1 181 95 ACCELERATED EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN VITAMIN D LEVELS AND KNEE PAIN IN COMMUNITY-DWELLING INDIVIDUALS. OBJECTIVES: TO EXAMINE THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND PAIN INTENSITY AND DISABILITY IN INDIVIDUALS WITH AND WITHOUT KNEE PAIN, AND TO EXAMINE THE ROLE OF EPIGENETICS IN THIS RELATIONSHIP. DESIGN: CROSS-SECTIONAL ANALYSIS OF DATA FROM THE UPLOAD-2 STUDY (UNDERSTANDING PAIN AND LIMITATIONS IN OSTEOARTHRITIC DISEASE-2). PARTICIPANTS: 189 INDIVIDUALS AGED 45-65 YEARS AND OLDER. MEASUREMENTS: SERUM VITAMIN D LEVELS, PAIN RELATED INTERFERENCE AND CHARACTERISTIC PAIN INTENSITY MEASURES, AND THE EPIGENETIC CLOCK GRIMAGE DERIVED FROM BLOOD ANALYSES. RESULTS: LOWER VITAMIN D WAS ASSOCIATED WITH ADVANCED EPIGENETIC AGING (AGEACCELGRIM), GREATER PAIN AND DISABILITY AND THAT (AGEACCELGRIM) MEDIATED THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND SELF-REPORTED PAIN (AB = -0.0799; CI [-0.1492, -0.0237]) AND DISABILITY (AB = -0.0669; CI [-0.1365, -0.0149]) OUTCOMES. CONCLUSION: THESE DATA SUPPORT THE NOTION THAT LIFESTYLE FACTORS SUCH AS NUTRITION STATUS PLAY A KEY ROLE IN AGING PROCESS, AS WELL AS THE DEVELOPMENT AND MAINTENANCE OF AGE-RELATED DISEASES SUCH AS PAIN. MODIFYING NUTRITION STATUS COULD HELP PROMOTE HEALTHY AGING AND REDUCE PAIN. 2022 2 1782 32 EFFECT OF A 3-WEEK MULTIDISCIPLINARY BODY WEIGHT REDUCTION PROGRAM ON THE EPIGENETIC AGE ACCELERATION IN OBESE ADULTS. OBESITY AND AGING SHARE COMMON MOLECULAR AND CELLULAR MECHANISMS UNDERLYING THE PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASES (CVD), WHICH OCCUR FREQUENTLY IN BOTH CONDITIONS. DNA METHYLATION (DNAM) AGE, A BIOMARKER OF THE EPIGENETIC CLOCK, HAS BEEN PROPOSED AS A MORE ACCURATE PREDICTOR OF BIOLOGICAL AGING THAN CHRONOLOGICAL AGE. A POSITIVE DIFFERENCE BETWEEN AN INDIVIDUAL'S CHRONOLOGICAL AGE AND DNAM AGE IS REFERRED TO AS EPIGENETIC AGE ACCELERATION. THE OBJECTIVE OF THE PRESENT STUDY WAS TO EVALUATE THE EFFECTS OF A 3-WEEK IN-HOSPITAL BODY WEIGHT REDUCTION PROGRAM (BWRP) ON THE EPIGENETIC AGE ACCELERATION, AS WELL AS ON OTHER CARDIOMETABOLIC OUTCOMES, IN A COHORT OF 72 OBESE ADULTS (F/M: 43/29; (CHRONOLOGICAL) AGE: 51.5 +/- 14.5 YRS; BMI: 46.5 +/- 6.3 KG/M2). AT THE END OF THE BWRP, WHEN CONSIDERING THE ENTIRE POPULATION, BMI DECREASED, AND CHANGES IN BODY COMPOSITION WERE OBSERVED. THE BWRP ALSO PRODUCED BENEFICIAL METABOLIC EFFECTS AS