1  6270 182 THE OBESOGENIC ENVIRONMENT: EPIGENETIC MODIFICATIONS IN PLACENTAL MELANOCORTIN 4 RECEPTOR GENE CONNECTED TO GESTATIONAL DIABETES AND SMOKING. BACKGROUND: MATERNAL METABOLIC INSULTS AS WELL AS GESTATIONAL DIABETES MELLITUS (GDM) INFLUENCE THE FETAL HEALTH AND MAY AFFECT 'OFFSPRING'S SUSCEPTIBILITY TO CHRONIC DISEASES VIA EPIGENETIC MODIFICATIONS. GDM, THE MOST COMMON METABOLIC DISORDER IN PREGNANCY, CAN BE CONSIDERED THE RESULT OF COMPLEX INTERACTIONS BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. A CRITICAL POINT IN THIS VIEW IS THE IDENTIFICATION OF GENES WHICH ARE EPIGENETICALLY MODIFIED UNDER THE INFLUENCE OF GDM. THE MELANOCORTIN 4 RECEPTOR (MC4R) GENE PLAYS A CRUCIAL ROLE IN NUTRITIONAL HEALTH BY SUPPRESSING APPETITE AND PARTICIPATING IN ENERGY CONTROL REGULATION. THE CORRELATIONS BETWEEN PREGNANT 'WOMEN'S METABOLIC PROFILES AND PLACENTAL EPIGENETIC MODIFICATIONS OF THIS GENE HAVE BEEN POORLY INVESTIGATED. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECT OF GDM AND MATERNAL CLINICAL PARAMETERS AT THE THIRD TRIMESTER OF PREGNANCY TO DNA METHYLATION LEVELS IN THE PLACENTA AT CPG SITES OF MC4R GENE. DESIGN AND METHODS: SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS, MEDITERRANEAN DIET ADHERENCE, SMOKING HABITS, AND PHYSICAL ACTIVITY WERE ASSESSED AT THE THIRD TRIMESTER OF PREGNANCY OF 60 CAUCASIAN PREGNANT WOMEN, OF WHICH 33 WITH GDM. CLINICAL PARAMETERS OF THE NEWBORNS WERE RECORDED AT BIRTH. MC4R DNA METHYLATION ON MATERNAL AND FETAL SIDES OF THE PLACENTA WAS ANALYZED USING BISULFITE PYROSEQUENCING. RESULTS: MC4R DNA METHYLATION LEVELS AT CPG1 AND CPG2 WERE LOWER ON THE FETAL SIDE OF THE PLACENTA IN GDM-AFFECTED WOMEN THAN IN NON-GDM-AFFECTED RECRUITS (P = 0.033). MOREOVER, DNA METHYLATION LEVELS ON THE MATERNAL SIDE AT CPG1 WERE POSITIVELY RELATED TO GLUCOSE CONCENTRATION AT 2-H ORAL GLUCOSE TOLERANCE TEST (OGTT). ON THE OTHER HAND, CPG2 DNA METHYLATION WAS POSITIVELY RELATED TO BOTH 1-H AND 2-H DURING OGTT. MATERNAL DNA METHYLATION LEVEL AT CPG2 WAS ALSO ASSOCIATED WITH LOW DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) AT THE THIRD TRIMESTER OF PREGNANCY (RHO = 0.340, P < 0.05), WHILE CPG1 METHYLATION WAS NEGATIVELY RELATED TO MATERNAL WEIGHT VARIATIONS AT DELIVERY (RHO = -0.316, P < 0.05). SIGNIFICANT ASSOCIATIONS BETWEEN MC4R DNA METHYLATION ON THE MATERNAL SIDE AND LIPID PROFILE AT THIRD TRIMESTER OF PREGNANCY IN WOMEN SMOKERS WERE FOUND. CONCLUSION: OUR RESULTS SUGGEST THAT MC4R METHYLATION PROFILE IN THE PLACENTA IS RELATED TO MATERNAL METABOLIC AND NUTRITIONAL CONDITIONS, POTENTIALLY AFFECTING FETAL PROGRAMMING AND THE FUTURE METABOLIC HEALTH OF THE NEWBORN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  3359  26 HISTONE H4 LYSINE 16 ACETYLATION CONTROLS CENTRAL CARBON METABOLISM AND DIET-INDUCED OBESITY IN MICE. NONCOMMUNICABLE DISEASES (NCDS) ACCOUNT FOR OVER 70% OF DEATHS WORLD-WIDE. PREVIOUS WORK HAS LINKED NCDS SUCH AS TYPE 2 DIABETES (T2D) TO DISRUPTION OF CHROMATIN REGULATORS. HOWEVER, THE EXACT MOLECULAR ORIGINS OF THESE CHRONIC CONDITIONS REMAIN ELUSIVE. HERE, WE IDENTIFY THE H4 LYSINE 16 ACETYLTRANSFERASE MOF AS A CRITICAL REGULATOR OF CENTRAL CARBON METABOLISM. HIGH-THROUGHPUT METABOLOMICS UNVEIL A SYSTEMIC AMINO ACID AND CARBOHYDRATE IMBALANCE IN MOF DEFICIENT MICE, MANIFESTING IN T2D PREDISPOSITION. ORAL GLUCOSE TOLERANCE TESTING (OGTT) REVEALS DEFECTS IN GLUCOSE