1 2624 168 EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) OF BMI, BMI CHANGE AND WAIST CIRCUMFERENCE IN AFRICAN AMERICAN ADULTS IDENTIFIES MULTIPLE REPLICATED LOCI. OBESITY IS AN IMPORTANT COMPONENT OF THE PATHOPHYSIOLOGY OF CHRONIC DISEASES. IDENTIFYING EPIGENETIC MODIFICATIONS ASSOCIATED WITH ELEVATED ADIPOSITY, INCLUDING DNA METHYLATION VARIATION, MAY POINT TO GENOMIC PATHWAYS THAT ARE DYSREGULATED IN NUMEROUS CONDITIONS. THE ILLUMINA 450K BEAD CHIP ARRAY WAS USED TO ASSAY DNA METHYLATION IN LEUKOCYTE DNA OBTAINED FROM 2097 AFRICAN AMERICAN ADULTS IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY. MIXED-EFFECTS REGRESSION MODELS WERE USED TO TEST THE ASSOCIATION OF METHYLATION BETA VALUE WITH CONCURRENT BODY MASS INDEX (BMI) AND WAIST CIRCUMFERENCE (WC), AND BMI CHANGE, ADJUSTING FOR BATCH EFFECTS AND POTENTIAL CONFOUNDERS. REPLICATION USING WHOLE-BLOOD DNA FROM 2377 WHITE ADULTS IN THE FRAMINGHAM HEART STUDY AND CD4+ T CELL DNA FROM 991 WHITES IN THE GENETICS OF LIPID LOWERING DRUGS AND DIET NETWORK STUDY WAS FOLLOWED BY TESTING USING ADIPOSE TISSUE DNA FROM 648 WOMEN IN THE MULTIPLE TISSUE HUMAN EXPRESSION RESOURCE COHORT. SEVENTY-SIX BMI-RELATED PROBES, 164 WC-RELATED PROBES AND 8 BMI CHANGE-RELATED PROBES PASSED THE THRESHOLD FOR SIGNIFICANCE IN ARIC (P < 1 X 10(-7); BONFERRONI), INCLUDING PROBES IN THE RECENTLY REPORTED HIF3A, CPT1A AND ABCG1 REGIONS. REPLICATION USING BLOOD DNA WAS ACHIEVED FOR 37 BMI PROBES AND 1 ADDITIONAL WC PROBE. SIXTEEN OF THESE ALSO REPLICATED IN ADIPOSE TISSUE, INCLUDING 15 NOVEL METHYLATION FINDINGS NEAR GENES INVOLVED IN LIPID METABOLISM, IMMUNE RESPONSE/CYTOKINE SIGNALING AND OTHER DIVERSE PATHWAYS, INCLUDING LGALS3BP, KDM2B, PBX1 AND BBS2, AMONG OTHERS. ADIPOSITY TRAITS ARE ASSOCIATED WITH DNA METHYLATION AT NUMEROUS CPG SITES THAT REPLICATE ACROSS STUDIES DESPITE VARIATION IN TISSUE TYPE, ETHNICITY AND ANALYTIC APPROACHES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  382  51 AN EPIGENOME-WIDE STUDY OF BODY MASS INDEX AND DNA METHYLATION IN BLOOD USING PARTICIPANTS FROM THE SISTER STUDY COHORT. BACKGROUND/OBJECTIVES: THE RELATIONSHIP BETWEEN OBESITY AND CHRONIC DISEASE RISK IS WELL-ESTABLISHED; THE UNDERLYING BIOLOGICAL MECHANISMS DRIVING THIS RISK INCREASE MAY INCLUDE OBESITY-RELATED EPIGENETIC MODIFICATIONS. TO EXPLORE THIS HYPOTHESIS, WE CONDUCTED A GENOME-WIDE ANALYSIS OF DNA METHYLATION AND BODY MASS INDEX (BMI) USING DATA FROM A SUBSET OF WOMEN IN THE SISTER STUDY. SUBJECTS/METHODS: THE SISTER STUDY IS A COHORT OF 50 884 US WOMEN WHO HAD A SISTER WITH BREAST CANCER BUT WERE FREE OF BREAST CANCER THEMSELVES AT ENROLLMENT. STUDY PARTICIPANTS COMPLETED EXAMINATIONS WHICH INCLUDED MEASUREMENTS OF HEIGHT AND WEIGHT, AND PROVIDED BLOOD SAMPLES. BLOOD DNA METHYLATION DATA GENERATED WITH THE ILLUMINA INFINIUM HUMANMETHYLATION27 BEADCHIP ARRAY COVERING 27,589 CPG SITES WAS AVAILABLE FOR 871 WOMEN FROM A PRIOR STUDY OF BREAST CANCER AND DNA METHYLATION. TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH BMI, WE ANALYZED THIS METHYLATION DATA USING ROBUST LINEAR REGRESSION WITH ADJUSTMENT FOR AGE AND CASE STATUS. FOR THOSE CPGS PASSING THE FALSE DISCOVERY RATE SIGNIFICANCE LEVEL, WE EXAMINED THE ASSOCIATION