOR RELEVANT DEMOGRAPHIC/CLINICAL FACTORS. EPIGENETIC AGING (E.G., HIGHER Z-SCORES) WAS SIGNIFICANTLY GREATER IN IL-6 C ALLELE CARRIERS (P = .002) AND IL-10 CC HOMOZYGOTES (P = .02) COMPARED TO OTHER GENOTYPE GROUPS. THE LIKELIHOOD OF ANY PAST/CURRENT HANA CONDITION DID NOT DIFFER BY IL-10 GENOTYPE BUT WAS 3.36 TIMES GREATER IN IL-6 C ALLELE CARRIERS VERSUS OTHERS (OR = 3.36, 95%CI = 1.09-10.34, P = .03). TNF-ALPHA GENOTYPE WAS NOT ASSOCIATED WITH EPIGENETIC AGING OR HANA CONDITIONS. IL-6 AND IL-10 SNPS MAY HELP TO IDENTIFY PLWH WHO ARE AT HIGH RISK FOR ACCELERATED AGING. THESE INSIGHTS INTO PATHOPHYSIOLOGICAL PATHWAYS MAY INFORM INTERVENTIONAL APPROACHES TO TREAT RAPID AGING AMONG PLWH. 2019 16 4740 54 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 17 6358 41 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 18 2626 41 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 19 4270 36 MICROBIAL DYSBIOSIS AND THE HOST AIRWAY EPITHELIAL RESPONSE: INSIGHTS INTO HIV-ASSOCIATED COPD USING MULTI'OMICS PROFILING. BACKGROUND: PEOPLE LIVING WITH HIV (PLWH) ARE AT INCREASED RISK OF DEVELOPING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDEPENDENT OF CIGARETTE SMOKING. WE HYPOTHESIZED THAT DYSBIOSIS IN PLWH IS ASSOCIATED WITH EPIGENETIC AND TRANSCRIPTOMIC DISRUPTIONS IN THE AIRWAY EPITHELIUM. METHODS: AIRWAY EPITHELIAL BRUSHINGS WERE COLLECTED FROM 18 COPD + HIV + , 16 COPD - HIV + , 22 COPD + HIV - AND 20 COPD - HIV - SUBJECTS. THE MICROBIOME, METHYLOME, AND TRANSCRIPTOME WERE PROFILED USING 16S SEQUENCING, ILLUMINA INFINIUM METHYLATION EPIC CHIP, AND RNA SEQUENCING, RESPECTIVELY. MULTI 'OMIC INTEGRATION WAS PERFORMED USING DATA INTEGRATION ANALYSIS FOR BIOMARKER DISCOVERY USING LATENT COMPONENTS. A CORRELATION > 0.7 WAS USED TO IDENTIFY KEY INTERACTIONS BETWEEN THE 'OMES. RESULTS: THE COPD + HIV -, COPD -HIV + , AND COPD + HIV + GROUPS HAD REDUCED SHANNON DIVERSITY (P = 0.004, P = 0.023, AND P = 5.5E-06, RESPECTIVELY) COMPARED TO INDIVIDUALS WITH NEITHER COPD NOR HIV, WITH THE COPD + HIV + GROUP DEMONSTRATING THE MOST REDUCED DIVERSITY. MICROBIAL COMMUNITIES WERE SIGNIFICANTLY DIFFERENT BETWEEN THE FOUR GROUPS (P = 0.001). MULTI 'OMIC INTEGRATION IDENTIFIED CORRELATIONS BETWEEN BACTEROIDETES PREVOTELLA, GENES FUZ, FASTKD3, AND ACVR1B, AND EPIGENETIC FEATURES CPG-FUZ AND CPG-PHLDB3. CONCLUSION: PLWH WITH COPD MANIFEST DECREASED DIVERSITY AND ALTERED MICROBIAL COMMUNITIES IN THEIR AIRWAY EPITHELIAL MICROBIOME. THE REDUCTION IN PREVOTELLA IN THIS GROUP WAS LINKED WITH EPIGENETIC AND TRANSCRIPTOMIC DISRUPTIONS IN HOST GENES INCLUDING FUZ, FASTKD3, AND ACVR1B. 2023 20 6835 28 [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