DEMONSTRATED BY DECREASES IN GLUCOSE, INSULIN, HOMA-IR, TOTAL CHOLESTEROL, AND LDL CHOLESTEROL. A POST-BWRP IMPROVEMENT IN CARDIOVASCULAR FUNCTION WAS ALSO EVIDENT (I.E., DECREASES IN SYSTOLIC AND DIASTOLIC BLOOD PRESSURES AND HEART RATE). THE BWRP REDUCED SOME MARKERS OF SYSTEMIC INFLAMMATION, PARTICULARLY C-REACTIVE PROTEIN (CRP). FINALLY, VASCULAR AGE (VA) AND FRAMINGHAM RISK SCORE (FRS) WERE REDUCED AFTER THE BWRP. WHEN CONSIDERING THE ENTIRE POPULATION, DNAM AGE AND EPIGENETIC AGE ACCELERATION DID NOT DIFFER AFTER THE BWRP. HOWEVER, WHEN SUBDIVIDING THE POPULATION INTO TWO GROUPS BASED ON EACH SUBJECT'S EPIGENETIC AGE ACCELERATION (I.E., 0 YRS), THE BWRP REDUCED THE EPIGENETIC AGE ACCELERATION ONLY IN OBESE SUBJECTS WITH A VALUE > 0 YRS (THUS BIOLOGICALLY OLDER THAN EXPECTED). AMONG ALL THE SINGLE DEMOGRAPHIC, LIFESTYLE, BIOCHEMICAL, AND CLINICAL CHARACTERISTICS INVESTIGATED, ONLY SOME MARKERS OF SYSTEMIC INFLAMMATION, SUCH AS CRP, WERE ASSOCIATED WITH THE EPIGENETIC AGE ACCELERATION. MOREOVER, CHRONOLOGICAL AGE WAS CORRELATED WITH DNAM AGE AND VA; FINALLY, THERE WAS A CORRELATION BETWEEN DNAM AGE AND VA. IN CONCLUSION, A 3-WEEK BWRP IS CAPABLE OF REDUCING THE EPIGENETIC AGE ACCELERATION IN OBESE ADULTS, BEING THE BWRP-INDUCED REJUVENATION EVIDENT IN SUBJECTS WITH AN EPIGENETIC AGE ACCELERATION > 0 YRS. BASED ON THE BWRP-INDUCED DECREASE IN CRP LEVELS, CHRONIC SYSTEMIC INFLAMMATION SEEMS TO PLAY A ROLE IN MEDIATING OBESITY-RELATED EPIGENETIC REMODELING AND BIOLOGICAL AGING. THUS, DUE TO THE STRONG ASSOCIATION OF CVD RISK WITH THE EPIGENETIC CLOCK AND MORBIDITY/MORTALITY, ANY EFFORT SHOULD BE MADE TO REDUCE THE LOW-GRADE CHRONIC INFLAMMATORY STATE IN OBESITY. 2022 3 6911 17 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES. 2012 4 4912 39 PAIN INTERFERENCE MEDIATES THE ASSOCIATION BETWEEN EPIGENETIC AGING AND GRIP STRENGTH IN MIDDLE TO OLDER AGED MALES AND FEMALES WITH CHRONIC PAIN. INTRODUCTION: CHRONIC PAIN IS ONE OF THE LEADING CAUSES OF DISABILITY THAT MAY ACCELERATE BIOLOGICAL AGING AND REDUCE PHYSICAL FUNCTION. EPIGENETIC CLOCKS PROVIDE AN ESTIMATE OF HOW THE SYSTEM AGES AND CAN PREDICT HEALTH OUTCOMES SUCH AS PHYSICAL FUNCTION. PHYSICAL FUNCTION DECLINES MAY BE ATTRIBUTED TO DECREASES IN MUSCLE QUALITY DUE TO DISUSE THAT CAN BE MEASURED QUICKLY AND NONINVASIVELY USING GRIP STRENGTH. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE ASSOCIATIONS AMONG SELF-REPORTED PAIN, GRIP STRENGTH, AND EPIGENETIC AGING IN THOSE WITH CHRONIC PAIN. METHODS: PARTICIPANTS (57.91 +/- 8.04 YEARS) COMPLETED PAIN QUESTIONNAIRES, A BLOOD DRAW AND HAND GRIP STRENGTH TASK. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), AND USED THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE). RESULTS: EXPLORATORY PATHWAY ANALYSES REVEALED THAT PAIN INTENSITY MEDIATED THE ASSOCIATION BETWEEN DNAMGRIMAGE-DIFFERENCE AND HANDGRIP STRENGTH IN MALES ONLY (BETA = -0.1115; CI [-0.2929, -0.0008]) AND PAIN INTERFERENCE MEDIATED THE ASSOCIATION BETWEEN DNAMGRIMAGE-DIFFERENCE AND HANDGRIP STRENGTH IN MALES BETA = -0.1401; CI [-0.3400, -0.0222]), AND FEMALES (BETA = -0.024; CI [-0.2918, -0.0020]). DISCUSSION: CHRONIC KNEE PAIN MAY ACCELERATE EPIGENETIC AGING PROCESSES THAT MAY INFLUENCE HANDGRIP STRENGTH IN OLDER AGE ADULTS. CHRONIC PAIN COULD BE A SYMPTOM OF THE AGING BODY THUS CONTRIBUTING TO DECLINES IN MUSCULOSKELETAL FUNCTION IN LATER LIFE. 2023 5 3162 35 GREATER STRESS AND TRAUMA MEDIATE RACE-RELATED DIFFERENCES IN EPIGENETIC AGE BETWEEN BLACK AND WHITE YOUNG ADULTS IN A COMMUNITY SAMPLE. BLACK AMERICANS SUFFER LOWER LIFE EXPECTANCY AND SHOW SIGNS OF ACCELERATED AGING COMPARED TO OTHER AMERICANS. WHILE PREVIOUS STUDIES OBSERVE THESE DIFFERENCES IN CHILDREN AND POPULATIONS WITH CHRONIC ILLNESS, WHETHER THESE PATHOLOGIC PROCESSES EXIST OR HOW THESE PATHOLOGIC PROCESSES PROGRESS HAS YET TO BE EXPLORED PRIOR TO THE ONSET OF SIGNIFICANT CHRONIC ILLNESS, WITHIN A YOUNG ADULT POPULATION. THEREFORE, WE INVESTIGATED RACE-RELATED DIFFERENCES IN EPIGENETIC AGE IN A CROSS-SECTIONAL SAMPLE OF YOUNG PUTATIVELY HEALTHY ADULTS AND ASSESSED WHETHER LIFETIME STRESS AND/OR TRAUMA MEDIATE THOSE DIFFERENCES. BIOLOGICAL AND PSYCHOLOGICAL DATA WERE COLLECTED FROM SELF-REPORTED HEALTHY ADULT VOLUNTEERS WITHIN THE LOCAL NEW HAVEN AREA (399 VOLUNTEERS, 19.8% BLACK, MEAN AGE: 29.28). STRESS AND TRAUMA DATA WAS COLLECTED USING THE CUMULATIVE ADVERSITY INVENTORY (CAI) INTERVIEW, WHICH ASSESSED SPECIFIC TYPES OF STRESSORS, INCLUDING MAJOR LIFE EVENTS, TRAUMATIC EVENTS, WORK, FINANCIAL, RELATIONSHIP AND CHRONIC STRESSORS CUMULATIVELY OVER TIME. GRIMAGE ACCELERATION (GAA), DETERMINED FROM WHOLE BLOOD COLLECTED FROM PARTICIPANTS, MEASURED EPIGENETIC AGE. IN ORDER TO UNDERSTAND THE IMPACT OF STRESS AND TRAUMA ON GAA, EXPLORATORY MEDIATION ANALYSES WERE THEN USED. WE FOUND CUMULATIVE STRESSORS ACROSS ALL TYPES OF