IN A REPLICATION SET COMPRISED OF A NON-OVERLAPPING GROUP OF 187 WOMEN FROM THE SISTER STUDY WHO HAD DNA METHYLATION DATA GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. ANALYSIS OF THIS EXPANDED 450 K ARRAY IDENTIFIED ADDITIONAL BMI-ASSOCIATED SITES WHICH WERE INVESTIGATED WITH TARGETED PYROSEQUENCING. RESULTS: FOUR CPG SITES REACHED GENOME-WIDE SIGNIFICANCE (FALSE DISCOVERY RATE (FDR) Q<0.05) IN THE DISCOVERY SET AND ASSOCIATIONS FOR ALL FOUR WERE SIGNIFICANT AT STRICT BONFERRONI CORRECTION IN THE REPLICATION SET. AN ADDITIONAL 23 SITES PASSED FDR IN THE REPLICATION SET AND FIVE WERE REPLICATED BY PYROSEQUENCING IN THE DISCOVERY SET. SEVERAL OF THE GENES IDENTIFIED INCLUDING ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 AND CRHR2 HAVE BEEN LINKED TO OBESITY AND OBESITY-RELATED CHRONIC DISEASES. CONCLUSIONS: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT OBESITY-RELATED EPIGENETIC DIFFERENCES ARE DETECTABLE IN BLOOD AND MAY BE RELATED TO RISK OF CHRONIC DISEASE.	2017	
                                                                                                                        
3 2627  47 EPIGENOME-WIDE ASSOCIATION STUDY OF ADIPOSITY AND FUTURE RISK OF OBESITY-RELATED DISEASES. BACKGROUND: OBESITY IS AN ESTABLISHED RISK FACTOR FOR SEVERAL COMMON CHRONIC DISEASES SUCH AS BREAST AND COLORECTAL CANCER, METABOLIC AND CARDIOVASCULAR DISEASES; HOWEVER, THE BIOLOGICAL BASIS FOR THESE RELATIONSHIPS IS NOT FULLY UNDERSTOOD. TO EXPLORE THE ASSOCIATION OF OBESITY WITH THESE CONDITIONS, WE INVESTIGATED PERIPHERAL BLOOD LEUCOCYTE (PBL) DNA METHYLATION MARKERS FOR ADIPOSITY AND THEIR CONTRIBUTION TO RISK OF INCIDENT BREAST AND COLORECTAL CANCER AND MYOCARDIAL INFARCTION. METHODS: DNA METHYLATION PROFILES (ILLUMINA INFINIUM((R)) HUMANMETHYLATION450 BEADCHIP) FROM 1941 INDIVIDUALS FROM FOUR POPULATION-BASED EUROPEAN COHORTS WERE ANALYSED IN RELATION TO BODY MASS INDEX, WAIST CIRCUMFERENCE, WAIST-HIP AND WAIST-HEIGHT RATIO WITHIN A META-ANALYTICAL FRAMEWORK. IN A SUBSET OF THESE INDIVIDUALS, DATA ON GENOME-WIDE GENE EXPRESSION LEVEL, BIOMARKERS OF GLUCOSE AND LIPID METABOLISM WERE ALSO AVAILABLE. VALIDATION OF METHYLATION MARKERS ASSOCIATED WITH ALL ADIPOSITY MEASURES WAS PERFORMED IN 358 INDIVIDUALS. FINALLY, WE INVESTIGATED THE ASSOCIATION OF OBESITY-RELATED METHYLATION MARKS WITH BREAST, COLORECTAL CANCER AND MYOCARDIAL INFARCTION WITHIN RELEVANT SUBSETS OF THE DISCOVERY POPULATION. RESULTS: WE IDENTIFIED 40 CPG LOCI WITH METHYLATION LEVELS ASSOCIATED WITH AT LEAST ONE ADIPOSITY MEASURE. OF THESE, ONE CPG LOCUS (CG06500161) IN ABCG1 WAS ASSOCIATED WITH ALL FOUR ADIPOSITY MEASURES (P = 9.07X10(-)(8) TO 3.27X10(-18)) AND LOWER TRANSCRIPTIONAL ACTIVITY OF THE FULL-LENGTH ISOFORM OF ABCG1 (P = 6.00X10(-7)), HIGHER TRIGLYCERIDE LEVELS (P = 5.37X10(-)(9)) AND HIGHER TRIGLYCERIDES-TO-HDL CHOLESTEROL RATIO (P = 1.03X10(-10)). OF THE 40 INFORMATIVE AND OBESITY-RELATED CPG LOCI, TWO (IN IL2RB AND FGF18) WERE SIGNIFICANTLY ASSOCIATED WITH COLORECTAL CANCER (INVERSELY, P < 1.6X10(-3)) AND ONE INTERGENIC LOCUS ON CHROMOSOME 1 WAS INVERSELY ASSOCIATED WITH MYOCARDIAL INFARCTION (P < 1.25X10(-3)), INDEPENDENTLY OF OBESITY AND ESTABLISHED RISK FACTORS. CONCLUSION: OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES, IN PARTICULAR ALTERED DNA METHYLATION PATTERNS, MAY BE AN INTERMEDIATE BIOMARKER AT THE INTERSECTION OF OBESITY AND OBESITY-RELATED DISEASES, AND COULD OFFER CLUES AS TO UNDERLYING BIOLOGICAL MECHANISMS.	2018	
                                            
