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 3027 34 GENETICS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE WITH MULTIFACTORIAL BACKGROUND, BASED ON THE INTERACTION OF ENVIRONMENTAL AND GENETIC FACTORS. ENVIRONMENTAL FACTORS ARE CLEARLY RELATED TO THE DEVELOPMENT OF THE DISEASE. HOWEVER, FAMILY AND TWIN STUDIES SUGGESTED GENETICS FACTORS TO BE ONE OF THE IMPORTANT DETERMINANTS FOR THE DEVELOPMENT OF COPD. DIFFERENT APPROACHES HAVE BEEN USED TO IDENTIFY GENES OF INTEREST. GENOMEWIDE LINKAGE ANALYSIS FOUND AREAS OF INTEREST ON DIFFERENT CHROMOSOMES, WITH SOME GENES LOCATED IN THIS REGIONS BEING IDENTIFIED AND REPLICATED AS SUSCEPTIBILITY GENES. NUMEROUS OF CANDIDATE GENES THAT COULD BE LINKED TO DISEASE PATHOGENESIS HAVE BEEN IMPLICATED IN COPD GENETICS. HOWEVER, THE CANDIDATE GENE APPROACH IS OFTEN LIMITED BY INCONSISTENT RESULTS IN OTHER STUDY POPULATIONS. RECENTLY, A COMBINATION OF DIFFERENT METHODS IS USED GIVING MORE EVIDENCE FOR SOME CANDIDATE GENES, INCLUDING TGFBETA-1, SURFACTANT, SERPINE2 AND MICROSOMAL EPOXIDE HYDROLASE. IN THE FUTURE ONGOING EXACT PHENOTYPE DEFINITION, COMBINATION OF SEVERAL APPROACHES, GENOME-WIDE ASSOCIATION STUDIES AND ANIMAL MODEL GENETICS WILL LEAD TO NEW INSIGHTS INTO THE GENETICS OF COPD, WITH EPIGENETIC FACTORS NEEDS TO BE FURTHER INVESTIGATED AND CONSIDERED IN CONCERT WITH GENETIC FINDINGS. 2007 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 2628 35 EPIGENOME-WIDE ASSOCIATION STUDY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG FUNCTION IN KOREANS. AIM: TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND REGIONS (DMRS) IN RELATION TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG FUNCTION TRAITS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF COPD AND SPIROMETRIC PARAMETERS, INCLUDING FORCED EXPIRATORY VOLUME IN 1 S (FEV1), FORCED VITAL CAPACITY (FVC) AND FEV1/FVC, IN BLOOD DNA USING THE INFINIUM HUMANMETHYLATION450 (N = 100, A KOREAN COPD COHORT). RESULTS: WE FOUND ONE SIGNIFICANT DMP (CG03559389, DIP2C) AND 104 SIGNIFICANT DMRS AFTER MULTIPLE-TESTING CORRECTION. OF THESE, 34 DMRS MAPPED TO GENES DIFFERENTIAL EXPRESSED WITH RESPECT TO THE SAME TRAIT. FIVE OF THE GENES WERE ASSOCIATED WITH MORE THAN TWO TRAITS: CTU2, USP36, ZNF516, KLK10 AND CPT1B. CONCLUSION: WE IDENTIFIED NOVEL DIFFERENTIAL METHYLATION LOCI RELATED TO COPD AND LUNG FUNCTION IN BLOOD DNA IN KOREANS AND CONFIRMED PREVIOUS FINDINGS IN NON-ASIANS. EPIGENETIC MODIFICATION COULD CONTRIBUTE TO THE ETIOLOGY OF THESE PHENOTYPES. 2017 5 1552 44 DNA METHYLATION IS PREDICTIVE OF MORTALITY IN CURRENT AND FORMER SMOKERS. RATIONALE: SMOKING RESULTS IN AT LEAST A DECADE LOWER LIFE EXPECTANCY. MORTALITY AMONG CURRENT SMOKERS IS TWO TO THREE TIMES AS HIGH AS NEVER SMOKERS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION OF THE HUMAN GENOME THAT HAS BEEN ASSOCIATED WITH BOTH CIGARETTE SMOKING AND MORTALITY.OBJECTIVES: WE SOUGHT TO IDENTIFY DNA METHYLATION MARKS IN BLOOD THAT ARE PREDICTIVE OF MORTALITY IN A SUBSET OF THE COPDGENE (GENETIC EPIDEMIOLOGY OF COPD) STUDY, REPRESENTING 101 DEATHS AMONG 667 CURRENT AND FORMER SMOKERS.METHODS: WE ASSAYED GENOME-WIDE DNA METHYLATION IN NON-HISPANIC WHITE SMOKERS WITH AND WITHOUT CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) USING BLOOD SAMPLES FROM THE COPDGENE ENROLLMENT VISIT. WE TESTED WHETHER DNA METHYLATION WAS ASSOCIATED WITH MORTALITY IN MODELS ADJUSTED FOR COPD STATUS, AGE, SEX, CURRENT SMOKING STATUS, AND PACK-YEARS OF CIGARETTE SMOKING. REPLICATION WAS PERFORMED IN A SUBSET OF 231 INDIVIDUALS FROM THE ECLIPSE (EVALUATION OF COPD LONGITUDINALLY TO