ASSIMILATION AND INSULIN SECRETION IN THESE ANIMALS. FURTHERMORE, MOF DEFICIENT MICE ARE RESISTANT TO DIET-INDUCED FAT GAIN DUE TO DEFECTS IN GLUCOSE UPTAKE IN ADIPOSE TISSUE. MOF-MEDIATED H4K16AC DEPOSITION CONTROLS EXPRESSION OF THE MASTER REGULATOR OF GLUCOSE METABOLISM, PPARG AND THE ENTIRE DOWNSTREAM TRANSCRIPTIONAL NETWORK. GLUCOSE UPTAKE AND LIPID STORAGE CAN BE RECONSTITUTED IN MOF-DEPLETED ADIPOCYTES IN VITRO BY ECTOPIC GLUT4 EXPRESSION, PPARGAMMA AGONIST THIAZOLIDINEDIONE (TZD) TREATMENT OR SIRT1 INHIBITION. HENCE, CHRONIC IMBALANCE IN H4K16AC PROMOTES A DESTABILISATION OF METABOLISM TRIGGERING THE DEVELOPMENT OF A METABOLIC DISORDER, AND ITS MAINTENANCE PROVIDES AN UNPRECEDENTED REGULATORY EPIGENETIC MECHANISM CONTROLLING DIET-INDUCED OBESITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  2420  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  2149  38 EPIGENETIC MARKERS TO PREDICT CONVERSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES. CONTEXT: LIFESTYLE FACTORS MEDIATE EPIGENETIC CHANGES THAT CAN CAUSE CHRONIC DISEASES. ALTHOUGH ANIMAL AND LABORATORY STUDIES LINK EPIGENETIC CHANGES TO DIABETES, EPIGENETIC INFORMATION IN WOMEN WITH GESTATIONAL DIABETES (GDM) AND TYPE 2 DIABETES IS LACKING. OBJECTIVE: THIS STUDY SOUGHT TO MEASURE EPIGENETIC MARKERS ACROSS PREGNANCY AND EARLY POSTPARTUM AND IDENTIFY MARKERS THAT COULD BE USED AS PREDICTORS FOR CONVERSION FROM GDM TO TYPE 2 DIABETES. DESIGN: GLOBAL HISTONE H3 DIMETHYLATION WAS MEASURED IN WHITE BLOOD CELLS AT THREE TIME POINTS: 30 WK GESTATION, 8-10 WK POSTPARTUM, AND 20 WK POSTPARTUM, FROM FOUR GROUPS OF WOMEN WITH AND WITHOUT DIABETES. SETTING AND PARTICIPANTS: A TOTAL OF 39 PARTICIPANTS (SIX TO NINE IN EACH GROUP) WERE RECRUITED INCLUDING: NONDIABETIC WOMEN; WOMEN WITH GDM WHO DEVELOPED POSTPARTUM TYPE 2 DIABETES; WOMEN WITH GDM WITHOUT POSTPARTUM TYPE 2 DIABETES; AND WOMEN WITH TYPE 2 DIABETES. MAIN OUTCOME MEASURE: PERCENTAGES OF DIMETHYLATION OF H3 HISTONES RELATIVE TO TOTAL H3 HISTONE METHYLATION WERE COMPARED BETWEEN DIABETIC/NONDIABETIC GROUPS USING APPROPRIATE COMPARATIVE STATISTICS. RESULTS: H3K27 DIMETHYLATION WAS 50-60% LOWER AT 8-10 AND 20 WK POSTPARTUM IN WOMEN WITH GDM WHO DEVELOPED TYPE 2 DIABETES, COMPARED WITH NONDIABETIC WOMEN. H3K4 DIMETHYLATION WAS 75% LOWER AT 8-10 WK POSTPARTUM IN WOMEN WITH GDM WHO SUBSEQUENTLY DEVELOPED TYPE 2 DIABETES COMPARED WITH WOMEN WHO HAD GDM WHO DID NOT. CONCLUSIONS: THE PERCENTAGE OF DIMETHYLATION OF HISTONES H3K27 AND H3K4 VARIED WITH DIABETIC STATE AND HAS THE POTENTIAL AS A PREDICTIVE TOOL TO IDENTIFY WOMEN WHO WILL CONVERT FROM GDM TO TYPE 2 DIABETES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
5  5090  51 PLACENTAL ADIPONECTIN GENE DNA METHYLATION LEVELS ARE ASSOCIATED WITH MOTHERS' BLOOD GLUCOSE CONCENTRATION. GROWING EVIDENCE SUGGESTS THAT EPIGENETIC PROFILE CHANGES OCCURRING DURING FETAL DEVELOPMENT IN RESPONSE TO IN UTERO ENVIRONMENT VARIATIONS COULD BE ONE OF THE MECHANISMS INVOLVED IN THE EARLY DETERMINANTS OF ADULT CHRONIC DISEASES. IN THIS STUDY, WE TESTED WHETHER MATERNAL GLYCEMIC STATUS IS ASSOCIATED WITH THE ADIPONECTIN GENE (ADIPOQ) DNA METHYLATION PROFILE IN PLACENTA TISSUE, IN MATERNAL CIRCULATING BLOOD CELLS, AND IN CORD BLOOD CELLS. WE FOUND THAT LOWER DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPOQ ON THE FETAL SIDE OF THE PLACENTA WERE CORRELATED WITH HIGHER MATERNAL GLUCOSE LEVELS