4 2921  51 GENE-SPECIFIC DIFFERENTIAL DNA METHYLATION AND CHRONIC ARSENIC EXPOSURE IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF ADULTS IN BANGLADESH. BACKGROUND: INORGANIC ARSENIC IS ONE OF THE MOST COMMON NATURALLY OCCURRING CONTAMINANTS FOUND IN THE ENVIRONMENT. ARSENIC IS ASSOCIATED WITH A NUMBER OF HEALTH OUTCOMES, WITH EPIGENETIC MODIFICATION SUGGESTED AS A POTENTIAL MECHANISM OF TOXICITY. OBJECTIVE: AMONG A SAMPLE OF 400 ADULT PARTICIPANTS, WE EVALUATED THE ASSOCIATION BETWEEN ARSENIC EXPOSURE, AS MEASURED BY BLOOD AND URINARY TOTAL ARSENIC CONCENTRATIONS, AND EPIGENOME-WIDE WHITE BLOOD CELL DNA METHYLATION. METHODS: WE USED LINEAR REGRESSION MODELS TO EXAMINE THE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND METHYLATION AT EACH CPG SITE, ADJUSTED FOR SEX, AGE, AND BATCH. DIFFERENTIALLY METHYLATED LOCI WERE SUBSEQUENTLY EXAMINED IN RELATION TO CORRESPONDING GENE EXPRESSION FOR FUNCTIONAL EVIDENCE OF GENE REGULATION. RESULTS: IN ADJUSTED ANALYSES, WE OBSERVED FOUR DIFFERENTIALLY METHYLATED CPG SITES WITH URINARY TOTAL ARSENIC CONCENTRATION AND THREE DIFFERENTIALLY METHYLATED CPG SITES WITH BLOOD ARSENIC CONCENTRATION, BASED ON THE BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLD OF P < 1 X 10(-7). METHYLATION OF PLA2G2C (PROBE CG04605617) WAS THE MOST SIGNIFICANTLY ASSOCIATED LOCUS IN RELATION TO BOTH URINARY (P = 3.40 X 10(-11)) AND BLOOD ARSENIC CONCENTRATIONS (P = 1.48 X 10(-11)). THREE ADDITIONAL NOVEL METHYLATION LOCI-SQSTM1 (CG01225779), SLC4A4 (CG06121226), AND IGH (CG13651690)--WERE ALSO SIGNIFICANTLY ASSOCIATED WITH ARSENIC EXPOSURE. FURTHER, THERE WAS EVIDENCE OF METHYLATION-RELATED GENE REGULATION BASED ON GENE EXPRESSION FOR A SUBSET OF DIFFERENTIALLY METHYLATED LOCI. CONCLUSIONS: WE OBSERVED SIGNIFICANT ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENE-SPECIFIC DIFFERENTIAL WHITE BLOOD CELL DNA METHYLATION, SUGGESTING THAT EPIGENETIC MODIFICATIONS MAY BE AN IMPORTANT PATHWAY UNDERLYING ARSENIC TOXICITY. THE SPECIFIC DIFFERENTIALLY METHYLATED LOCI IDENTIFIED MAY INFORM POTENTIAL PATHWAYS FOR FUTURE INTERVENTIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                    
5  497  33 ASSOCIATION BETWEEN BMI AND DNA METHYLATION IN BLOOD OR NORMAL ADULT BREAST TISSUE: A SYSTEMATIC REVIEW. BACKGROUND/AIM: SEVERAL STUDIES HAVE INVESTIGATED THE INFLUENCE OF OBESITY ON DNA METHYLATION (DNAM) TO FIND BIOMARKERS ASSOCIATED WITH THE DETECTION OF CHRONIC DISEASES, INCLUDING BREAST CANCER. THE AIM OF THE STUDY WAS TO SYSTEMATICALLY REVIEW STUDIES EXAMINING THE ASSOCIATION OF BODY MASS INDEX (BMI) AND DNAM IN BLOOD OR NORMAL BREAST TISSUE. MATERIALS AND METHODS: THREE SCIENTIFIC LITERATURE DATABASES (PUBMED, EMBASE AND WEB OF SCIENCE) WERE SCREENED UNTIL MAY 2018. RESULTS: TWENTY-FOUR STUDIES WERE INCLUDED ALONG WITH OURS IN WHICH WE INVESTIGATED THIS RELATION IN THE NORMAL BREAST TISSUE OF 40 