IDENTIFY PREDICTIVE SURROGATE ENDPOINTS) STUDY.MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED SEVEN CPG SITES ASSOCIATED WITH MORTALITY (FALSE DISCOVERY RATE < 20%) THAT REPLICATED IN THE ECLIPSE COHORT (P < 0.05). NONE OF THESE MARKS WERE ASSOCIATED WITH LONGITUDINAL LUNG FUNCTION DECLINE IN SURVIVORS, SMOKING HISTORY, OR CURRENT SMOKING STATUS. HOWEVER, DIFFERENTIAL METHYLATION OF TWO REPLICATED PIK3CD (PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA) SITES WERE ASSOCIATED WITH LUNG FUNCTION AT ENROLLMENT (P < 0.05). WE ALSO OBSERVED ASSOCIATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION FOR THE PIK3CD SITES.CONCLUSIONS: THIS STUDY IS THE FIRST TO IDENTIFY VARIABLE DNA METHYLATION ASSOCIATED WITH ALL-CAUSE MORTALITY IN SMOKERS WITH AND WITHOUT COPD. EVALUATING PREDICTIVE EPIGENOMIC MARKS OF SMOKERS IN PERIPHERAL BLOOD MAY ALLOW FOR TARGETED RISK STRATIFICATION AND AID IN DELIVERY OF FUTURE TAILORED THERAPEUTIC INTERVENTIONS. 2020 6 383 43 AN EPIGENOME-WIDE STUDY OF DNA METHYLATION PROFILES AND LUNG FUNCTION AMONG AMERICAN INDIANS IN THE STRONG HEART STUDY. BACKGROUND: EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION (DNAM), ARE OFTEN RELATED TO ENVIRONMENTAL EXPOSURES, AND ARE INCREASINGLY RECOGNIZED AS KEY PROCESSES IN THE PATHOGENESIS OF CHRONIC LUNG DISEASE. AMERICAN INDIAN COMMUNITIES HAVE A HIGH BURDEN OF LUNG DISEASE COMPARED TO THE NATIONAL AVERAGE. THE OBJECTIVE OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION OF DNAM AND LUNG FUNCTION IN THE STRONG HEART STUDY (SHS). WE CONDUCTED A CROSS-SECTIONAL STUDY OF AMERICAN INDIAN ADULTS, 45-74 YEARS OF AGE WHO PARTICIPATED IN THE SHS. DNAM WAS MEASURED USING THE ILLUMINA INFINIUM HUMAN METHYLATIONEPIC PLATFORM AT BASELINE (1989-1991). LUNG FUNCTION WAS MEASURED VIA SPIROMETRY, INCLUDING FORCED EXPIRATORY VOLUME IN 1 S (FEV1) AND FORCED VITAL CAPACITY (FVC), AT VISIT 2 (1993-1995). AIRFLOW LIMITATION WAS DEFINED AS FEV1 < 70% PREDICTED AND FEV1/FVC < 0.7, RESTRICTION WAS DEFINED AS FEV1/FVC > 0.7 AND FVC < 80% PREDICTED, AND NORMAL SPIROMETRY WAS DEFINED AS FEV1/FVC > 0.7, FEV1 > 70% PREDICTED, FVC > 80% PREDICTED. WE USED ELASTIC-NET MODELS TO SELECT RELEVANT CPGS FOR LUNG FUNCTION AND SPIROMETRY-DEFINED LUNG DISEASE. WE ALSO CONDUCTED BIOINFORMATIC ANALYSES TO EVALUATE THE BIOLOGICAL PLAUSIBILITY OF THE FINDINGS. RESULTS: AMONG 1677 PARTICIPANTS, 21.2% HAD SPIROMETRY-DEFINED AIRFLOW LIMITATION AND 13.6% HAD SPIROMETRY-DEFINED RESTRICTIVE PATTERN LUNG FUNCTION. ELASTIC-NET MODELS SELECTED 1118 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AS PREDICTORS OF AIRFLOW LIMITATION AND 1385 FOR RESTRICTIVE PATTERN LUNG FUNCTION. A TOTAL OF 12 DMPS OVERLAPPED BETWEEN AIRFLOW LIMITATION AND RESTRICTIVE PATTERN. EGFR, MAPK1 AND PRPF8 GENES WERE THE MOST CONNECTED NODES IN THE PROTEIN-PROTEIN INTERACTION NETWORK. MANY OF THE DMPS TARGETED GENES WITH BIOLOGICAL ROLES RELATED TO LUNG FUNCTION SUCH AS PROTEIN KINASES. CONCLUSION: WE FOUND MULTIPLE DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CHRONIC LUNG DISEASE. THESE SIGNALS COULD CONTRIBUTE TO BETTER UNDERSTAND MOLECULAR MECHANISMS INVOLVED IN LUNG DISEASE, AS ASSESSED SYSTEMICALLY, AS WELL AS TO IDENTIFY PATTERNS THAT COULD BE USEFUL FOR DIAGNOSTIC PURPOSES. FURTHER EXPERIMENTAL AND LONGITUDINAL STUDIES ARE NEEDED TO ASSESS WHETHER DNA METHYLATION HAS A CAUSAL ROLE IN LUNG DISEASE. 