1  5005 159 PERIPHERAL BLOOD DNA METHYLATION-BASED MACHINE LEARNING MODELS FOR PREDICTION OF KNEE OSTEOARTHRITIS PROGRESSION: BIOLOGIC SPECIMENS AND DATA FROM THE OSTEOARTHRITIS INITIATIVE AND JOHNSTON COUNTY OSTEOARTHRITIS PROJECT. OBJECTIVE: THE LACK OF ACCURATE BIOMARKERS TO PREDICT KNEE OSTEOARTHRITIS (OA) PROGRESSION IS A KEY UNMET NEED IN OA CLINICAL RESEARCH. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP BASELINE PERIPHERAL BLOOD EPIGENETIC BIOMARKER MODELS TO PREDICT KNEE OA PROGRESSION. METHODS: GENOME-WIDE BUFFY COAT DNA METHYLATION PATTERNS FROM 554 INDIVIDUALS FROM THE OSTEOARTHRITIS BIOMARKERS CONSORTIUM (OABC) WERE DETERMINED USING ILLUMINA INFINIUM METHYLATIONEPIC 850K ARRAYS. DATA WERE DIVIDED INTO MODEL DEVELOPMENT AND VALIDATION SETS, AND MACHINE LEARNING MODELS WERE TRAINED TO CLASSIFY FUTURE OA PROGRESSION BY KNEE PAIN, RADIOGRAPHIC IMAGING, KNEE PAIN PLUS RADIOGRAPHIC IMAGING, AND ANY PROGRESSION (PAIN, RADIOGRAPHIC, OR BOTH). PARSIMONIOUS MODELS USING THE TOP 13 CPG SITES MOST FREQUENTLY SELECTED DURING DEVELOPMENT WERE TESTED ON INDEPENDENT SAMPLES FROM PARTICIPANTS IN THE JOHNSTON COUNTY OSTEOARTHRITIS (JOCO OA) PROJECT (N = 128) AND A PREVIOUSLY PUBLISHED OSTEOARTHRITIS INITIATIVE (OAI) DATA SET (N = 55). RESULTS: FULL MODELS ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC-ONLY PROGRESSION (MEAN +/- SEM ACCURACY 87 +/- 0.8%, AREA UNDER THE CURVE [AUC] 0.94 +/- 0.004), PAIN-ONLY PROGRESSION (ACCURACY 89 +/- 0.9%, AUC 0.97 +/- 0.004), PAIN PLUS RADIOGRAPHIC PROGRESSION (ACCURACY 72 +/- 0.7%, AUC 0.79 +/- 0.006), AND ANY PROGRESSION (ACCURACY 78 +/- 0.4%, AUC 0.86 +/- 0.004). PAIN-ONLY AND RADIOGRAPHIC-ONLY PROGRESSORS WERE NOT DISTINGUISHABLE (MEAN +/- SEM ACCURACY 58 +/- 1%, AUC 0.62 +/- 0.001). PARSIMONIOUS MODELS SHOWED SIMILAR PERFORMANCE AND ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC PROGRESSORS IN THE OABC COHORT AND IN BOTH VALIDATION COHORTS (MEAN +/- SEM ACCURACY 80 +/- 0.3%, AUC 0.88 +/- 0.003 [USING JOCO OA PROJECT DATA], ACCURACY 80 +/- 0.8%, AUC 0.89 +/- 0.002 [USING PREVIOUS OAI DATA]). CONCLUSION: OUR DATA SUGGEST THAT PAIN AND STRUCTURAL PROGRESSION SHARE SIMILAR EARLY SYSTEMIC IMMUNE EPIGENOTYPES. FURTHER STUDIES SHOULD FOCUS ON EVALUATING THE PATHOPHYSIOLOGIC CONSEQUENCES OF DIFFERENTIAL DNA METHYLATION AND PERIPHERAL BLOOD CELL EPIGENOTYPES IN INDIVIDUALS WITH KNEE OA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2    93  53 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3   403  43 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022	