BREAST CANCER PATIENTS. CONCLUSION: BMI-ASSOCIATED CPG SITES WERE HIGHLY VARIABLE WITH FEW IDENTIFIED IN LESS THAN HALF OF THE STUDIES. NEVERTHELESS, A FEW GENES POTENTIALLY ASSOCIATED WITH BMI WERE HIGHLIGHTED IN BLOOD (CPT1A, ABCG1, SREBF1 AND LGALS3BP) AND IN NORMAL BREAST TISSUE (PTPRN2 AND ABLIM2). THE VARIABILITY OF THE RESULTS COULD BE EXPLAINED BY THE TISSUE AND CELL-SPECIFICITY OF METHYLATION AND DIFFERENCES IN METHODOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6 3557  45 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	
                                                                                                                                                                                                                                                                   
7 4091  42 MATERNAL PRECONCEPTION BODY MASS INDEX AND OFFSPRING CORD BLOOD DNA METHYLATION: EXPLORATION OF EARLY LIFE ORIGINS OF DISEASE. MATERNAL OBESITY IS ASSOCIATED WITH A VARIETY OF COMMON DISEASES IN THE OFFSPRING. ONE POSSIBLE UNDERLYING MECHANISM COULD BE MATERNAL OBESITY INDUCED ALTERATIONS IN DNA METHYLATION. HOWEVER, THIS HYPOTHESIS IS YET TO BE TESTED. WE PERFORMED EPIGENOMIC MAPPING OF CORD BLOOD AMONG 308 BLACK MOTHER-INFANT PAIRS DELIVERED AT TERM AT THE BOSTON MEDICAL CENTER USING THE ILLUMINA HUMANMETHYLATION27 BEADCHIP. LINEAR REGRESSION AND PATHWAY ANALYSES WERE CONDUCTED TO EVALUATE THE ASSOCIATIONS BETWEEN DNA METHYLATION LEVELS AND PREPREGNANCY MATERNAL BMI (<25, 25-30, >/=30 KG/M(2) ). THE METHYLATION LEVELS OF 20 CPG SITES WERE ASSOCIATED WITH MATERNAL BMI AT A SIGNIFICANCE LEVEL OF P-VALUE <10(-4) IN THE OVERALL SAMPLE, AND BOYS AND GIRLS, SEPARATELY. ONE CPG SITE REMAINED STATISTICALLY SIGNIFICANT AFTER CORRECTION FOR MULTIPLE COMPARISONS (FDR CORRECTED P-VALUE = 0.04) AND WAS ANNOTATED TO A POTENTIAL CANCER GENE, ZCCHC10. SOME OF THE OTHER CPG SITE ANNOTATED GENES APPEAR TO BE CRITICAL TO THE DEVELOPMENT OF CANCERS AND CARDIOVASCULAR DISEASES (I.E., WNT16, C18ORF8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). SIGNIFICANT FINDINGS FROM PATHWAY ANALYSIS, SUCH AS INFECTIOUS AND INFLAMMATORY AND LIPID METABOLISM PATHWAYS, LENDS SUPPORT FOR THE POTENTIAL IMPACT OF MATERNAL BMI ON THE ABOVE STATED DISORDERS. THIS STUDY DEMONSTRATES THAT PREPREGNANCY MATERNAL BMI MIGHT LEAD TO ALTERATIONS IN OFFSPRING DNA METHYLATION IN GENES RELEVANT TO THE DEVELOPMENT OF A RANGE OF COMPLEX CHRONIC DISEASES, PROVIDING EVIDENCE OF TRANS-GENERATIONAL INFLUENCE ON DISEASE SUSCEPTIBILITY VIA EPIGENETIC MECHANISM.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 3951  51 LOCUS-SPECIFIC DIFFERENTIAL DNA METHYLATION AND URINARY ARSENIC: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AMONG ADULTS WITH LOW-TO-MODERATE ARSENIC EXPOSURE. BACKGROUND: CHRONIC EXPOSURE TO ARSENIC (AS), A HUMAN TOXICANT AND CARCINOGEN, REMAINS A GLOBAL PUBLIC HEALTH PROBLEM. HEALTH RISKS PERSIST AFTER AS EXPOSURE HAS ENDED, SUGGESTING EPIGENETIC DYSREGULATION AS A MECHANISTIC LINK BETWEEN EXPOSURE AND HEALTH OUTCOMES. OBJECTIVES: WE INVESTIGATED THE ASSOCIATION BETWEEN TOTAL URINARY AS AND LOCUS-SPECIFIC DNA METHYLATION IN THE STRONG HEART STUDY, A COHORT OF AMERICAN INDIAN ADULTS