2022 7 6761 39 X CHROMOSOME-WIDE ANALYSIS IDENTIFIES DNA METHYLATION SITES INFLUENCED BY CIGARETTE SMOKING. BACKGROUND: TOBACCO SMOKING IS A MAJOR CAUSE OF CHRONIC DISEASE WORLDWIDE. SMOKING MAY INDUCE CELLULAR AND MOLECULAR CHANGES INCLUDING EPIGENETIC MODIFICATION, WITH BOTH SHORT-TERM AND LONG-TERM MODIFICATION PATTERNS THAT MAY CONTRIBUTE TO PHENOTYPIC EXPRESSION OF DISEASES. RECENT EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED DOZENS OF SMOKING-RELATED DNA METHYLATION (DNAM) SITES. HOWEVER, THE X CHROMOSOMAL DNAM SITES HAVE BEEN LARGELY OVERLOOKED DUE TO A LACK OF AN ANALYTICAL FRAMEWORK FOR DEALING WITH THE SEX-DIMORPHIC DISTRIBUTION. TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES ON THE X CHROMOSOME, WE EXAMINED THE MODALITY OF EACH X CHROMOSOMAL DNAM SITE AND CONDUCTED A SEX-SPECIFIC ASSOCIATION STUDY OF CIGARETTE SMOKING. RESULTS: WE USED A DISCOVERY SAMPLE OF 139 MIDDLE-AGE TWINS, AND THREE REPLICATION SAMPLES OF 78 TWINS, 464 AND 333 UNRELATED INDIVIDUALS INCLUDING 47, 17, 22, AND 89 CURRENT SMOKERS, RESPECTIVELY. AFTER CORRECTION FOR MULTIPLE TESTING, THE TOP SMOKING-RELATED DNAM SITES IN BCOR AND TSC22D3 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, AMONG CURRENT SMOKERS. THESE SMOKING-ASSOCIATED SITES WERE REPLICATED WITH META-ANALYSIS P-VALUES OF 9.17 X 10(-12) AND 1.61 X 10(-9). FOR BOTH SITES, THE SMOKING EFFECTS ON METHYLATION LEVELS WERE LARGER IN MALES THAN THAT IN FEMALES. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING X CHROMOSOME METHYLATION PATTERNS AND THEIR ASSOCIATIONS WITH ENVIRONMENTAL EXPOSURES AND DISEASE PHENOTYPES AND DEMONSTRATE A ROBUST STATISTICAL METHODOLOGY FOR SUCH STUDY. EXISTING EWAS OF HUMAN DISEASES SHOULD INCORPORATE THE X CHROMOSOMAL SITES TO COMPLETE A COMPREHENSIVE EPIGENOME-WIDE SCAN. 2016 8 4256 37 METHYLOMIC MARKERS OF PERSISTENT CHILDHOOD ASTHMA: A LONGITUDINAL STUDY OF ASTHMA-DISCORDANT MONOZYGOTIC TWINS. BACKGROUND: ASTHMA IS THE MOST COMMON CHRONIC INFLAMMATORY DISORDER IN CHILDREN. THE AETIOLOGY OF ASTHMA PATHOLOGY IS COMPLEX AND HIGHLY HETEROGENEOUS, INVOLVING THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS THAT IS HYPOTHESIZED TO INVOLVE EPIGENETIC PROCESSES. OUR AIM WAS TO EXPLORE WHETHER METHYLOMIC VARIATION IN EARLY CHILDHOOD IS ASSOCIATED WITH DISCORDANCE FOR ASTHMA SYMPTOMS WITHIN MONOZYGOTIC (MZ) TWIN PAIRS RECRUITED FROM THE ENVIRONMENTAL RISK (E-RISK) LONGITUDINAL TWIN STUDY. WE ALSO AIMED TO IDENTIFY DIFFERENCES IN DNA METHYLATION THAT ARE ASSOCIATED WITH ASTHMA THAT DEVELOPS IN CHILDHOOD AND PERSISTS INTO EARLY ADULTHOOD AS THESE MAY REPRESENT USEFUL PROGNOSTIC BIOMARKERS. RESULTS: WE EXAMINED GENOME-WIDE PATTERNS OF DNA METHYLATION IN BUCCAL CELL SAMPLES COLLECTED FROM 37 MZ TWIN PAIRS DISCORDANT FOR ASTHMA AT AGE 10. DNA METHYLATION AT INDIVIDUAL CPG SITES DEMONSTRATED SIGNIFICANT VARIABILITY WITHIN DISCORDANT MZ TWIN PAIRS WITH THE TOP-RANKED NOMINALLY SIGNIFICANT DIFFERENTIALLY METHYLATED POSITION (DMP) LOCATED IN THE HGSNAT GENE. WE STRATIFIED OUR ANALYSIS BY ASSESSING DNA METHYLATION DIFFERENCES IN A SUB-GROUP OF MZ TWIN PAIRS WHO REMAINED PERSISTENTLY DISCORDANT FOR ASTHMA AT AGE 18. THE TOP-RANKED NOMINALLY SIGNIFICANT DMP ASSOCIATED WITH PERSISTING ASTHMA IS LOCATED IN THE VICINITY OF THE HLX GENE, WHICH HAS BEEN PREVIOUSLY IMPLICATED IN CHILDHOOD ASTHMA. CONCLUSIONS: WE IDENTIFIED DNA METHYLATION DIFFERENCES ASSOCIATED WITH CHILDHOOD ASTHMA IN PERIPHERAL DNA SAMPLES FROM DISCORDANT MZ TWIN PAIRS. OUR DATA SUGGEST THAT DIFFERENCES IN DNA METHYLATION ASSOCIATED WITH CHILDHOOD ASTHMA WHICH PERSISTS INTO EARLY ADULTHOOD ARE DISTINCT FROM THOSE ASSOCIATED WITH ASTHMA WHICH REMITS. 