4  3637  33 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  4249  33 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6   779  35 CELL-FREE DNA PROMOTER HYPERMETHYLATION AS A DIAGNOSTIC MARKER FOR PANCREATIC DUCTAL ADENOCARCINOMA - AN EXTERNAL VALIDATION STUDY. BACKGROUND: WE RECENTLY IDENTIFIED A DIAGNOSTIC PREDICTION MODEL BASED ON PROMOTER HYPERMETHYLATION OF EIGHT SELECTED GENES IN PLASMA CELL-FREE (CF) DNA, WHICH SHOWED PROMISING RESULTS AS A DIAGNOSTIC BIOMARKER FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDAC). THE AIM OF THE PRESENT STUDY WAS TO VALIDATE THIS BIOMARKER PROFILE IN AN EXTERNAL PATIENT COHORT AND EXAMINE ANY ADDITIONAL EFFECT OF SERUM CA 19-9. METHODS: PATIENTS WITH PDAC (N = 346, STAGE I-IV) AND CHRONIC PANCREATITIS (N = 25) WERE INCLUDED. METHYLATION-SPECIFIC PCR OF A 28-GENE PANEL WAS PERFORMED ON SERUM CFDNA SAMPLES. THE PREVIOUSLY DEVELOPED DIAGNOSTIC PREDICTION MODEL (AGE>65 YEARS, BMP3, RASSF1A, BNC1, MESTV2, TFPI2, APC, SFRP1 AND SFRP2) WAS VALIDATED ALONE AND IN COMBINATION WITH SERUM CA 19-9 IN THIS EXTERNAL PATIENT COHORT. RESULTS: PATIENTS WITH PDAC HAD A HIGHER NUMBER OF HYPERMETHYLATED GENES (MEAN 8.11, 95% CI 7.70-8.52) THAN PATIENTS WITH CHRONIC PANCREATITIS (MEAN 5.60, 95% CI 4.42-6.78, P = 0.011). VALIDATION OF THE DIAGNOSTIC PREDICTION MODEL YIELDED AN AUC OF 0.77 (95% CI 0.69-0.84). THE COMBINATION OF SERUM CA 19-9 AND OUR TEST HAD AN AUC OF 0.93 (95% CI 0.89-0.96) IN THE PRIMARY STUDY AND 0.85 (95% CI 0.79-0.91) IN THE VALIDATION STUDY. CONCLUSION: IN THIS VALIDATION STUDY, PDAC WAS ASSOCIATED WITH A HIGHER NUMBER OF HYPERMETHYLATED GENES IN SERUM CFDNA THAN CHRONIC PANCREATITIS. OUR DIAGNOSTIC TEST WAS SUPERIOR TO THE PREDICTIVE VALUE OF SERUM CA 19-9 ALONE IN BOTH THE PRIMARY AND THE VALIDATION STUDY. THE COMBINATION OF OUR TEST WITH CA 19-9 MAY SERVE AS A CLINICALLY USEFUL DIAGNOSTIC BIOMARKER FOR PDAC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7   241  22 ADIPOCYTE, IMMUNE CELLS, AND MIRNA CROSSTALK: A NOVEL REGULATOR OF METABOLIC DYSFUNCTION AND OBESITY. OBESITY IS CHARACTERIZED AS A COMPLEX AND MULTIFACTORIAL EXCESS ACCRETION OF ADIPOSE TISSUE (AT) ACCOMPANIED WITH ALTERATIONS IN THE IMMUNE RESPONSE THAT AFFECTS VIRTUALLY ALL AGE AND SOCIOECONOMIC GROUPS AROUND THE GLOBE. THE ABNORMAL ACCUMULATION OF AT LEADS TO SEVERAL METABOLIC DISEASES, INCLUDING NONALCOHOLIC FATTY LIVER DISORDER (NAFLD), LOW-GRADE INFLAMMATION, TYPE 2 DIABETES MELLITUS (T2DM), CARDIOVASCULAR DISORDERS (CVDS), AND CANCER. AT IS AN ENDOCRINE ORGAN COMPOSED OF ADIPOCYTES AND IMMUNE CELLS, INCLUDING B-CELLS, T-CELLS AND MACROPHAGES. THESE IMMUNE CELLS SECRETE VARIOUS CYTOKINES AND CHEMOKINES AND CROSSTALK WITH ADIPOKINES TO MAINTAIN METABOLIC HOMEOSTASIS AND LOW-GRADE CHRONIC INFLAMMATION. A NOVEL FORM OF ADIPOKINES, MICRORNA (MIRS), IS EXPRESSED IN MANY DEVELOPING PERIPHERAL TISSUES, INCLUDING ATS, T-CELLS, AND MACROPHAGES, AND MODULATES THE IMMUNE RESPONSE. MIRS ARE ESSENTIAL FOR INSULIN RESISTANCE, MAINTAINING THE TUMOR MICROENVIRONMENT, AND OBESITY-ASSOCIATED INFLAMMATION (OAI). THE ABNORMAL REGULATION OF AT, T-CELLS, AND MACROPHAGE MIRS