WITH LOW-TO-MODERATE AS EXPOSURE [TOTAL URINARY AS, MEAN (+/-SD) MUG/G CREATININE: 11.7 (10.6)]. METHODS: DNA METHYLATION WAS MEASURED IN 2,325 PARTICIPANTS USING THE ILLUMINA METHYLATIONEPIC ARRAY. WE IMPLEMENTED LINEAR MODELS TO TEST DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND THE DMRCATE METHOD TO IDENTIFY REGIONS (DMRS) AND CONDUCTED GENE ONTOLOGY ENRICHMENT ANALYSIS. MODELS WERE ADJUSTED FOR ESTIMATED CELL TYPE PROPORTIONS, AGE, SEX, BODY MASS INDEX, SMOKING, EDUCATION, ESTIMATED GLOMERULAR FILTRATION RATE, AND STUDY CENTER. ARSENIC WAS MEASURED IN URINE AS THE SUM OF INORGANIC AND METHYLATED SPECIES. RESULTS: IN ADJUSTED MODELS, METHYLATION AT 20 CPGS WAS ASSOCIATED WITH URINARY AS AFTER FALSE DISCOVERY RATE (FDR) CORRECTION (FDR < 0.05). AFTER BONFERRONI CORRECTION, 5 CPGS REMAINED ASSOCIATED WITH TOTAL URINARY AS (PBONFERRONI < 0.05), LOCATED IN SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. WE IDENTIFIED ONE DMR ON CHROMOSOME 11 (CHR11:2,322,050-2,323,247), ANNOTATED TO C11ORF2; TSPAN32 GENES. DISCUSSION: THIS IS ONE OF THE FIRST EPIGENOME-WIDE ASSOCIATION STUDIES TO INVESTIGATE AS EXPOSURE AND LOCUS-SPECIFIC DNA METHYLATION USING THE ILLUMINA METHYLATIONEPIC ARRAY AND THE LARGEST EPIGENOME-WIDE STUDY OF AS EXPOSURE. THE TOP DMP WAS LOCATED IN SLC7A11A, A GENE INVOLVED IN CYSTINE/GLUTAMATE TRANSPORT AND THE BIOSYNTHESIS OF GLUTATHIONE, AN ANTIOXIDANT THAT MAY PROTECT AGAINST AS-INDUCED OXIDATIVE STRESS. ADDITIONAL DMPS WERE LOCATED IN GENES ASSOCIATED WITH TUMOR DEVELOPMENT AND GLUCOSE METABOLISM. FURTHER RESEARCH IS NEEDED, INCLUDING RESEARCH IN MORE DIVERSE POPULATIONS, TO INVESTIGATE WHETHER AS-RELATED DNA METHYLATION SIGNATURES ARE ASSOCIATED WITH GENE EXPRESSION OR MAY SERVE AS BIOMARKERS OF DISEASE DEVELOPMENT. HTTPS://DOI.ORG/10.1289/EHP6263.	2020	

9 6190  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                            
10 6761  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11 2420  45 EPIGENETIC SIGNATURE OF IMPAIRED FASTING GLUCOSE IN THE OLD ORDER AMISH. INTRODUCTION: TYPE 2 DIABETES (T2D) IS A COMMON CHRONIC DISEASE WITH SUBSTANTIAL DISEASE BURDEN AND ECONOMIC IMPACT. LIFESTYLE CHANGES CAN SIGNIFICANTLY ALTER THE COURSE OF THE DISEASE, IF DETECTED AT AN EARLY STAGE. DNA METHYLATION SIGNATURE MAY SERVE AS A BIOMARKER FOR EARLY DETECTION OF INCREASED T2D RISK. DESIGN: DNA METHYLATION PROFILING WAS PERFORMED USING THE ILLUMINA INFINIUM HUMAN METHYLATION 450K BEAD CHIP ARRAY IN 24 NORMOGLYCEMIC OLD ORDER AMISH (OOA) INDIVIDUALS WHO LATER DEVELOPED IMPAIRED FASTING GLUCOSE (IFG) (CASES), AND 24 OOA INDIVIDUALS WHO REMAINED NORMOGLYCEMIC AFTER AN AVERAGE FOLLOW UP OF 10 YEARS (CONTROLS). CASES AND CONTROLS WERE MATCHED ON AGE, SEX, BMI, BASELINE FASTING GLUCOSE, AND GLUCOSE LEVEL AFTER 2 H FROM 75 G ORAL GLUCOSE TOLERANCE TEST (OGTT). RESULTS: ASSOCIATION ANALYSIS FOUND NO SIGNIFICANT DIFFERENCE IN EITHER GLOBAL METHYLATION OR INDIVIDUAL PROBE METHYLATION BETWEEN CASES AND CONTROLS, HOWEVER, THE TOP 34 SUGGESTIVE SIGNIFICANT SITES WERE LOCATED IN GENES WITH INTERESTING BIOLOGICAL LINKS TO T2D AND GLYCEMIC TRAITS. THESE GENES INCLUDE BTC THAT PLAYS A ROLE IN PANCREATIC CELL PROLIFERATION AND INSULIN