2015 9 4744 53 NOVEL INSIGHTS INTO THE GENETICS OF SMOKING BEHAVIOUR, LUNG FUNCTION, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (UK BILEVE): A GENETIC ASSOCIATION STUDY IN UK BIOBANK. BACKGROUND: UNDERSTANDING THE GENETIC BASIS OF AIRFLOW OBSTRUCTION AND SMOKING BEHAVIOUR IS KEY TO DETERMINING THE PATHOPHYSIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE USED UK BIOBANK DATA TO STUDY THE GENETIC CAUSES OF SMOKING BEHAVIOUR AND LUNG HEALTH. METHODS: WE SAMPLED INDIVIDUALS OF EUROPEAN ANCESTRY FROM UK BIOBANK, FROM THE MIDDLE AND EXTREMES OF THE FORCED EXPIRATORY VOLUME IN 1 S (FEV1) DISTRIBUTION AMONG HEAVY SMOKERS (MEAN 35 PACK-YEARS) AND NEVER SMOKERS. WE DEVELOPED A CUSTOM ARRAY FOR UK BIOBANK TO PROVIDE OPTIMUM GENOME-WIDE COVERAGE OF COMMON AND LOW-FREQUENCY VARIANTS, DENSE COVERAGE OF GENOMIC REGIONS ALREADY IMPLICATED IN LUNG HEALTH AND DISEASE, AND TO ASSAY RARE CODING VARIANTS RELEVANT TO THE UK POPULATION. WE INVESTIGATED WHETHER THERE WERE SHARED GENETIC CAUSES BETWEEN DIFFERENT PHENOTYPES DEFINED BY EXTREMES OF FEV1. WE ALSO LOOKED FOR NOVEL VARIANTS ASSOCIATED WITH EXTREMES OF FEV1 AND SMOKING BEHAVIOUR AND ASSESSED REGIONS OF THE GENOME THAT HAD ALREADY SHOWN EVIDENCE FOR A ROLE IN LUNG HEALTH AND DISEASE. WE SET GENOME-WIDE SIGNIFICANCE AT P<5 X 10(-8). FINDINGS: UK BIOBANK PARTICIPANTS WERE RECRUITED FROM MARCH 15, 2006, TO JULY 7, 2010. SAMPLE SELECTION FOR THE UK BILEVE STUDY STARTED ON NOV 22, 2012, AND WAS COMPLETED ON DEC 20, 2012. WE SELECTED 50,008 UNIQUE SAMPLES: 10,002 INDIVIDUALS WITH LOW FEV1, 10,000 WITH AVERAGE FEV1, AND 5002 WITH HIGH FEV1 FROM EACH OF THE HEAVY SMOKER AND NEVER SMOKER GROUPS. WE NOTED A SUBSTANTIAL SHARING OF GENETIC CAUSES OF LOW FEV1 BETWEEN HEAVY SMOKERS AND NEVER SMOKERS (P=2.29 X 10(-16)) AND BETWEEN INDIVIDUALS WITH AND WITHOUT DOCTOR-DIAGNOSED ASTHMA (P=6.06 X 10(-11)). WE DISCOVERED SIX NOVEL GENOME-WIDE SIGNIFICANT SIGNALS OF ASSOCIATION WITH EXTREMES OF FEV1, INCLUDING SIGNALS AT FOUR NOVEL LOCI (KANSL1, TSEN54, TET2, AND RBM19/TBX5) AND INDEPENDENT SIGNALS AT TWO PREVIOUSLY REPORTED LOCI (NPNT AND HLA-DQB1/HLA-DQA2). THESE VARIANTS ALSO SHOWED ASSOCIATION WITH COPD, INCLUDING IN INDIVIDUALS WITH NO HISTORY OF SMOKING. THE NUMBER OF COPIES OF A 150 KB REGION CONTAINING THE 5' END OF KANSL1, A GENE THAT IS IMPORTANT FOR EPIGENETIC GENE REGULATION, WAS ASSOCIATED WITH EXTREMES OF FEV1. WE ALSO DISCOVERED FIVE NEW GENOME-WIDE SIGNIFICANT SIGNALS FOR SMOKING BEHAVIOUR, INCLUDING A VARIANT IN NCAM1 (CHROMOSOME 11) AND A VARIANT ON CHROMOSOME 2 (BETWEEN TEX41 AND PABPC1P2) THAT HAS A TRANS EFFECT ON EXPRESSION OF NCAM1 IN BRAIN TISSUE. INTERPRETATION: BY SAMPLING FROM THE EXTREMES OF THE LUNG FUNCTION DISTRIBUTION IN UK BIOBANK, WE IDENTIFIED NOVEL GENETIC CAUSES OF LUNG FUNCTION AND SMOKING BEHAVIOUR. THESE RESULTS PROVIDE NEW INSIGHT INTO THE SPECIFIC MECHANISMS UNDERLYING AIRFLOW OBSTRUCTION, COPD, AND TOBACCO ADDICTION, AND SHOW SUBSTANTIAL SHARED GENETIC ARCHITECTURE UNDERLYING AIRFLOW OBSTRUCTION ACROSS INDIVIDUALS, IRRESPECTIVE OF SMOKING BEHAVIOUR AND OTHER AIRWAY DISEASE. FUNDING: MEDICAL RESEARCH COUNCIL. 2015 10 6091 28 THE EFFECTS OF ENDOCRINE DISRUPTORS ON ADIPOGENESIS AND OSTEOGENESIS IN MESENCHYMAL STEM CELLS: A REVIEW. ENDOCRINE-DISRUPTING CHEMICALS (EDCS) ARE PREVALENT IN THE ENVIRONMENT, AND EPIDEMIOLOGIC STUDIES HAVE SUGGESTED THAT HUMAN EXPOSURE IS LINKED TO CHRONIC DISEASES, SUCH AS OBESITY AND DIABETES. IN VITRO EXPERIMENTS HAVE FURTHER DEMONSTRATED THAT EDCS PROMOTE CHANGES IN MESENCHYMAL STEM CELLS (MSCS), LEADING TO INCREASES IN ADIPOGENIC DIFFERENTIATION, DECREASES IN OSTEOGENIC DIFFERENTIATION, ACTIVATION OF PRO-INFLAMMATORY CYTOKINES, INCREASES IN OXIDATIVE STRESS, AND EPIGENETIC CHANGES. STUDIES HAVE ALSO SHOWN ALTERATION IN