EVENTS (MEAN DIFFERENCE OF 6.9 P = 2.14E-4) AND GAA (BETA = 2.29 YEARS [1.57-3.01, P = 9.70E-10] FOR RACE, PARTIAL ETA(2) = 0.091, MODEL ADJUSTED R(2) = 0.242) WERE SIGNIFICANTLY GREATER IN BLACK COMPARED TO WHITE PARTICIPANTS. CRITICALLY, CAI TOTAL SCORE (PROPORTION MEDIATED: 0.185 [0.073-0.34, P = 6E-4]) SIGNIFICANTLY MEDIATED THE RELATIONSHIP BETWEEN RACE AND GAA. FURTHER ANALYSIS ATTRIBUTED THIS DIFFERENCE TO MORE TRAUMATIC EVENTS, PARTICULARLY ASSAULTIVE TRAUMAS AND DEATH OF LOVED ONES. OUR RESULTS SUGGEST THAT, PRIOR TO DEVELOPMENT OF SIGNIFICANT CHRONIC DISEASE, BLACK INDIVIDUALS HAVE INCREASED EPIGENETIC AGE COMPARED TO WHITE PARTICIPANTS AND THAT INCREASED CUMULATIVE STRESS AND TRAUMATIC EVENTS MAY CONTRIBUTE SIGNIFICANTLY TO THIS EPIGENETIC AGING DIFFERENCE. 2023 6 5095 22 PLASMA PROTEOMIC BIOMARKER SIGNATURE OF AGE PREDICTS HEALTH AND LIFE SPAN. OLDER AGE IS A STRONG SHARED RISK FACTOR FOR MANY CHRONIC DISEASES, AND THERE IS INCREASING INTEREST IN IDENTIFYING AGING BIOMARKERS. HERE, A PROTEOMIC ANALYSIS OF 1301 PLASMA PROTEINS WAS CONDUCTED IN 997 INDIVIDUALS BETWEEN 21 AND 102 YEARS OF AGE. WE IDENTIFIED 651 PROTEINS ASSOCIATED WITH AGE (506 OVER-REPRESENTED, 145 UNDERREPRESENTED WITH AGE). MEDIATION ANALYSIS SUGGESTED A ROLE FOR PARTIAL CIS-EPIGENETIC CONTROL OF PROTEIN EXPRESSION WITH AGE. OF THE AGE-ASSOCIATED PROTEINS, 33.5% AND 45.3%, WERE ASSOCIATED WITH MORTALITY AND MULTIMORBIDITY, RESPECTIVELY. THERE WAS ENRICHMENT OF PROTEINS ASSOCIATED WITH INFLAMMATION AND EXTRACELLULAR MATRIX AS WELL AS SENESCENCE-ASSOCIATED SECRETORY PROTEINS. A 76-PROTEIN PROTEOMIC AGE SIGNATURE PREDICTED ACCUMULATION OF CHRONIC DISEASES AND ALL-CAUSE MORTALITY. THESE DATA SUPPORT THE USE OF PROTEOMIC BIOMARKERS TO MONITOR AGING TRAJECTORIES AND TO IDENTIFY INDIVIDUALS AT HIGHER RISK OF DISEASE TO BE TARGETED FOR IN DEPTH DIAGNOSTIC PROCEDURES AND EARLY INTERVENTIONS. 2020 7 2967 23 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES. 2022 8 275 19 AGE-RELATED CLONAL HAEMOPOIESIS IS ASSOCIATED WITH INCREASED EPIGENETIC AGE. AGE-RELATED CLONAL HAEMOPOIESIS (ARCH) IN HEALTHY INDIVIDUALS WAS INITIALLY OBSERVED THROUGH AN INCREASED SKEWING IN X-CHROMOSOME INACTIVATION [1]. MORE RECENTLY, SEVERAL GROUPS REPORTED THAT ARCH IS DRIVEN BY SOMATIC MUTATIONS [2], WITH THE MOST PREVALENT ARCH MUTATIONS BEING IN THE DNMT3A AND TET2 GENES, PREVIOUSLY DESCRIBED AS DRIVERS OF MYELOID MALIGNANCIES. ARCH