SECRETION, ITGA1 A KNOWN BONE MINERAL DENSITY GENE THAT WAS RECENTLY FOUND TO BE ASSOCIATED ALSO WITH T2D AND GLYCEMIC TRAITS, AND MAY EXPLAIN THE LINK BETWEEN T2D AND BMD, AND RPTOR AND TSC2 BOTH OF WHICH ARE PART OF INSULIN SIGNALING PATHWAY. CONCLUSIONS: THESE RESULTS MAY SHED LIGHT ON THE INITIATION AND DEVELOPMENT OF HYPERGLYCEMIA AND T2D AND HELP TO IDENTIFY HIGH RISK INDIVIDUALS FOR EARLY INTERVENTION; HOWEVER, FURTHER STUDIES ARE REQUIRED FOR VALIDATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12 1909  44 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13 1607  33 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  381  40 AN EPIGENOME-WIDE ASSOCIATION STUDY OF EARLY-ONSET MAJOR DEPRESSION IN MONOZYGOTIC TWINS. MAJOR DEPRESSION (MD) IS A DEBILITATING MENTAL HEALTH CONDITION WITH PEAK PREVALENCE OCCURRING EARLY IN LIFE. GENOME-WIDE EXAMINATION OF DNA METHYLATION (DNAM) OFFERS AN ATTRACTIVE COMPLEMENT TO STUDIES OF ALLELIC RISK GIVEN IT CAN REFLECT THE COMBINED INFLUENCE OF GENES AND ENVIRONMENT. THE CURRENT STUDY USED MONOZYGOTIC TWINS TO IDENTIFY DIFFERENTIALLY AND VARIABLY METHYLATED REGIONS OF THE GENOME THAT DISTINGUISH TWINS WITH AND WITHOUT A LIFETIME HISTORY OF EARLY-ONSET MD. THE SAMPLE INCLUDED 150 CAUCASIAN MONOZYGOTIC TWINS BETWEEN THE AGES OF 15 AND 20 (73% FEMALE; MAGE = 17.52 SD = 1.28) WHO WERE ASSESSED DURING A DEVELOPMENTAL STAGE CHARACTERIZED BY RELATIVELY DISTINCT NEUROPHYSIOLOGICAL CHANGES. ALL TWINS WERE GENERALLY HEALTHY AND CURRENTLY FREE OF MEDICATIONS WITH PSYCHOTROPIC EFFECTS. DNAM WAS MEASURED IN PERIPHERAL BLOOD CELLS USING THE INFINIUM HUMAN BEADCHIP 450 K ARRAY. MD ASSOCIATIONS WITH EARLY-ONSET MD WERE DETECTED AT 760 DIFFERENTIALLY AND VARIABLY METHYLATED PROBES/REGIONS THAT MAPPED TO 428 GENES. GENES AND GENOMIC REGIONS INVOLVED NEURAL CIRCUITRY FORMATION, PROJECTION, FUNCTIONING, AND PLASTICITY. GENE ENRICHMENT ANALYSES IMPLICATED GENES RELATED TO NEURON STRUCTURES AND NEURODEVELOPMENTAL PROCESSES INCLUDING CELL-CELL ADHESION GENES (E.G., PCDHA GENES). GENES PREVIOUSLY IMPLICATED IN MOOD AND PSYCHIATRIC DISORDERS AS WELL AS CHRONIC STRESS (E.G., NRG3) ALSO WERE IDENTIFIED. DNAM REGIONS ASSOCIATED WITH EARLY-ONSET MD WERE FOUND TO OVERLAP GENETIC LOCI IDENTIFIED IN THE LATEST PSYCHIATRIC GENOMICS CONSORTIUM META-ANALYSIS OF DEPRESSION. UNDERSTANDING THE TIME COURSE OF EPIGENETIC INFLUENCES DURING EMERGING ADULTHOOD MAY CLARIFY DEVELOPMENTAL PHASES WHERE CHANGES IN THE DNA METHYLOME MAY MODULATE INDIVIDUAL DIFFERENCES IN MD RISK.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15 6083  39 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 6080  35 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION.	2023	
                                                                                      