DURING THE SECOND TRIMESTER OF PREGNANCY (2-H GLUCOSE AFTER THE ORAL GLUCOSE TOLERANCE TEST; R(S) </= -0.21, P < 0.05). LOWER DNA METHYLATION LEVELS ON THE MATERNAL SIDE OF THE PLACENTA WERE ASSOCIATED WITH HIGHER INSULIN RESISTANCE INDEX (HOMEOSTASIS MODEL ASSESSMENT OF INSULIN RESISTANCE) DURING THE SECOND AND THIRD TRIMESTERS OF PREGNANCY (R(S) </= -0.27, P < 0.05). FINALLY, LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH HIGHER MATERNAL CIRCULATING ADIPONECTIN LEVELS THROUGHOUT PREGNANCY (R(S) </= -0.26, P < 0.05). IN CONCLUSION, THE ADIPOQ DNA METHYLATION PROFILE WAS ASSOCIATED WITH MATERNAL GLUCOSE STATUS AND WITH MATERNAL CIRCULATING ADIPONECTIN CONCENTRATION. BECAUSE ADIPONECTIN IS SUSPECTED TO HAVE INSULIN-SENSITIZING PROPRIETIES, THESE EPIGENETIC ADAPTATIONS HAVE THE POTENTIAL TO INDUCE SUSTAINED GLUCOSE METABOLISM CHANGES IN THE MOTHER AND OFFSPRING LATER IN LIFE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  4504  38 MOTHER'S PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNAS: FINDINGS FROM THE ENVIRONAGE BIRTH COHORT. THERE IS INCREASING EVIDENCE THAT THE PREDISPOSITION FOR DEVELOPMENT OF CHRONIC DISEASES ARISES AT THE EARLIEST TIMES OF LIFE. IN THIS CONTEXT, MATERNAL PRE-PREGNANCY WEIGHT MIGHT MODIFY FETAL METABOLISM AND THE CHILD'S PREDISPOSITION TO DEVELOP DISEASE LATER IN LIFE. THE AIM OF THIS STUDY IS TO INVESTIGATE THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) AND MIRNA ALTERATIONS IN PLACENTAL TISSUE AT BIRTH. IN 211 MOTHER-NEWBORN PAIRS FROM THE ENVIRONAGE BIRTH COHORT, WE ASSESSED PLACENTAL EXPRESSION OF SEVEN MIRNAS IMPORTANT IN CRUCIAL CELLULAR PROCESSES IMPLICATED IN ADIPOGENESIS AND/OR OBESITY. MULTIPLE LINEAR REGRESSION MODELS WERE USED TO ADDRESS THE ASSOCIATIONS BETWEEN PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNA EXPRESSION. MATERNAL PRE-PREGNANCY BMI AVERAGED (+/-SD) 23.9 (+/-4.1) KG/M(2). IN NEWBORN GIRLS (NOT IN BOYS) PLACENTAL MIR-20A, MIR-34A AND MIR-222 EXPRESSION WAS LOWER WITH HIGHER MATERNAL PRE-PREGNANCY BMI. IN ADDITION, THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BMI AND PLACENTAL EXPRESSION OF THESE MIRNAS IN GIRLS WAS MODIFIED BY GESTATIONAL WEIGHT GAIN. THE LOWER EXPRESSION OF THESE MIRNAS IN PLACENTA IN ASSOCIATION WITH PRE-PREGNANCY BMI, WAS ONLY EVIDENT IN MOTHERS WITH LOW WEIGHT GAIN (<14 KG). THE PLACENTAL EXPRESSION OF MIR-20A, MIR-34A, MIR-146A, MIR-210 AND MIR-222 MAY PROVIDE A SEX-SPECIFIC BASIS FOR EPIGENETIC EFFECTS OF PRE-PREGNANCY BMI.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  3117  60 GESTATIONAL DIABETES MELLITUS EPIGENETICALLY AFFECTS GENES PREDOMINANTLY INVOLVED IN METABOLIC DISEASES. OFFSPRING EXPOSED TO GESTATIONAL DIABETES MELLITUS (GDM) HAVE AN INCREASED RISK FOR CHRONIC DISEASES, AND ONE PROMISING MECHANISM FOR FETAL METABOLIC PROGRAMMING IS EPIGENETICS. THEREFORE, WE POSTULATED THAT GDM EXPOSURE IMPACTS THE OFFSPRING'S METHYLOME AND USED AN EPIGENOMIC APPROACH TO EXPLORE THIS HYPOTHESIS. PLACENTA AND CORD BLOOD SAMPLES WERE OBTAINED FROM 44 NEWBORNS, INCLUDING 30 EXPOSED TO GDM. WOMEN WERE RECRUITED AT FIRST TRIMESTER OF PREGNANCY AND FOLLOWED UNTIL DELIVERY. GDM WAS ASSESSED AFTER A 75-G ORAL GLUCOSE TOLERANCE TEST AT 24-28 WEEKS OF PREGNANCY. DNA METHYLATION WAS MEASURED AT>485,000 CPG SITES (INFINIUM HUMANMETHYLATION450 BEADCHIPS). INGENUITY PATHWAY ANALYSIS WAS CONDUCTED TO IDENTIFY METABOLIC PATHWAYS