TROPHIC FACTOR PRODUCTION, DIFFERENTIATION ABILITY, AND IMMUNOMODULATORY CAPACITY OF MSCS, WHICH HAVE SIGNIFICANT IMPLICATIONS TO THE CURRENT STUDIES EXPLORING MSCS FOR TISSUE ENGINEERING AND REGENERATIVE MEDICINE APPLICATIONS AND THE TREATMENT OF INFLAMMATORY CONDITIONS. THUS, THE CONSIDERATION OF THE EFFECTS OF EDCS ON MSCS IS VITAL WHEN DETERMINING POTENTIAL THERAPEUTIC USES OF MSCS, AS INCREASED EXPOSURE TO EDCS MAY CAUSE MSCS TO BE LESS EFFECTIVE THERAPEUTICALLY. THIS REVIEW FOCUSES ON THE ADIPOGENIC AND OSTEOGENIC DIFFERENTIATION EFFECTS OF EDCS AS THESE ARE MOST RELEVANT TO THE THERAPEUTIC USES OF MSCS IN TISSUE ENGINEERING, REGENERATIVE MEDICINE, AND INFLAMMATORY CONDITIONS. THIS REVIEW WILL HIGHLIGHT THE EFFECTS OF EDCS, INCLUDING ORGANOPHOSPHATES, PLASTICIZERS, INDUSTRIAL SURFACTANTS, COOLANTS, AND LUBRICANTS, ON MSC BIOLOGY. 2016 11 3420 45 HUMAN LUNG DNA METHYLATION QUANTITATIVE TRAIT LOCI COLOCALIZE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE GENOME-WIDE ASSOCIATION LOCI. RATIONALE: AS THE THIRD LEADING CAUSE OF DEATH IN THE UNITED STATES, THE IMPACT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) MAKES IDENTIFICATION OF ITS MOLECULAR MECHANISMS OF GREAT IMPORTANCE. GENOME-WIDE ASSOCIATION STUDIES (GWASS) HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS ASSOCIATED WITH COPD. HOWEVER, GENETIC VARIATION ONLY EXPLAINS A SMALL FRACTION OF THE SUSCEPTIBILITY TO COPD, AND SUB-GENOME-WIDE SIGNIFICANT LOCI MAY PLAY A ROLE IN PATHOGENESIS. OBJECTIVES: REGULATORY ANNOTATION WITH EPIGENETIC EVIDENCE MAY GIVE PRIORITY FOR FURTHER INVESTIGATION, PARTICULARLY FOR GWAS ASSOCIATIONS IN NONCODING REGIONS. WE PERFORMED INTEGRATIVE GENOMICS ANALYSES USING DNA METHYLATION PROFILING AND GENOME-WIDE SNP GENOTYPING FROM LUNG TISSUE SAMPLES FROM 90 SUBJECTS WITH COPD AND 36 CONTROL SUBJECTS. METHODS: WE PERFORMED METHYLATION QUANTITATIVE TRAIT LOCI (MQTL) ANALYSES, TESTING FOR SNPS ASSOCIATED WITH PERCENT DNA METHYLATION AND ASSESSED THE COLOCALIZATION OF THESE RESULTS WITH PREVIOUS COPD GWAS FINDINGS USING BAYESIAN METHODS IN THE R PACKAGE COLOC TO HIGHLIGHT POTENTIAL REGULATORY FEATURES OF THE LOCI. MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED 942,068 UNIQUE SNPS AND 33,996 UNIQUE CPG SITES AMONG THE SIGNIFICANT (5% FALSE DISCOVERY RATE) CIS-MQTL RESULTS. THE GENOME-WIDE SIGNIFICANT AND SUBTHRESHOLD (P < 10(-4)) GWAS SNPS WERE ENRICHED IN THE SIGNIFICANT MQTL SNPS (HYPERGEOMETRIC TEST P < 0.00001). WE OBSERVED ENRICHMENT FOR SITES LOCATED IN CPG SHORES AND SHELVES, BUT NOT CPG ISLANDS. USING BAYESIAN COLOCALIZATION, WE IDENTIFIED LOCI IN REGIONS NEAR KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, AND IL27. CONCLUSIONS: COLOCALIZATION OF MQTL AND GWAS LOCI PROVIDES REGULATORY CHARACTERIZATION OF SIGNIFICANT AND SUBTHRESHOLD GWAS FINDINGS, SUPPORTING A ROLE FOR GENETIC CONTROL OF METHYLATION IN COPD PATHOGENESIS. 2018 12 2411 46 EPIGENETIC SCORES FOR THE CIRCULATING PROTEOME AS TOOLS FOR DISEASE PREDICTION. PROTEIN BIOMARKERS HAVE BEEN IDENTIFIED ACROSS MANY AGE-RELATED MORBIDITIES. HOWEVER, CHARACTERISING EPIGENETIC INFLUENCES COULD FURTHER INFORM DISEASE PREDICTIONS. HERE, WE LEVERAGE EPIGENOME-WIDE DATA TO STUDY LINKS BETWEEN THE DNA METHYLATION (DNAM) SIGNATURES OF THE CIRCULATING PROTEOME AND INCIDENT DISEASES. USING DATA FROM FOUR COHORTS, WE TRAINED AND TESTED EPIGENETIC SCORES (EPISCORES) FOR 953 PLASMA PROTEINS, IDENTIFYING 109 SCORES THAT EXPLAINED BETWEEN 1% AND 58% OF THE VARIANCE IN PROTEIN LEVELS AFTER ADJUSTING FOR KNOWN PROTEIN QUANTITATIVE TRAIT LOCI (PQTL) GENETIC EFFECTS. BY PROJECTING THESE EPISCORES