MAY CHANGE THE FUNCTION OF DIFFERENT ORGANS INCLUDING THE PANCREAS, HEART, LIVER, AND SKELETAL MUSCLE. SINCE OBESITY AND INFLAMMATION ARE CLOSELY ASSOCIATED, THE DYSREGULATED EXPRESSION OF MIRS IN INFLAMMATORY ADIPOCYTES, T-CELLS, AND MACROPHAGES SUGGEST THE IMPORTANCE OF MIRS IN OAI. THEREFORE, IN THIS REVIEW ARTICLE, WE HAVE ELABORATED THE ROLE OF MIRS AS EPIGENETIC REGULATORS AFFECTING ADIPOCYTE DIFFERENTIATION, IMMUNE RESPONSE, AT BROWNING, ADIPOGENESIS, LIPID METABOLISM, INSULIN RESISTANCE (IR), GLUCOSE HOMEOSTASIS, OBESITY, AND METABOLIC DISORDERS. FURTHER, WE WILL DISCUSS A SET OF ALTERED MIRS AS NOVEL BIOMARKERS FOR METABOLIC DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR OBESITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8  1956  39 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                      
9   173  31 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  1955  32 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  6018  29 THE ASSOCIATION OF EPIGENETIC AGE ACCELERATION AND MULTIMORBIDITY AT AGE 90 IN THE WOMEN'S HEALTH INITIATIVE. BACKGROUND: EPIGENETIC AGE ACCELERATION (EAA), A MEASURE OF ACCELERATED BIOLOGICAL AGING, HAS BEEN ASSOCIATED WITH INCREASED RISK OF SEVERAL AGE-RELATED CHRONIC CONDITIONS. THIS IS THE FIRST STUDY TO PROSPECTIVELY EXAMINE THE RELATIONSHIP BETWEEN EAA AND BOTH MULTIMORBIDITY COUNT AND A WEIGHTED MULTIMORBIDITY SCORE AMONG LONG-LIVED POSTMENOPAUSAL WOMEN. METHODS: WE INCLUDED 1,951 WOMEN FROM THE WOMEN'S HEALTH INITIATIVE WHO COULD HAVE SURVIVED TO AGE 90. EAA WAS ESTIMATED USING THE HORVATH PAN-TISSUE, HANNUM, PHENOAGE AND GRIMAGE "CLOCKS." TWELVE CHRONIC CONDITIONS WERE INCLUDED IN THE MULTIMORBIDITY COUNT. THE MULTIMORBIDITY SCORE WAS WEIGHTED FOR EACH MORBIDITY'S RELATIONSHIP WITH MORTALITY IN THE STUDY POPULATION. USING MIXED-EFFECTS POISSON AND LINEAR REGRESSION MODELS THAT INCLUDED BASELINE COVARIATES ASSOCIATED WITH BOTH EAA AND MULTIMORBIDITY, WE ESTIMATED RELATIVE RISKS (RRS) AND 95% CONFIDENCE INTERVALS (CIS) FOR THE RELATIONSHIPS BETWEEN EACH EAA MEASURE AT STUDY BASELINE WITH BOTH MULTIMORBIDITY COUNT AND WEIGHTED MULTIMORBIDITY SCORE AT AGE 90, RESPECTIVELY. RESULTS: FOR EVERY ONE-STANDARD DEVIATION INCREASE IN AGEACCELPHENO, THE RATE OF MULTIMORBIDITY ACCUMULATION INCREASED 6% (RR=1.06; 95% CI=1.01-1.12; P=0.025) AND THE MULTIMORBIDITY SCORE BY 7% (RR=1.07; 95% CI=1.01-1.13; P=0.014) FOR WOMEN WHO SURVIVED TO AGE 90. THE RESULTS FOR A ONE-STANDARD DEVIATION INCREASE IN AGEACCELHORVATH, AGEACCELHANNUM AND AGEACCELGRIM WITH MULTIMORBIDITY ACCUMULATION AND SCORE WERE WEAKER COMPARED TO AGEACCELPHENO, AND THE LATTER TWO DID NOT REACH STATISTICAL SIGNIFICANCE. CONCLUSION: AGEACCELPHENO AND AGEACCELHANNUM MAY PREDICT MULTIMORBIDITY COUNT AND SCORE AT AGE 90 IN OLDER WOMEN AND, THUS, MAY BE USEFUL AS A BIOMARKER PREDICTOR