EPIGENETICALLY AFFECTED BY GDM. OUR RESULTS SHOWED THAT 3,271 AND 3,758 GENES IN PLACENTA AND CORD BLOOD, RESPECTIVELY, WERE POTENTIALLY DIFFERENTIALLY METHYLATED BETWEEN SAMPLES EXPOSED OR NOT TO GDM (P-VALUES DOWN TO 1 X 10(-06); NONE REACHED THE GENOME-WIDE SIGNIFICANCE LEVELS), WITH MORE THAN 25% (N = 1,029) BEING COMMON TO BOTH TISSUES. MEAN DNA METHYLATION DIFFERENCES BETWEEN GROUPS WERE 5.7 +/- 3.2% AND 3.4 +/- 1.9% FOR PLACENTA AND CORD BLOOD, RESPECTIVELY. THESE GENES WERE LIKELY INVOLVED IN THE METABOLIC DISEASES PATHWAY (UP TO 115 GENES (11%), P-VALUES FOR PATHWAYS = 1.9 X 10(-13)<P<4.0 X 10(-03); INCLUDING DIABETES MELLITUS P = 4.3 X 10(-11)). AMONG THE DIFFERENTIALLY METHYLATED GENES, 326 IN PLACENTA AND 117 IN CORD BLOOD WERE ALSO ASSOCIATED WITH NEWBORN WEIGHT. OUR RESULTS THEREFORE SUGGEST THAT GDM HAS EPIGENETIC EFFECTS ON GENES PREFERENTIALLY INVOLVED IN THE METABOLIC DISEASES PATHWAY, WITH CONSEQUENCES ON FETAL GROWTH AND DEVELOPMENT, AND PROVIDE SUPPORTIVE EVIDENCE THAT DNA METHYLATION IS INVOLVED IN FETAL METABOLIC PROGRAMMING.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  4010  44 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  1837  48 EFFECTS OF PALMITATE ON GENOME-WIDE MRNA EXPRESSION AND DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. BACKGROUND: CIRCULATING FREE FATTY ACIDS ARE OFTEN ELEVATED IN PATIENTS WITH TYPE 2 DIABETES (T2D) AND OBESE INDIVIDUALS. CHRONIC EXPOSURE TO HIGH LEVELS OF SATURATED FATTY ACIDS HAS DETRIMENTAL EFFECTS ON ISLET FUNCTION AND INSULIN SECRETION. ALTERED GENE EXPRESSION AND EPIGENETICS MAY CONTRIBUTE TO T2D AND OBESITY. HOWEVER, THERE IS LIMITED INFORMATION ON WHETHER FATTY ACIDS ALTER THE GENOME-WIDE TRANSCRIPTOME PROFILE IN CONJUNCTION WITH DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. TO DISSECT THE MOLECULAR MECHANISMS LINKING LIPOTOXICITY TO IMPAIRED INSULIN SECRETION, WE INVESTIGATED THE EFFECTS OF A 48 H PALMITATE TREATMENT IN VITRO ON GENOME-WIDE MRNA EXPRESSION AND DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. METHODS: GENOME-WIDE MRNA EXPRESSION WAS ANALYZED USING AFFYMETRIX GENECHIP((R)) HUMAN GENE 1.0 ST WHOLE TRANSCRIPT-BASED ARRAY (N = 13) AND GENOME-WIDE DNA METHYLATION WAS ANALYZED USING INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 13) IN HUMAN PANCREATIC ISLETS EXPOSED TO PALMITATE OR CONTROL MEDIA FOR 48 H. A NON-PARAMETRIC PAIRED WILCOXON STATISTICAL TEST WAS USED TO ANALYZE MRNA EXPRESSION. APOPTOSIS WAS MEASURED USING APO-ONE((R)) HOMOGENEOUS CASPASE-3/7 ASSAY (N = 4). RESULTS: WHILE GLUCOSE-STIMULATED INSULIN SECRETION WAS DECREASED, THERE WAS NO SIGNIFICANT EFFECT ON APOPTOSIS IN HUMAN ISLETS EXPOSED TO PALMITATE. WE IDENTIFIED 1,860 DIFFERENTIALLY EXPRESSED GENES IN PALMITATE-TREATED HUMAN ISLETS. THESE INCLUDE CANDIDATE GENES FOR T2D, SUCH AS TCF7L2, GLIS3, HNF1B AND SLC30A8. ADDITIONALLY, GENES IN GLYCOLYSIS/GLUCONEOGENESIS, PYRUVATE METABOLISM, FATTY ACID METABOLISM, GLUTATHIONE METABOLISM AND ONE CARBON POOL BY FOLATE WERE DIFFERENTIALLY EXPRESSED IN PALMITATE-TREATED HUMAN ISLETS. PALMITATE TREATMENT ALTERED THE GLOBAL DNA METHYLATION LEVEL AND DNA METHYLATION LEVELS OF CPG ISLAND SHELVES AND SHORES, 5'UTR, 3'UTR AND GENE BODY REGIONS IN HUMAN ISLETS. MOREOVER, 290 GENES WITH DIFFERENTIAL EXPRESSION HAD A CORRESPONDING CHANGE IN DNA METHYLATION, FOR EXAMPLE, TCF7L2 AND GLIS3. IMPORTANTLY, OUT OF THE GENES DIFFERENTIALLY EXPRESSED DUE TO PALMITATE TREATMENT IN HUMAN ISLETS, 67 WERE ALSO ASSOCIATED WITH BMI AND 37 WERE DIFFERENTIALLY EXPRESSED IN ISLETS FROM T2D PATIENTS. CONCLUSION: OUR STUDY DEMONSTRATES THAT PALMITATE TREATMENT OF HUMAN PANCREATIC ISLETS GIVES RISE TO EPIGENETIC MODIFICATIONS THAT TOGETHER WITH ALTERED GENE EXPRESSION MAY CONTRIBUTE TO IMPAIRED INSULIN SECRETION AND T2D.