17 1271  38 CYTOSINE METHYLATION PREDICTS RENAL FUNCTION DECLINE IN AMERICAN INDIANS. DIABETIC NEPHROPATHY ACCOUNTS FOR MOST OF THE EXCESS MORTALITY IN INDIVIDUALS WITH DIABETES, BUT THE MOLECULAR MECHANISMS BY WHICH NEPHROPATHY DEVELOPS ARE LARGELY UNKNOWN. HERE WE TESTED CYTOSINE METHYLATION LEVELS AT 397,063 GENOMIC CPG SITES FOR ASSOCIATION WITH DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OVER A SIX YEAR PERIOD IN 181 DIABETIC PIMA INDIANS. METHYLATION LEVELS AT 77 SITES SHOWED SIGNIFICANT ASSOCIATION WITH EGFR DECLINE AFTER CORRECTION FOR MULTIPLE COMPARISONS. A MODEL INCLUDING METHYLATION LEVEL AT TWO PROBES (CG25799291 AND CG22253401) IMPROVED PREDICTION OF EGFR DECLINE IN ADDITION TO BASELINE EGFR AND THE ALBUMIN TO CREATININE RATIO WITH THE PERCENT OF VARIANCE EXPLAINED SIGNIFICANTLY IMPROVING FROM 23.1% TO 42.2%. CG22253401 WAS ALSO SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE IN A CASE-CONTROL STUDY DERIVED FROM THE CHRONIC RENAL INSUFFICIENCY COHORT. PROBES AT WHICH METHYLATION SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE WERE LOCALIZED TO GENE REGULATORY REGIONS AND ENRICHED FOR GENES WITH METABOLIC FUNCTIONS AND APOPTOSIS. THREE OF THE 77 PROBES THAT WERE ASSOCIATED WITH EGFR DECLINE IN BLOOD SAMPLES SHOWED DIRECTIONALLY CONSISTENT AND SIGNIFICANT ASSOCIATION WITH FIBROSIS IN MICRODISSECTED HUMAN KIDNEY TISSUE, AFTER CORRECTION FOR MULTIPLE COMPARISONS. THUS, CYTOSINE METHYLATION LEVELS MAY PROVIDE BIOMARKERS OF DISEASE PROGRESSION IN DIABETIC NEPHROPATHY AND EPIGENETIC VARIATIONS CONTRIBUTE TO THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 2488  38 EPIGENETICALLY DYSREGULATED GENES AND PATHWAYS IMPLICATED IN THE PATHOGENESIS OF NON-SYNDROMIC HIGH MYOPIA. MYOPIA, COMMONLY REFERRED TO AS NEARSIGHTEDNESS, IS ONE OF THE MOST COMMON CAUSES OF VISUAL DISABILITY THROUGHOUT THE WORLD. IT AFFECTS MORE PEOPLE WORLDWIDE THAN ANY OTHER CHRONIC VISUAL IMPAIRMENT CONDITION. ALTHOUGH THE PREVALENCE VARIES AMONG VARIOUS ETHNIC GROUPS, THE INCIDENCE OF MYOPIA IS INCREASING IN ALL POPULATIONS ACROSS GLOBE. THUS, IT IS CONSIDERED A PRESSING PUBLIC HEALTH PROBLEM. BOTH GENETICS AND ENVIRONMENT PLAY A ROLE IN DEVELOPMENT OF MYOPIA. TO ELUCIDATE THE EPIGENETIC MECHANISM(S) UNDERLYING THE PATHOPHYSIOLOGY OF HIGH-MYOPIA, WE CONDUCTED METHYLATION PROFILING IN 18 CASES AND 18 MATCHED CONTROLS (AGED 4-12 YEARS), USING ILLUMINA METHYLATIONEPIC BEADCHIPS ARRAY. THE DEGREE OF MYOPIA WAS VARIABLE AMONG SUBJECTS, RANGING FROM -6 TO -15D. WE IDENTIFIED 1541 HYPERMETHYLATED CPGS, REPRESENTING 1745 GENES (2.0-FOLD OR HIGHER) (FALSE DISCOVERY RATE (FDR) P </= 0.05), MULTIPLE CPGS WERE P < 5 X 10(-8) WITH A RECEIVER OPERATING CHARACTERISTIC AREA UNDER THE CURVE (ROC-AUC) >/= 0.75 IN HIGH-MYOPIA SUBJECTS COMPARED TO CONTROLS. AMONG THESE, 48 CPGS HAD EXCELLENT CORRELATION (AUC >/= 0.90). HEREIN, WE PRESENT THE FIRST GENOME-WIDE DNA METHYLATION ANALYSIS IN A UNIQUE HIGH-MYOPIA COHORT, SHOWING EXTENSIVE AND DISCRETE METHYLATION CHANGES RELATIVE TO CONTROLS. THE GENES WE IDENTIFIED HOLD SIGNIFICANT POTENTIAL AS TARGETS FOR NOVEL THERAPEUTIC INTERVENTION EITHER ALONE, OR IN COMBINATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19 1573  40 DNA METHYLATION PATTERNS IN NEWBORNS EXPOSED TO TOBACCO IN UTERO. BACKGROUND: MATERNAL SMOKING DURING PREGNANCY IS A MAJOR RISK FACTOR FOR ADVERSE HEALTH OUTCOMES. THE MAIN OBJECTIVE OF THE STUDY WAS TO ASSESS THE IMPACT OF IN UTERO TOBACCO EXPOSURE ON DNA METHYLATION IN CHILDREN BORN AT TERM WITH APPROPRIATE WEIGHT AT BIRTH. METHODS: TWENTY MOTHER-NEWBORN DYADS, AFTER UNCOMPLICATED PREGNANCIES, IN THE ABSENCE OF