OF MULTIMORBIDITY BURDEN IN THE LAST DECADES OF LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  6679  48 USING MACHINE LEARNING TO PREDICT OBESITY BASED ON GENOME-WIDE AND EPIGENOME-WIDE GENE-GENE AND GENE-DIET INTERACTIONS. OBESITY IS ASSOCIATED WITH MANY CHRONIC DISEASES THAT IMPAIR HEALTHY AGING AND IS GOVERNED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AND THEIR COMPLEX INTERACTIONS. THIS STUDY AIMED TO DEVELOP A MODEL THAT PREDICTS AN INDIVIDUAL'S RISK OF OBESITY BY BETTER CHARACTERIZING THESE COMPLEX RELATIONS AND INTERACTIONS FOCUSING ON DIETARY FACTORS. FOR THIS PURPOSE, WE CONDUCTED A COMBINED GENOME-WIDE AND EPIGENOME-WIDE SCAN FOR BODY MASS INDEX (BMI) AND UP TO THREE-WAY INTERACTIONS AMONG 402,793 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), 415,202 DNA METHYLATION SITES (DMSS), AND 397 DIETARY AND LIFESTYLE FACTORS USING THE GENERALIZED MULTIFACTOR DIMENSIONALITY REDUCTION (GMDR) METHOD. THE TRAINING SET CONSISTED OF 1,573 PARTICIPANTS IN EXAM 8 OF THE FRAMINGHAM OFFSPRING STUDY (FOS) COHORT. AFTER IDENTIFYING GENETIC, EPIGENETIC, AND DIETARY FACTORS THAT PASSED STATISTICAL SIGNIFICANCE, WE APPLIED MACHINE LEARNING (ML) ALGORITHMS TO PREDICT PARTICIPANTS' OBESITY STATUS IN THE TEST SET, TAKEN AS A SUBSET OF INDEPENDENT SAMPLES (N = 394) FROM THE SAME COHORT. THE QUALITY AND ACCURACY OF PREDICTION MODELS WERE EVALUATED USING THE AREA UNDER THE RECEIVER OPERATING CHARACTERISTIC CURVE (ROC-AUC). GMDR IDENTIFIED 213 SNPS, 530 DMSS, AND 49 DIETARY AND LIFESTYLE FACTORS AS SIGNIFICANT PREDICTORS OF OBESITY. COMPARING SEVERAL ML ALGORITHMS, WE FOUND THAT THE STOCHASTIC GRADIENT BOOSTING MODEL PROVIDED THE BEST PREDICTION ACCURACY FOR OBESITY WITH AN OVERALL ACCURACY OF 70%, WITH ROC-AUC OF 0.72 IN TEST SET SAMPLES. TOP PREDICTORS OF THE BEST-FIT MODEL WERE 21 SNPS, 230 DMSS IN GENES SUCH AS CPT1A, ABCG1, SLC7A11, RNF145, AND SREBF1, AND 26 DIETARY FACTORS, INCLUDING PROCESSED MEAT, DIET SODA, FRENCH FRIES, HIGH-FAT DAIRY, ARTIFICIAL SWEETENERS, ALCOHOL INTAKE, AND SPECIFIC NUTRIENTS AND FOOD COMPONENTS, SUCH AS CALCIUM AND FLAVONOLS. IN CONCLUSION, WE DEVELOPED AN INTEGRATED APPROACH WITH ML TO PREDICT OBESITY USING OMICS AND DIETARY DATA. THIS EXTENDS OUR KNOWLEDGE OF THE DRIVERS OF OBESITY, WHICH CAN INFORM PRECISION NUTRITION STRATEGIES FOR THE PREVENTION AND TREATMENT OF OBESITY. CLINICAL TRIAL REGISTRATION: [WWW.CLINICALTRIALS.GOV], THE FRAMINGHAM HEART STUDY (FHS), [NCT00005121].	