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  4066  42 MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION AS AN INDICATOR OF OFFSPRING METABOLIC SYNDROME RISK IN LATER LIFE THROUGH EPIGENETIC IMPRINTING: A SYSTEMATIC REVIEW. AIMS: THIS REVIEW EXAMINED WHETHER MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION EFFECTS AN OFFSPRING'S LIKELIHOOD OF DEVELOPING CHRONIC METABOLIC RELATED CONDITIONS DUE TO EPIGENETIC IMPRINTING. METHODS: A LITERATURE SEARCH WAS CONDUCTED IN MULTIPLE SCIENCE DATABASES AND LIMITED TO STUDIES PUBLISHED AFTER 2012, IN ENGLISH LANGUAGE AND PEER REVIEWED. THE DATA FROM SELECTED ARTICLES WERE EXTRACTED AND A QUALITATIVE APPROACH WAS EMPLOYED DUE TO HETEROGENEITY OF RESULTS. RESULTS: NEWBORNS FROM OBESE FATHERS SHOWED ALTERED METHYLATION OVERALL AND SIGNIFICANT HYPOMETHYLATION AT THE INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. HIGH MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) WAS ASSOCIATED WITH ALTERED OFFSPRING DNA METHYLATION LEVELS AND GESTATIONAL DIABETES MELLITUS INDUCED SIGNIFICANTLY INCREASED METHYLATION LEVELS IN OFFSPRING. GESTATIONAL WEIGHT GAIN WAS NOT ASSOCIATED WITH DIFFERENTIALLY METHYLATED CORD BLOOD. BIRTH WEIGHT WAS HIGHER IN OFFSPRING EXPOSED TO FAMINE IN EARLY GESTATION. OFFSPRING BORN POST MATERNAL BARIATRIC SURGERY SHOWED A LOWER PERCENTAGE OF BODY FAT AND IMPROVED FASTING INSULIN LEVELS COMPARED TO SIBLINGS BORN PRE-MATERNAL BARIATRIC SURGERY. CONCLUSIONS: THE AVAILABLE EVIDENCE SUGGESTS THAT POOR MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION CAN INCREASE THE RISK OF METABOLIC SYNDROME IN OFFSPRING, THROUGH EPIGENETIC IMPRINTING. POTENTIAL PARENTS SHOULD BE ADVISED THAT MAINTAINING A HEALTHY DIET AND BMI IS LIKELY TO REDUCE THE RISK OF METABOLIC SYNDROME IN OFFSPRING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11   649  49 BIRTHWEIGHT, MATERNAL WEIGHT TRAJECTORIES AND GLOBAL DNA METHYLATION OF LINE-1 REPETITIVE ELEMENTS. LOW BIRTHWEIGHT, PREMATURE BIRTH, INTRAUTERINE GROWTH RETARDATION, AND MATERNAL MALNUTRITION HAVE BEEN RELATED TO AN INCREASED RISK OF CARDIOVASCULAR DISEASE, TYPE 2 DIABETES MELLITUS, OBESITY, AND NEUROPSYCHIATRIC DISORDERS LATER IN LIFE. CONVERSELY, HIGH BIRTHWEIGHT HAS BEEN LINKED TO FUTURE RISK OF CANCER. GLOBAL DNA METHYLATION ESTIMATED BY THE METHYLATION OF REPETITIVE SEQUENCES IN THE GENOME IS AN INDICATOR OF SUSCEPTIBILITY TO CHRONIC DISEASES. WE USED DATA AND BIOSPECIMENS FROM AN EPIGENETIC BIRTH COHORT TO EXPLORE THE ASSOCIATION BETWEEN TRAJECTORIES OF FETAL AND MATERNAL WEIGHT AND LINE-1 METHYLATION IN 319 MOTHER-CHILD DYADS. NEWBORNS WITH LOW OR HIGH BIRTHWEIGHT HAD SIGNIFICANTLY LOWER LINE-1 METHYLATION LEVELS IN THEIR CORD BLOOD COMPARED TO NORMAL WEIGHT INFANTS AFTER ADJUSTING FOR GESTATIONAL AGE, SEX OF THE CHILD, MATERNAL AGE AT DELIVERY, AND MATERNAL SMOKING DURING PREGNANCY (P = 0.007 AND P = 0.036, RESPECTIVELY), BUT THE MAGNITUDE OF THE DIFFERENCE WAS SMALL. INFANTS BORN PREMATURELY ALSO HAD LOWER LINE-1 METHYLATION LEVELS IN CORD