INTO AN INDEPENDENT SAMPLE (GENERATION SCOTLAND; N = 9537) AND RELATING THEM TO INCIDENT MORBIDITIES OVER A FOLLOW-UP OF 14 YEARS, WE UNCOVERED 137 EPISCORE-DISEASE ASSOCIATIONS. THESE ASSOCIATIONS WERE LARGELY INDEPENDENT OF IMMUNE CELL PROPORTIONS, COMMON LIFESTYLE AND HEALTH FACTORS, AND BIOLOGICAL AGING. NOTABLY, WE FOUND THAT OUR DIABETES-ASSOCIATED EPISCORES HIGHLIGHTED PREVIOUS TOP BIOMARKER ASSOCIATIONS FROM PROTEOME-WIDE ASSESSMENTS OF DIABETES. THESE EPISCORES FOR PROTEIN LEVELS CAN THEREFORE BE A VALUABLE RESOURCE FOR DISEASE PREDICTION AND RISK STRATIFICATION. 2022 13 1550 37 DNA METHYLATION IS ASSOCIATED WITH AIRFLOW OBSTRUCTION IN PATIENTS LIVING WITH HIV. INTRODUCTION: PEOPLE LIVING WITH HIV (PLWH) SUFFER FROM AGE-RELATED COMORBIDITIES SUCH AS COPD. THE PROCESSES RESPONSIBLE FOR REDUCED LUNG FUNCTION IN PLWH ARE LARGELY UNKNOWN. WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY TO INVESTIGATE WHETHER BLOOD DNA METHYLATION IS ASSOCIATED WITH IMPAIRED LUNG FUNCTION IN PLWH. METHODS: USING BLOOD DNA METHYLATION PROFILES FROM 161 PLWH, WE TESTED THE EFFECT OF METHYLATION ON FEV(1), FEV(1)/FVC RATIO AND FEV(1) DECLINE OVER A MEDIAN OF 5 YEARS. WE EVALUATED THE GLOBAL METHYLATION OF PLWH WITH AIRFLOW OBSTRUCTION BY TESTING THE DIFFERENTIAL METHYLATION OF TRANSPOSABLE ELEMENTS ALU AND LINE-1, A WELL-DESCRIBED MARKER OF EPIGENETIC AGEING. RESULTS: AIRFLOW OBSTRUCTION AS DEFINED BY A FEV(1)/FVC<0.70 WAS ASSOCIATED WITH 1393 DIFFERENTIALLY METHYLATED POSITIONS (DMPS), WHILE 4676 WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION BASED ON THE FEV(1)/FVC100 MILLION PEOPLE GLOBALLY AND INCREASES RISK FOR CHRONIC DISEASES. ONE POSSIBLE TOXICITY MECHANISM IS EPIGENETIC MODIFICATION. PREVIOUS EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG-SPECIFIC DNA METHYLATION. TO PROVIDE ADDITIONAL EVIDENCE THAT OBSERVED ASSOCIATIONS REPRESENT CAUSAL RELATIONSHIPS, WE EXAMINE THE ASSOCIATION BETWEEN GENETIC DETERMINANTS OF ARSENIC METABOLISM EFFICIENCY (PERCENT DIMETHYLARSINIC ACID, DMA%, IN URINE) AND DNA METHYLATION AMONG INDIVIDUALS FROM THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (N = 379) AND BANGLADESH VITAMIN E AND SELENIUM TRIAL (N = 393). METHODS: WE USED MULTIVARIATE LINEAR MODELS TO ASSESS THE ASSOCIATION OF METHYLATION AT 221 ARSENIC-ASSOCIATED CPGS WITH DMA% AND MEASURES OF GENETICALLY PREDICTED DMA% DERIVED FROM THREE SNPS (RS9527, RS11191527, AND RS61735836). WE ALSO CONDUCTED TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES TO ESTIMATE THE ASSOCIATION BETWEEN ARSENIC METABOLISM EFFICIENCY AND CPG METHYLATION. RESULTS: AMONG THE ASSOCIATIONS BETWEEN DMA% AND METHYLATION AT EACH OF 221 CPGS, 64% WERE DIRECTIONALLY CONSISTENT WITH ASSOCIATIONS OBSERVED BETWEEN ARSENIC EXPOSURE AND THE 221 CPGS FROM A PRIOR EWAS. SIMILARLY, AMONG THE ASSOCIATIONS BETWEEN GENETICALLY PREDICTED DMA% AND EACH CPG, 62% WERE DIRECTIONALLY CONSISTENT WITH THE PRIOR EWAS RESULTS. TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES PRODUCED SIMILAR CONCLUSIONS. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT ARSENIC EXPOSURE EFFECTS DNA METHYLATION AT SPECIFIC CPGS IN WHOLE BLOOD. OUR NOVEL APPROACH FOR ASSESSING THE IMPACT OF ARSENIC EXPOSURE ON DNA METHYLATION REQUIRES LARGER SAMPLES IN ORDER TO DRAW MORE ROBUST CONCLUSIONS FOR SPECIFIC CPG SITES. 2020 15 502 46 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849. 