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13   404  36 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  5909  32 TARGETED DEEP SEQUENCING OF PLASMA CIRCULATING CELL-FREE DNA REVEALS VIMENTIN AND FIBULIN 1 AS POTENTIAL EPIGENETIC BIOMARKERS FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE SECOND MOST COMMON CAUSE OF CANCER DEATH WORLDWIDE, BUT IS STILL LACKING SENSITIVE AND SPECIFIC BIOMARKERS FOR EARLY DIAGNOSIS AND PROGNOSIS. IN THIS STUDY, WE APPLIED TARGETED MASSIVELY PARALLEL SEMICONDUCTOR SEQUENCING TO ASSESS METHYLATION ON A PANEL OF GENES (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM AND YWHAZ) IN PLASMA CIRCULATING CELL-FREE DNA (CFDNA) AND TO EVALUATE THE POTENTIAL OF THESE GENES AS HCC BIOMARKERS IN TWO DIFFERENT SERIES, ONE FROM FRANCE (42 HCC CASES AND 42 CONTROLS) AND ONE FROM THAILAND (42 HCC CASES, 26 CHRONIC LIVER DISEASE CASES AND 42 CONTROLS). WE ALSO ANALYZED A SET OF HCC AND ADJACENT TISSUES AND LIVER CELL LINES TO FURTHER COMPARE WITH 'THE CANCER GENOME ATLAS' (TCGA) DATA. THE METHYLATION IN CFDNA WAS DETECTED FOR FBLN1, PSMA7, PXDN AND VIM, WITH DIFFERENCES IN METHYLATION PATTERNS BETWEEN CASES AND CONTROLS FOR FBLN1 AND VIM. THE AVERAGE METHYLATION LEVEL ACROSS ANALYZED CPG-SITES WAS ASSOCIATED WITH HIGHER ODDS OF HCC FOR VIM (1.48 [1.02, 2.16] FOR FRENCH CASES AND 2.18 [1.28, 3.72] FOR THAI CASES), AND LOWER ODDS OF HCC FOR FBLN1 (0.89 [0.76, 1.03] FOR FRENCH CASES AND 0.75 [0.63, 0.88] FOR THAI CASES). IN CONCLUSION, OUR STUDY PROVIDES EVIDENCE THAT CHANGES IN VIM AND FBLN1 METHYLATION LEVELS IN CFDNA ARE ASSOCIATED WITH HCC AND COULD REPRESENT USEFUL PLASMA-BASED BIOMARKERS. ALSO, THE POTENTIAL TO INVESTIGATE METHYLATION PATTERNS IN CFDNA COULD BRING NEW STRATEGIES FOR HCC DETECTION AND MONITORING HIGH-RISK GROUPS AND RESPONSE TO TREATMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  2678  29 EVALUATION OF A PROGNOSTIC EPIGENETIC CLASSIFICATION SYSTEM IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. BACKGROUND: METHYLATION AT 5 CPG SITES WAS PREVIOUSLY SHOWN TO CLASSIFY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO 3 PROGNOSTIC SUBGROUPS. HERE, WE AIMED TO VALIDATE THE MARKER SET IN AN ADDITIONAL COHORT AND TO EVALUATE ITS CLINICAL UTILITY FOR CLL PATIENT STRATIFICATION. METHODS: WE EVALUATED THIS EPIGENETIC MARKER SET IN 79 GERMAN PATIENTS USING BISULFITE TREATMENT FOLLOWED BY PYROSEQUENCING AND CLASSIFICATION USING A SUPPORT VECTOR MACHINE-LEARNING TOOL. RESULTS: THE N-CLL, I-CLL, AND M-CLL CLASSIFICATION WAS DETECTED IN 28 (35%), 10 (13%), AND 41 (51%) PATIENTS, RESPECTIVELY. EPIGENETIC GROUPING WAS ASSOCIATED WITH IGHV MUTATIONAL STATUS (P = 2 X 10(-12)), ISOLATED DEL13Q (P = 9 X 10(-6)), DEL17P (P = .015), COMPLEX KARYOTYPE (P = .005), VH-USAGE, AND CLINICAL OUTCOME AS TIME TO FIRST TREATMENT (P = 1.4 X 10(-12)) AND OVERALL SURVIVAL (P = .003). MULTIVARIATE COX REGRESSION ANALYSIS IDENTIFIED N-CLL AS A FACTOR FOR EARLIER TREATMENT HAZARD RATIO (HR), 6.3 (95% CONFIDENCE INTERVAL [CI] 2.4-16.4; P = .0002) COMPARED TO IGHV MUTATIONAL STATUS (HR 4.6, 95% CI 1.9-11.3, P = .0008). IN ADDITION, WHEN COMPARING THE PROGNOSTIC VALUE OF THE EPIGENETIC CLASSIFICATION SYSTEM WITH THE IGHV CLASSIFICATION, EPIGENETIC