BLOOD COMPARED TO TERM INFANTS, AND THIS DIFFERENCE, THOUGH SMALL, WAS STATISTICALLY SIGNIFICANT (P = 0.004). WE DID NOT FIND IMPORTANT ASSOCIATIONS BETWEEN MATERNAL PREPREGNANCY BMI OR GESTATIONAL WEIGHT GAIN AND GLOBAL METHYLATION OF THE CORD BLOOD OR FETAL PLACENTAL TISSUE. IN CONCLUSION, WE FOUND SIGNIFICANT DIFFERENCES IN CORD BLOOD LINE-1 METHYLATION AMONG NEWBORNS WITH LOW AND HIGH BIRTHWEIGHT AS WELL AS AMONG PREMATURELY BORN INFANTS. FUTURE STUDIES MAY ELUCIDATE WHETHER CHROMOSOMAL INSTABILITIES OR OTHER FUNCTIONAL CONSEQUENCES OF THESE CHANGES CONTRIBUTE TO THE INCREASED RISK OF CHRONIC DISEASES AMONG INDIVIDUALS WITH THESE CHARACTERISTICS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  3557  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   518  57 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  1292  46 DECREASED BLOOD PRESSURE IS RELATED TO CHANGES IN NF-KB PROMOTER METHYLATION LEVELS AFTER BARIATRIC SURGERY. BACKGROUND: OBESITY IS CHARACTERIZED BY A CHRONIC, LOW-GRADE INFLAMMATION, AND BARIATRIC SURGERY IS PROPOSED AS AN EFFECTIVE TREATMENT FOR REDUCING THE OBESITY-RELATED CO-MORBIDITIES. EPIGENETIC MODIFICATIONS COULD BE INVOLVED IN THE METABOLIC IMPROVEMENT AFTER SURGERY. OBJECTIVE: THE MAIN AIM OF THIS STUDY WAS TO EVALUATE WHETHER DNA METHYLATION PATTERN FROM GENES RELATED TO INFLAMMATION AND INSULIN RESPONSE IS ASSOCIATED WITH THE METABOLIC IMPROVEMENT AFTER BARIATRIC SURGERY IN MORBIDLY OBESE PATIENTS AND IF THESE CHANGES DEPEND ON THE SURGICAL PROCEDURE. SETTING: UNIVERSITY HOSPITAL, SPAIN. METHODS: WE STUDIED 60 SEVERELY OBESE PATIENTS; 31 UNDERWENT ROUX-EN-Y GASTRIC BYPASS AND 29 UNDERWENT LAPAROSCOPIC SLEEVE GASTRECTOMY. ALL PATIENTS WERE EXAMINED BEFORE AND AT 6 MONTHS AFTER BARIATRIC SURGERY. DNA METHYLATION PROFILE OF GENES RELATED TO THE INFLAMMATORY RESPONSE AND INSULIN SENSITIVITY WAS MEASURED BY PYROSEQUENCING. RESULTS: THE PROMOTER METHYLATION LEVELS OF THE NFKB1 GENE WERE INCREASED SIGNIFICANTLY AFTER SURGERY (2.16 +/- .9 VERSUS 2.8 +/- 1.03). THE DECREASE IN BLOOD PRESSURE, BOTH SYSTOLIC AND DIASTOLIC, AFTER SURGERY WAS SIGNIFICANTLY ASSOCIATED WITH THE CHANGES IN THE PROMOTER METHYLATION LEVELS OF THE NFKB1 GENE (BETA = -.513, P = .003 AND BETA = -.543, P = .004, RESPECTIVELY). A DECREASE IN INFLAMMATION STATUS, MEASURED BY HIGH SENSITIVITY C-REACTIVE PROTEIN VALUES, WAS ASSOCIATED WITH CHANGES IN SLC19A1 METHYLATION LEVELS. CONCLUSION: OUR STUDY SHOWS FOR THE FIRST TIME AN ASSOCIATION BETWEEN NFKB1 METHYLATION LEVELS AND BLOOD PRESSURE AFTER BARIATRIC SURGERY, HIGHLIGHTING THE POSSIBLE FUNCTION OF THIS GENE IN THE REGULATION OF ARTERIAL PRESSURE. REGARDING SLC19A1, THIS GENE COULD POSITION AS A POTENTIAL TARGET LINKING INFLAMMATION AND INSULIN RESISTANCE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  3456  44 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16   521  49 ASSOCIATIONS BETWEEN MATERNAL PSYCHOSOCIAL STRESS, DNA METHYLATION, AND NEWBORN BIRTH WEIGHT IDENTIFIED BY INVESTIGATING METHYLATION AT INDIVIDUAL, REGIONAL, AND GENOME LEVELS. STRESS IS KNOWN TO AFFECT HEALTH THROUGHOUT LIFE AND INTO FUTURE GENERATIONS, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNKNOWN. WE TESTED THE HYPOTHESIS THAT MATERNAL PSYCHOSOCIAL STRESS INFLUENCES DNA METHYLATION (DNAM), WHICH IN TURN IMPACTS NEWBORN HEALTH OUTCOMES. SPECIFICALLY, WE ANALYZED DNAM AT INDIVIDUAL, REGIONAL, AND