2019 16 713 36 CADMIUM EXPOSURE AND AGE-ASSOCIATED DNA METHYLATION CHANGES IN NON-SMOKING WOMEN FROM NORTHERN THAILAND. DNA METHYLATION CHANGES WITH AGE, AND MAY SERVE AS A BIOMARKER OF AGING. CADMIUM (CD) MODIFIES CELLULAR PROCESSES THAT PROMOTE AGING AND DISRUPTS METHYLATION GLOBALLY. WHETHER CD MODIFIES AGING PROCESSES BY INFLUENCING ESTABLISHMENT OF AGE-ASSOCIATED METHYLATION MARKS IS CURRENTLY UNKNOWN. IN THIS PILOT STUDY, WE CHARACTERIZED METHYLATION PROFILES IN > 450 000 CPG SITES IN 40 NON-SMOKING WOMEN (AGE 40-80) DIFFERENTIALLY EXPOSED TO ENVIRONMENTAL CD FROM THAILAND. BASED ON SPECIFIC GRAVITY ADJUSTED URINARY CD, WE CLASSIFIED THEM AS HIGH (HE) AND LOW (LE) EXPOSED AND AGE-MATCHED WITHIN 5 YEARS. URINARY CD WAS DEFINED AS BELOW 2 MICROG/L IN THE LE GROUP. WE PREDICTED EPIGENETIC AGE (DNAM-AGE) USING TWO PUBLISHED METHODS BY HORVATH AND HANNUM AND EXAMINED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGIC AGE (DELTAAGE). WE ASSESSED DIFFERENCES BY CD EXPOSURE USING LINEAR MIXED MODELS ADJUSTED FOR ESTIMATED WHITE BLOOD CELL PROPORTIONS, BMI, AND URINARY CREATININE. WE IDENTIFIED 213 AGE-ASSOCIATED CPG SITES IN OUR POPULATION (P < 10(-4)). COUNTERINTUITIVELY, THE MEAN DELTAAGE WAS SMALLER IN HE VS. LE (HANNUM: 3.6 VS. 7.6 YEARS, P = 0.0093; HORVATH: 2.4 VS. 4.5 YEARS, P = 0.1308). THE CD EXPOSED GROUP WAS ASSOCIATED WITH CHANGES IN METHYLATION (P < 0.05) AT 12, 8, AND 20 AGE-ASSOCIATED SITES IDENTIFIED IN OUR POPULATION, HANNUM, AND HORVATH. FROM THE RESULTS OF THIS PILOT STUDY, ELEVATED CD EXPOSURE IS ASSOCIATED WITH METHYLATION CHANGES AT AGE-ASSOCIATED SITES AND SMALLER DIFFERENCES BETWEEN DNAM-AGE AND CHRONOLOGIC AGE, IN CONTRAST TO EXPECTED AGE-ACCELERATING EFFECTS. CD MAY MODIFY EPIGENETIC AGING, AND BIOMARKERS OF AGING WARRANT FURTHER INVESTIGATION WHEN EXAMINING CD AND ITS RELATIONSHIP WITH CHRONIC DISEASE AND MORTALITY. 2017 17 178 36 ACCELERATED EPIGENETIC AGING AS A RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND DECREASED LUNG FUNCTION IN TWO PROSPECTIVE COHORT STUDIES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A FREQUENT DIAGNOSIS IN OLDER INDIVIDUALS AND CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY. GIVEN THE LINK BETWEEN LUNG DISEASE AND AGING, WE NEED TO UNDERSTAND HOW MOLECULAR INDICATORS OF AGING RELATE TO LUNG FUNCTION AND DISEASE. USING DATA FROM THE POPULATION-BASED KORA (COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG) SURVEYS, WE ASSOCIATED BASELINE EPIGENETIC (DNA METHYLATION) AGE ACCELERATION WITH INCIDENT COPD AND LUNG FUNCTION. MODELS WERE ADJUSTED FOR AGE, SEX, SMOKING, HEIGHT, WEIGHT, AND BASELINE LUNG DISEASE AS APPROPRIATE. ASSOCIATIONS WERE REPLICATED IN THE NORMATIVE AGING STUDY. OF 770 KORA PARTICIPANTS, 131 DEVELOPED INCIDENT COPD OVER 7 YEARS. BASELINE ACCELERATED EPIGENETIC AGING WAS SIGNIFICANTLY ASSOCIATED WITH INCIDENT COPD. THE CHANGE IN AGE ACCELERATION (FOLLOW-UP - BASELINE) WAS MORE STRONGLY ASSOCIATED WITH COPD THAN BASELINE AGING ALONE. THE ASSOCIATION BETWEEN THE CHANGE IN AGE ACCELERATION BETWEEN BASELINE AND FOLLOW-UP AND INCIDENT COPD REPLICATED IN THE NORMATIVE AGING STUDY. ASSOCIATIONS WITH SPIROMETRIC LUNG FUNCTION PARAMETERS WERE WEAKER THAN THOSE WITH COPD, BUT A META-ANALYSIS OF BOTH COHORTS PROVIDE SUGGESTIVE EVIDENCE OF ASSOCIATIONS. ACCELERATED EPIGENETIC AGING, BOTH BASELINE MEASURES AND CHANGES OVER TIME, MAY BE A RISK FACTOR FOR COPD AND REDUCED LUNG FUNCTION. 