GROUPING PERFORMED BETTER COMPARED TO IGHV MUTATIONAL STATUS USING KAPLAN-MEIER ESTIMATION AND ALLOWED THE IDENTIFICATION OF A THIRD, INTERMEDIATE (I-CLL) GROUP. THUS, OUR STUDY CONFIRMED THE PROGNOSTIC VALUE OF THE EPIGENETIC MARKER SET FOR PATIENT STRATIFICATION IN ROUTINE CLINICAL DIAGNOSTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  3995  37 LONGITUDINAL STUDY OF DNA METHYLATION OF INFLAMMATORY GENES AND CANCER RISK. BACKGROUND: CHRONIC INFLAMMATION PLAYS A KEY ROLE IN CANCER ETIOLOGY. DNA METHYLATION MODIFICATION, ONE OF THE EPIGENETIC MECHANISMS REGULATING GENE EXPRESSION, IS CONSIDERED A HALLMARK OF CANCER. HUMAN AND ANIMAL MODELS HAVE IDENTIFIED NUMEROUS LINKS BETWEEN DNA METHYLATION AND INFLAMMATORY BIOMARKERS. OUR OBJECTIVE WAS TO PROSPECTIVELY AND LONGITUDINALLY EXAMINE ASSOCIATIONS BETWEEN METHYLATION OF FOUR INFLAMMATORY GENES AND CANCER RISK. METHODS: WE INCLUDED 795 NORMATIVE AGING STUDY PARTICIPANTS WITH BLOOD DRAWN ONE TO FOUR TIMES FROM 1999 TO 2012 (MEDIAN FOLLOW-UP, 10.6 YEARS). PROMOTER DNA METHYLATION OF IL6, ICAM-1, IFN, AND TLR2 IN BLOOD LEUKOCYTES WAS MEASURED USING PYROSEQUENCING AT MULTIPLE CPG SITES AND AVERAGED BY GENE FOR DATA ANALYSIS. WE USED COX REGRESSION MODELS TO EXAMINE PROSPECTIVE ASSOCIATIONS OF BASELINE AND TIME-DEPENDENT METHYLATION WITH CANCER RISK AND COMPARED MEAN METHYLATION DIFFERENCES OVER TIME BETWEEN CANCER CASES AND CANCER-FREE PARTICIPANTS. RESULTS: BASELINE IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.49; P = 0.04) AND PROSTATE CANCER INCIDENCE (HR, 1.69; P = 0.02). BASELINE ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.43; P = 0.02; HR, 0.70; P = 0.03, RESPECTIVELY). IN OUR TIME-DEPENDENT ANALYSES, IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.79; P = 0.007) AND PROSTATE CANCER (HR, 1.57; P = 0.03) INCIDENCE; AND ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, RESPECTIVELY). WE DETECTED SIGNIFICANT ICAM-1 HYPERMETHYLATION IN CANCER CASES (P = 0.0003) 10 TO 13 YEARS PREDIAGNOSIS. CONCLUSION: HYPERMETHYLATION OF IFN AND ICAM-1 MAY PLAY IMPORTANT ROLES IN EARLY CARCINOGENESIS, PARTICULARLY THAT OF PROSTATE CANCER. IMPACT: THESE METHYLATION CHANGES COULD INFORM THE DEVELOPMENT OF EARLY DETECTION BIOMARKERS AND POTENTIAL TREATMENTS OF INFLAMMATION-RELATED CARCINOGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  5746  32 SMOKING-RELATED DNA METHYLATION IS ASSOCIATED WITH DNA METHYLATION PHENOTYPIC AGE ACCELERATION: THE VETERANS AFFAIRS NORMATIVE AGING STUDY. DNA METHYLATION MAY PLAY A CRITICAL ROLE IN AGING AND AGE-RELATED DISEASES. DNA METHYLATION PHENOTYPIC AGE (DNAMPHENOAGE) IS A NEW AGING BIOMARKER AND PREDICTOR OF CHRONIC DISEASE RISK. WHILE SMOKING IS A STRONG RISK FACTOR FOR CHRONIC DISEASES AND INFLUENCES METHYLATION, ITS INFLUENCE ON DNAMPHENOAGE IS UNKNOWN. WE INVESTIGATED ASSOCIATIONS OF