GENOME-WIDE LEVELS TO TEST FOR ASSOCIATIONS WITH MATERNAL STRESS AND NEWBORN BIRTH WEIGHT. MATERNAL VENOUS BLOOD AND NEWBORN CORD BLOOD (N = 24 AND 22, RESPECTIVELY) WERE ASSAYED FOR METHYLATION AT APPROXIMATELY 450,000 CPG SITES. METHYLATION WAS ANALYZED BY EXAMINING CPG SITES INDIVIDUALLY IN AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), AS REGIONAL GROUPS USING VARIABLY METHYLATED REGION (VMR) ANALYSIS IN MATERNAL BLOOD ONLY, AND THROUGH THE EPIGENOME-WIDE MEASURES USING GENOME-WIDE MEAN METHYLATION (GMM), HORVATH'S EPIGENETIC CLOCK, AND MITOTIC AGE. THESE METHYLATION MEASURES WERE TESTED FOR ASSOCIATION WITH THREE MEASURES OF MATERNAL STRESS (MATERNAL WAR TRAUMA, CHRONIC STRESS, AND EXPERIENCE OF SEXUAL VIOLENCE) AND ONE HEALTH OUTCOME (NEWBORN BIRTH WEIGHT). WE OBSERVED THAT MATERNAL EXPERIENCES OF WAR TRAUMA, CHRONIC STRESS, AND SEXUAL ASSAULT WERE EACH ASSOCIATED WITH DECREASED NEWBORN BIRTH WEIGHT (P < 1.95 X 10(-7) IN ALL CASES). TESTING INDIVIDUAL CPG SITES USING EWAS, WE OBSERVED NO ASSOCIATIONS BETWEEN DNAM AND ANY MEASURE OF MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER MATERNAL OR CORD BLOOD, AFTER BONFERRONI MULTIPLE TESTING CORRECTION. HOWEVER, THE TOP-RANKED CPG SITE IN MATERNAL BLOOD THAT ASSOCIATED WITH MATERNAL CHRONIC STRESS AND SEXUAL VIOLENCE BEFORE MULTIPLE TESTING CORRECTION IS LOCATED NEAR THE SPON1 GENE. TESTING AT A REGIONAL LEVEL, WE FOUND INCREASED METHYLATION OF A VMR IN MATERNAL BLOOD NEAR SPON1 THAT WAS ASSOCIATED WITH CHRONIC STRESS AND SEXUAL VIOLENCE AFTER BONFERRONI MULTIPLE TESTING CORRECTION (P = 1.95 X 10(-7) AND 8.3 X 10(-6), RESPECTIVELY). AT THE EPIGENOMIC LEVEL, CORD BLOOD GMM WAS ASSOCIATED WITH SIGNIFICANTLY HIGHER LEVELS OF WAR TRAUMA (P = 0.025) AND WAS SUGGESTIVELY ASSOCIATED WITH SEXUAL VIOLENCE (P = 0.053). THE OTHER TWO EPIGENOME-WIDE MEASURES WERE NOT ASSOCIATED WITH MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER TISSUE TYPE. DESPITE OUR SMALL SAMPLE SIZE, WE IDENTIFIED ASSOCIATIONS EVEN AFTER CONSERVATIVE MULTIPLE TESTING CORRECTION. SPECIFICALLY, WE FOUND ASSOCIATIONS BETWEEN DNAM AND THE THREE MEASURES OF MATERNAL STRESS ACROSS BOTH TISSUES; SPECIFICALLY, A VMR IN MATERNAL BLOOD AND GMM IN CORD BLOOD WERE BOTH ASSOCIATED WITH DIFFERENT MEASURES OF MATERNAL STRESS. THE ASSOCIATION OF CORD BLOOD GMM, BUT NOT MATERNAL BLOOD GMM, WITH MATERNAL STRESS MAY SUGGEST DIFFERENT RESPONSES TO STRESS IN MOTHER AND NEWBORN. IT IS NOTEWORTHY THAT WE FOUND ASSOCIATIONS ONLY WHEN CPG SITES WERE ANALYZED IN AGGREGATE, EITHER AS VMRS OR AS A BROAD SUMMARY MEASURE OF GMM.	2019	

17  4609  36 NEONATAL DNA METHYLATION AND CHILDHOOD LOW PROSOCIAL BEHAVIOR: AN EPIGENOME-WIDE ASSOCIATION META-ANALYSIS. LOW PROSOCIAL BEHAVIOR IN CHILDHOOD HAS BEEN CONSISTENTLY LINKED TO LATER PSYCHOPATHOLOGY, WITH EVIDENCE SUPPORTING THE INFLUENCE OF BOTH GENETIC AND ENVIRONMENTAL FACTORS ON ITS DEVELOPMENT. ALTHOUGH NEONATAL DNA METHYLATION (DNAM) HAS BEEN FOUND TO PROSPECTIVELY ASSOCIATE WITH A RANGE OF PSYCHOLOGICAL TRAITS IN CHILDHOOD, ITS POTENTIAL ROLE IN PROSOCIAL DEVELOPMENT HAS YET TO BE INVESTIGATED. THIS STUDY INVESTIGATED PROSPECTIVE ASSOCIATIONS BETWEEN CORD BLOOD DNAM AT BIRTH AND LOW PROSOCIAL BEHAVIOR WITHIN AND ACROSS FOUR LONGITUDINAL BIRTH COHORTS FROM THE PREGNANCY AND CHILDHOOD EPIGENETICS (PACE) CONSORTIUM. WE EXAMINED (A) DEVELOPMENTAL TRAJECTORIES OF "CHRONIC-LOW" VERSUS "TYPICAL" PROSOCIAL