2020 18 2643 42 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE. 2013 19 6691 44 VARIABLE DNA METHYLATION IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG FUNCTION. RATIONALE: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ASSOCIATED WITH LOCAL (LUNG) AND SYSTEMIC (BLOOD) INFLAMMATION AND MANIFESTATIONS. DNA METHYLATION IS AN IMPORTANT REGULATOR OF GENE TRANSCRIPTION, AND GLOBAL AND SPECIFIC GENE METHYLATION MARKS MAY VARY WITH CIGARETTE SMOKE EXPOSURE. OBJECTIVES: TO PERFORM A COMPREHENSIVE ASSESSMENT OF METHYLATION MARKS IN DNA FROM SUBJECTS WELL PHENOTYPED FOR NONNEOPLASTIC LUNG DISEASE. METHODS: WE CONDUCTED ARRAY-BASED METHYLATION SCREENS, USING A TEST-REPLICATION APPROACH, IN TWO FAMILY-BASED COHORTS (N = 1,085 AND 369 SUBJECTS). MEASUREMENTS AND MAIN RESULTS: WE OBSERVED 349 CPG SITES SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE AND SEVERITY OF COPD IN BOTH COHORTS. SEVENTY PERCENT OF THE ASSOCIATED CPG SITES WERE OUTSIDE OF CPG ISLANDS, WITH THE MAJORITY OF CPG SITES RELATIVELY HYPOMETHYLATED. GENE ONTOLOGY ANALYSIS BASED ON THESE 349 CPGS (330 GENES) SUGGESTED THE INVOLVEMENT OF A NUMBER OF GENES RESPONSIBLE FOR IMMUNE AND INFLAMMATORY SYSTEM PATHWAYS, RESPONSES TO STRESS AND EXTERNAL STIMULI, AS WELL AS WOUND HEALING AND COAGULATION CASCADES. INTERESTINGLY, OUR OBSERVATIONS INCLUDE SIGNIFICANT, REPLICABLE ASSOCIATIONS BETWEEN SERPINA1 HYPOMETHYLATION AND COPD AND LOWER AVERAGE LUNG FUNCTION PHENOTYPES (COMBINED P VALUES: COPD, 1.5 X 10(-23); FEV(1)/FVC, 1.5 X 10(-35); FEV(1), 2.2 X 10(-40)). CONCLUSIONS: GENETIC AND EPIGENETIC PATHWAYS MAY BOTH CONTRIBUTE TO COPD. MANY OF THE TOP ASSOCIATIONS BETWEEN COPD AND DNA METHYLATION OCCUR IN BIOLOGICALLY PLAUSIBLE PATHWAYS. THIS LARGE-SCALE ANALYSIS SUGGESTS THAT DNA METHYLATION MAY BE A BIOMARKER OF COPD AND MAY HIGHLIGHT NEW PATHWAYS OF COPD PATHOGENESIS. 2012 20 3557 47 IMPACT OF BMI AND WAIST CIRCUMFERENCE ON EPIGENOME-WIDE DNA METHYLATION AND IDENTIFICATION OF EPIGENETIC BIOMARKERS IN BLOOD: AN EWAS IN MULTI-ETHNIC ASIAN INDIVIDUALS. BACKGROUND: THE PREVALENCE OF OBESITY AND ITS RELATED CHRONIC DISEASES HAVE BEEN INCREASING ESPECIALLY IN ASIAN COUNTRIES. OBESITY-RELATED GENETIC VARIANTS HAVE BEEN IDENTIFIED, BUT THESE EXPLAIN LITTLE OF THE VARIATION IN BMI. RECENT STUDIES REPORTED ASSOCIATIONS BETWEEN DNA METHYLATION AND OBESITY, MOSTLY IN NON-ASIAN POPULATIONS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ON GENERAL ADIPOSITY (BODY MASS INDEX, BMI) AND ABDOMINAL ADIPOSITY (WAIST CIRCUMFERENCE, WC) IN 409 MULTI-ETHNIC ASIAN INDIVIDUALS AND REPLICATED BMI AND WAIST-ASSOCIATED DNA METHYLATION CPGS IDENTIFIED IN OTHER POPULATIONS. THE CROSS-LAGGED PANEL MODEL AND MENDELIAN RANDOMIZATION WERE USED TO ASSESS THE TEMPORAL RELATIONSHIP BETWEEN METHYLATION AND BMI. THE TEMPORAL RELATIONSHIP BETWEEN THE IDENTIFIED CPGS AND INFLAMMATION AND METABOLIC MARKERS WAS ALSO EXAMINED. RESULTS: EWAS IDENTIFIED 116 DNA METHYLATION CPGS INDEPENDENTLY ASSOCIATED WITH BMI AND EIGHT INDEPENDENTLY ASSOCIATED WITH WC AT FALSE DISCOVERY RATE P(FDR) < 0.05 IN 409 ASIAN SAMPLES. WE REPLICATED 110 BMI-ASSOCIATED CPGS PREVIOUSLY REPORTED IN EUROPEANS AND IDENTIFIED SIX NOVEL BMI-ASSOCIATED CPGS AND TWO NOVEL WC-ASSOCIATED CPGS. WE OBSERVED HIGH CONSISTENCY IN ASSOCIATION DIRECTION OF EFFECT COMPARED TO STUDIES IN OTHER POPULATIONS. CAUSAL RELATIONSHIP ANALYSES INDICATED THAT BMI WAS MORE LIKELY TO BE THE CAUSE OF DNA METHYLATION ALTERATION, RATHER THAN THE CONSEQUENCE. THE CAUSAL ANALYSES USING BMI-ASSOCIATED METHYLATION RISK SCORE ALSO SUGGESTED THAT HIGHER LEVELS OF THE INFLAMMATION MARKER IL-6 WERE LIKELY THE CONSEQUENCE OF METHYLATION CHANGE. CONCLUSION: OUR STUDY PROVIDES EVIDENCE OF AN ASSOCIATION BETWEEN OBESITY AND DNA METHYLATION IN MULTI-ETHNIC ASIANS AND SUGGESTS THAT OBESITY CAN DRIVE METHYLATION CHANGE. THE RESULTS ALSO SUGGESTED POSSIBLE CAUSAL INFLUENCE THAT OBESITY-RELATED METHYLATION CHANGES MIGHT HAVE ON INFLAMMATION AND LIPOPROTEIN LEVELS. 2021