PERINATAL ILLNESS WERE INCLUDED. ALL MOTHERS WERE HEALTHY WITH NO CARDIOVASCULAR RISK FACTORS, EXCEPT FOR THE ASSOCIATED RISKS AMONG THOSE MOTHERS WHO SMOKED. UMBILICAL CORD BLOOD AND MATERNAL PERIPHERAL VENOUS BLOOD WERE COLLECTED AND AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING A 450 K EPIGENOME-WIDE SCAN (ILLUMINA INFINIUM HUMANMETHYLATION 450BEADCHIP) WITH ADJUSTMENT TO NORMALIZE THE DNA METHYLATION FOR DATA CELL VARIABILITY IN WHOLE BLOOD. RESULTS: THE MATERNAL PLASMATIC COTININE LEVELS RANGED FROM 10.70-115.40 NG/ML IN THE EXPOSED GROUP TO 0-0.59 NG/ML IN THE NON-EXPOSED GROUP. AFTER ADJUSTING FOR MULTIPLE COMPARISONS IN 427102 PROBES, STATISTICALLY SIGNIFICANT DIFFERENCES FOR 31 CPG SITES, ASSOCIATED TO 25 GENES WERE OBSERVED. THERE WAS A GREATER THAN EXPECTED PROPORTION OF STATISTICALLY-SIGNIFICANT LOCI LOCATED IN CPG ISLANDS (FISHER'S EXACT TEST, P = 0.029) AND OF THOSE CPG ISLANDS, 90.3% EXHIBIT HIGHER METHYLATION LEVELS IN THE EXPOSED GROUP. THE MOST STRIKING AND SIGNIFICANT CPG SITE, CG05727225, IS LOCATED IN THE CHROMOSOME 11P15.4, WITHIN THE ADRENOMEDULLIN GENE. CONCLUSIONS: IN UTERO TOBACCO EXPOSURE, EVEN IN THE ABSENCE OF FETAL GROWTH RESTRICTION, MAY ALTER THE EPIGENOME, CONTRIBUTING TO GLOBAL DNA HYPOMETHYLATION. THEREFORE, DNA STATUS CAN BE USED AS A BIOMARKER OF PRENATAL INSULTS. CONSIDERING THE POSSIBILITY TO REVERSE EPIGENETIC MODIFICATIONS, A WINDOW OF OPPORTUNITY EXISTS TO CHANGE THE PROGRAMMED CHRONIC DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  274  34 AGE-RELATED CHANGES IN DNA METHYLATION AFFECT RENAL HISTOLOGY AND POST-TRANSPLANT FIBROSIS. DURING AGEING, KIDNEY FUNCTION DECREASES DUE TO RENAL TUBULAR ATROPHY, INTERSTITIAL FIBROSIS, GLOMERULOSCLEROSIS AND ARTERIOSCLEROSIS. RECENTLY, CHANGES IN DNA METHYLATION WERE SHOWN TO CONTRIBUTE TO VARIOUS AGEING PROCESSES. HOWEVER, IT IS UNKNOWN WHETHER SUCH CHANGES ALSO CONTRIBUTE TO AGE-RELATED KIDNEY DYSFUNCTION. TO ASSESS THIS, WE PROFILED GENOME-WIDE CHANGES IN DNA METHYLATION (OVER 800 000 CPG SITES) IN 95 RENAL BIOPSIES OBTAINED PRIOR TO KIDNEY TRANSPLANTATION FROM DONORS AGED 16 TO 73 YEARS. DONOR AGE SIGNIFICANTLY ASSOCIATED WITH THE METHYLATION OF 92 778 CPGS (FALSE DISCOVERY RATE UNDER 0.05), CORRESPONDING TO 10 285 DIFFERENTIALLY METHYLATED REGIONS. THESE REGIONS WERE MOST FREQUENTLY LOCATED IN GENES INVOLVED IN THE WNT/BETA-CATENIN SIGNALING PATHWAY. USING AN INDEPENDENT COHORT OF 67 BIOPSIES, WE AUTONOMOUSLY VALIDATED THESE FINDINGS. INTERESTINGLY, THE METHYLATION STATUS OF THESE 92 778 AGE-RELATED CPGS WAS ASSOCIATED WITH GLOMERULOSCLEROSIS (34.4% OF CPGS AT A FALSE DISCOVERY RATE UNDER 0.05) AND INTERSTITIAL FIBROSIS (0.9%) AND GRAFT FUNCTION AT ONE YEAR AFTER TRANSPLANTATION, BUT NOT WITH TUBULAR ATROPHY AND ARTERIOSCLEROSIS. NO ASSOCIATION WAS OBSERVED WITH ANY OF THESE PATHOLOGIES AT THE TIME OF TRANSPLANTATION (0% AT A FALSE DISCOVERY RATE UNDER 0.05). THUS, AGE-ASSOCIATED CHANGES IN DNA METHYLATION AT THE TIME OF TRANSPLANTATION PREDICT FUTURE INJURY OF TRANSPLANTED KIDNEYS. SPECIFICALLY, OUR EPIGENOME-WIDE ASSOCIATION STUDY DEMONSTRATES THAT EPIGENETIC RENAL AGEING IS IMPLICATED IN PROGRESSIVE FIBROSIS IN BOTH THE GLOMERULUS AND THE INTERSTITIUM.	2019