BEHAVIOR ACROSS CHILDHOOD IN A CASE-CONTROL DESIGN (N = 2,095), AND (B) CONTINUOUS "LOW PROSOCIAL" SCORES AT COMPARABLE CROSS-COHORT TIME-POINTS (N = 2,121). META-ANALYSES WERE PERFORMED TO EXAMINE DIFFERENTIALLY METHYLATED POSITIONS AND REGIONS. AT THE COHORT-SPECIFIC LEVEL, THREE CPGS WERE FOUND TO ASSOCIATE WITH CHRONIC LOW PROSOCIAL BEHAVIOR; HOWEVER, NONE OF THESE ASSOCIATIONS WAS REPLICATED IN ANOTHER COHORT. META-ANALYSIS REVEALED NO EPIGENOME-WIDE SIGNIFICANT CPGS OR REGIONS. OVERALL, WE FOUND NO EVIDENCE FOR ASSOCIATIONS BETWEEN DNAM PATTERNS AT BIRTH AND LOW PROSOCIAL BEHAVIOR ACROSS CHILDHOOD. FINDINGS HIGHLIGHT THE IMPORTANCE OF EMPLOYING MULTI-COHORT APPROACHES TO REPLICATE EPIGENETIC ASSOCIATIONS AND REDUCE THE RISK OF FALSE POSITIVE DISCOVERIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  1343  50 DETECTING CORD BLOOD CELL TYPE-SPECIFIC EPIGENETIC ASSOCIATIONS WITH GESTATIONAL DIABETES MELLITUS AND EARLY CHILDHOOD GROWTH. BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE PROVIDED OPPORTUNITIES TO UNDERSTAND THE ROLE OF EPIGENETIC MECHANISMS IN DEVELOPMENT AND PATHOPHYSIOLOGY OF MANY CHRONIC DISEASES. HOWEVER, AN IMPORTANT LIMITATION OF CONVENTIONAL EWAS IS THAT PROFILES OF EPIGENETIC VARIABILITY ARE OFTEN OBTAINED IN SAMPLES OF MIXED CELL TYPES. HERE, WE AIM TO ASSESS WHETHER CHANGES IN CORD BLOOD DNA METHYLATION (DNAM) ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) EXPOSURE AND EARLY CHILDHOOD GROWTH MARKERS OCCUR IN A CELL TYPE-SPECIFIC MANNER. RESULTS: WE ANALYZED 275 CORD BLOOD SAMPLES COLLECTED AT DELIVERY FROM A PROSPECTIVE PRE-BIRTH COHORT WITH GENOME-WIDE DNAM PROFILED BY THE ILLUMINA METHYLATIONEPIC ARRAY. WE ESTIMATED PROPORTIONS OF SEVEN COMMON CELL TYPES IN EACH SAMPLE USING A CORD BLOOD-SPECIFIC DNAM REFERENCE PANEL. LEVERAGING A RECENTLY DEVELOPED APPROACH NAMED CELLDMC, WE PERFORMED CELL TYPE-SPECIFIC EWAS TO IDENTIFY CPG LOCI SIGNIFICANTLY ASSOCIATED WITH GDM, OR 3-YEAR-OLD BODY MASS INDEX (BMI) Z-SCORE. A TOTAL OF 1410 CPG LOCI DISPLAYED SIGNIFICANT CELL TYPE-SPECIFIC DIFFERENCES IN METHYLATION LEVEL BETWEEN 23 GDM CASES AND 252 CONTROLS WITH A FALSE DISCOVERY RATE < 0.05. GENE ONTOLOGY ENRICHMENT ANALYSIS INDICATED THAT LDL TRANSPORTATION EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM B-CELLS DNAM ANALYSES AND THE MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM NATURAL KILLER CELLS DNAM ANALYSES. IN ADDITION, WE IDENTIFIED FOUR AND SIX LOCI ASSOCIATED WITH 3-YEAR-OLD BMI Z-SCORE THAT WERE SPECIFIC TO CD8+ T-CELLS AND MONOCYTES, RESPECTIVELY. BY PERFORMING GENOME-WIDE PERMUTATION TESTS, WE VALIDATED THAT MOST OF OUR DETECTED SIGNALS HAD LOW FALSE POSITIVE RATES. CONCLUSION: COMPARED TO CONVENTIONAL EWAS ADJUSTING FOR THE EFFECTS OF CELL TYPE HETEROGENEITY, THE PROPOSED APPROACH BASED ON CELL TYPE-SPECIFIC EWAS COULD PROVIDE ADDITIONAL BIOLOGICALLY MEANINGFUL ASSOCIATIONS BETWEEN CPG METHYLATION, PRENATAL MATERNAL GDM OR 3-YEAR-OLD BMI. WITH CAREFUL VALIDATION, THESE FINDINGS MAY PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS, PROGRAMMING, AND CONSEQUENCES OF RELATED CHILDHOOD METABOLIC DYSREGULATION. THEREFORE, WE PROPOSE THAT CELL TYPE-SPECIFIC ANALYSES ARE WORTH CAUTIOUS EXPLORATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  3179  44 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  1785  30 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021