SELF-REPORTED AND EPIGENETIC SMOKING INDICATORS WITH DNAMPHENOAGE ACCELERATION IN A LONGITUDINAL AGING STUDY IN EASTERN MASSACHUSETTS. DNA METHYLATION WAS MEASURED IN WHOLE BLOOD SAMPLES FROM MULTIPLE VISITS FOR 692 MALE PARTICIPANTS IN THE VETERANS AFFAIRS NORMATIVE AGING STUDY DURING 1999-2013. ACCELERATION WAS DEFINED USING RESIDUALS FROM LINEAR REGRESSION OF THE DNAMPHENOAGE ON THE CHRONOLOGICAL AGE. CUMULATIVE SMOKING (PACK-YEARS) WAS SIGNIFICANTLY ASSOCIATED WITH DNAMPHENOAGE ACCELERATION, WHEREAS SELF-REPORTED SMOKING STATUS WAS NOT. WE OBSERVED SIGNIFICANT VALIDATED ASSOCIATIONS BETWEEN SMOKING-RELATED LOCI AND DNAMPHENOAGE ACCELERATION FOR 52 CPG SITES, WHERE 18 WERE HYPOMETHYLATED AND 34 WERE HYPERMETHYLATED, MAPPED TO 16 GENES. THE AHRR GENE HAD THE MOST LOCI (N = 8) AMONG THE 16 GENES. WE GENERATED A SMOKING AGING INDEX BASED ON THESE 52 LOCI, WHICH SHOWED POSITIVE SIGNIFICANT ASSOCIATIONS WITH DNAMPHENOAGE ACCELERATION. THESE EPIGENETIC BIOMARKERS MAY HELP TO PREDICT AGE-RELATED RISKS DRIVEN BY SMOKING.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  1952  20 EPIGENETIC AGE ACCELERATION AMONG SURVIVORS OF PEDIATRIC MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMOR. SURVIVORS OF CHILDHOOD CENTRAL NERVOUS SYSTEM (CNS) TUMORS EXPERIENCE EARLY-ONSET AGING-RELATED PHENOTYPES. DNA METHYLATION (DNAM) AGE IS AN EMERGING EPIGENETIC BIOMARKER OF PHYSIOLOGIC AGE AND MAY BE PREDICTIVE OF CHRONIC HEALTH CONDITIONS IN LONG-TERM SURVIVORS. THIS REPORT DESCRIBES THE COURSE OF EPIGENETIC AGE ACCELERATION USING POST-DIAGNOSIS BLOOD SAMPLES (MEDIAN: 3.9 YEARS POST-DIAGNOSIS; RANGE: 0.04-15.96) FROM 83 SURVIVORS OF PEDIATRIC CNS TUMORS. EPIGENETIC AGE ACCELERATION WAS DETECTED IN 72% OF PATIENTS, WITH AN AVERAGE DIFFERENCE BETWEEN CHRONOLOGIC AND DNAM AGE OF 2.58 YEARS (95% CI: 1.75-3.41, P < 0.001). TIME FROM DIAGNOSIS TO SAMPLE COLLECTION CORRELATED WITH THE MAGNITUDE OF EPIGENETIC AGE ACCELERATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19   713  35 CADMIUM EXPOSURE AND AGE-ASSOCIATED DNA METHYLATION CHANGES IN NON-SMOKING WOMEN FROM NORTHERN THAILAND. DNA METHYLATION CHANGES WITH AGE, AND MAY SERVE AS A BIOMARKER OF AGING. CADMIUM (CD) MODIFIES CELLULAR PROCESSES THAT PROMOTE AGING AND DISRUPTS METHYLATION GLOBALLY. WHETHER CD MODIFIES AGING PROCESSES BY INFLUENCING ESTABLISHMENT OF AGE-ASSOCIATED METHYLATION MARKS IS CURRENTLY UNKNOWN. IN THIS PILOT STUDY, WE CHARACTERIZED METHYLATION PROFILES IN > 450 000 CPG SITES IN 40 NON-SMOKING WOMEN (AGE 40-80) DIFFERENTIALLY EXPOSED TO ENVIRONMENTAL CD FROM THAILAND. BASED ON SPECIFIC GRAVITY ADJUSTED URINARY CD, WE CLASSIFIED THEM AS HIGH (HE) AND LOW (LE) EXPOSED AND AGE-MATCHED WITHIN 5 YEARS. URINARY CD WAS DEFINED AS BELOW 2 MICROG/L IN THE LE GROUP. WE PREDICTED EPIGENETIC AGE (DNAM-AGE) USING TWO PUBLISHED METHODS BY HORVATH AND HANNUM AND EXAMINED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGIC AGE (DELTAAGE). WE ASSESSED DIFFERENCES BY CD EXPOSURE USING LINEAR MIXED MODELS ADJUSTED FOR ESTIMATED WHITE BLOOD CELL PROPORTIONS, BMI, AND URINARY CREATININE. WE IDENTIFIED 213 AGE-ASSOCIATED CPG SITES IN OUR POPULATION (P < 10(-4)). COUNTERINTUITIVELY, THE MEAN DELTAAGE WAS SMALLER IN HE VS. LE (HANNUM: 3.6 VS. 7.6 YEARS, P = 0.0093; HORVATH: 2.4 VS. 4.5 YEARS, P = 0.1308). THE CD EXPOSED GROUP WAS ASSOCIATED WITH CHANGES IN METHYLATION (P < 0.05) AT 12, 8, AND 20 AGE-ASSOCIATED SITES IDENTIFIED IN OUR POPULATION, HANNUM, AND HORVATH. FROM THE RESULTS OF THIS PILOT STUDY, ELEVATED CD EXPOSURE IS ASSOCIATED WITH METHYLATION CHANGES AT AGE-ASSOCIATED SITES AND SMALLER DIFFERENCES BETWEEN DNAM-AGE AND CHRONOLOGIC AGE, IN CONTRAST TO EXPECTED AGE-ACCELERATING EFFECTS. CD MAY MODIFY EPIGENETIC AGING, AND BIOMARKERS OF AGING WARRANT FURTHER INVESTIGATION WHEN EXAMINING CD AND ITS RELATIONSHIP WITH CHRONIC DISEASE AND MORTALITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20   335  36 ALTERATIONS IN DNA METHYLATION ASSOCIATE WITH FATTY LIVER AND METABOLIC ABNORMALITIES IN A MULTI-ETHNIC COHORT OF PRE-TEENAGE CHILDREN. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN. EPIGENETIC ALTERATIONS, SUCH AS THROUGH DNA METHYLATION (DNAM), MAY LINK ADVERSE CHILDHOOD EXPOSURES AND FATTY LIVER AND PROVIDE NON-INVASIVE METHODS FOR IDENTIFYING CHILDREN AT HIGH RISK FOR NAFLD AND ASSOCIATED METABOLIC DYSFUNCTION. WE INVESTIGATED THE ASSOCIATION BETWEEN DIFFERENTIAL DNAM AND LIVER FAT CONTENT (LFC) AND LIVER INJURY IN PRE-ADOLESCENT CHILDREN. LEVERAGING DATA FROM THE NEWBORN EPIGENETICS STUDY (NEST), WE ENROLLED 90 MOTHER-CHILD DYADS AND USED LINEAR REGRESSION TO IDENTIFY CPG SITES AND DIFFERENTIALLY METHYLATED REGIONS (DMRS) IN PERIPHERAL BLOOD ASSOCIATED WITH LFC AND ALANINE AMINOTRANSFERASE (ALT) LEVELS IN 7-12YO CHILDREN. DNAM WAS MEASURED USING INFINIUM HUMANMETHYLATIONEPIC BEADCHIPS (ILLUMINA). LFC AND FIBROSIS WERE QUANTIFIED BY MAGNETIC RESONANCE IMAGING PROTON DENSITY FAT FRACTION AND ELASTOGRAPHY. MEDIAN LFC WAS 1.4% (RANGE, 0.3-13.4%) AND MRE WAS 2.5 KPA (RANGE, 1.5-3.6KPA). THREE CHILDREN HAD LFC >/= 5%, WHILE SIX (7.6%) MET OUR DEFINITION OF NAFLD (LFC >/= 3.7%). ALL CHILDREN WITH NAFLD WERE OBESE AND FIVE WERE BLACK. LFC WAS ASSOCIATED WITH 88 DMRS AND 106 CPGS (FDR<5%). THE TOP TWO CPGS, CG25474373 AND CG07264203, MAPPED TO OR NEAR RFTN2 AND PRICKLE2 GENES. THESE TWO CPG SITES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH A NAFLD DIAGNOSIS. AS HIGHER LFC ASSOCIATES WITH AN ADVERSE CARDIOMETABOLIC PROFILE ALREADY IN CHILDHOOD, ALTERED DNAM MAY IDENTIFY THESE CHILDREN EARLY IN DISEASE COURSE FOR TARGETED INTERVENTION. LARGER, LONGITUDINAL STUDIES ARE NEEDED TO VALIDATE THESE FINDINGS AND DETERMINE MECHANISTIC RELEVANCE.	2022