IS ASSOCIATED WITH AN INCREASED RISK FOR HAEMATOLOGICAL CANCERS [2]. ARCH ALSO CONFERS AN INCREASED RISK FOR NON-HAEMATOLOGICAL DISEASES, SUCH AS CARDIOVASCULAR DISEASE, ATHEROSCLEROSIS, AND CHRONIC ISCHEMIC HEART FAILURE, FOR WHICH AGE IS A MAIN RISK FACTOR [3,4]. WHETHER ARCH IS LINKED TO ACCELERATED AGEING HAS REMAINED UNEXPLORED. THE MOST ACCURATE AND COMMONLY USED TOOLS TO MEASURE AGE ACCELERATION ARE EPIGENETIC CLOCKS: THEY ARE BASED ON AGE-RELATED METHYLATION DIFFERENCES AT SPECIFIC CPG SITES [5]. DEVIATIONS FROM CHRONOLOGICAL AGE TOWARDS AN INCREASED EPIGENETIC AGE HAVE BEEN ASSOCIATED WITH INCREASED RISK OF EARLIER MORTALITY AND AGE-RELATED MORBIDITIES [5,6]. HERE WE PRESENT EVIDENCE OF ACCELERATED EPIGENETIC AGE IN INDIVIDUALS WITH ARCH. 2019 9 1964 34 EPIGENETIC AGING, KNEE PAIN AND PHYSICAL PERFORMANCE IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. KNEE PAIN IS A LEADING CAUSE OF DISABILITY IN THE AGING POPULATION AND MAY INDIRECTLY ACCELERATE BIOLOGICAL AGING PROCESSES. CHRONOLOGICAL AGING INCREASES THE RISK OF DEVELOPING OF KNEE PAIN AND KNEE PAIN REDUCES PHYSICAL FUNCTION; HOWEVER, LIMITED DATA EXIST ON HOW EPIGENETIC AGING, A KNOWN HALLMARK OF BIOLOGICAL AGING SHOWN TO PREDICT HEALTH SPAN AND MORTALITY, MAY INFLUENCE THIS RELATIONSHIP. THE PURPOSE OF THIS STUDY WAS TO EXAMINE WHETHER DECREASED PHYSICAL PERFORMANCE ASSOCIATED WITH KNEE PAIN IS MEDIATED BY MARKERS OF EPIGENETIC AGING. PARTICIPANTS (57.91 +/- 8.04 YEARS) WITH LOW IMPACT KNEE PAIN (N = 95), HIGH IMPACT KNEE PAIN (N = 53) AND PAIN-FREE CONTROLS (N = 26) COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW AND A SHORT PHYSICAL PERFORMANCE BATTERY (SPPB) THAT INCLUDED BALANCE, WALKING, AND SIT TO STAND TASKS. WE EMPLOYED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN AND SHOWN TO PREDICT OVERALL MORTALITY RISK (DNAMGRIMAGE). BOOTSTRAPPED-MEDIATION ANALYSES WERE USED TO DETERMINE ASSOCIATIONS OF DNAMGRIMAGE AND SPPB BETWEEN PAIN GROUPS. THOSE WITH HIGH IMPACT AND LOW IMPACT PAIN HAD A BIOLOGICALLY OLDER EPIGENETIC AGE (5.14Y +/- 5.66 AND 1.32Y +/- 5.41, RESPECTIVELY). HOWEVER, WHILE THERE WERE DIRECT EFFECTS OF PAIN ON OVERALL PHYSICAL PERFORMANCE, THESE WERE NOT EXPLAINED BY EPIGENETIC AGING. EPIGENETIC AGING ONLY MEDIATED THE EFFECT OF PAIN ON BALANCE PERFORMANCE. FUTURE WORK IS NEEDED TO EXAMINE PAIN'S IMPACT ON BIOLOGICAL AGING PROCESSES INCLUDING EPIGENETIC AGING AND ITS ULTIMATE EFFECT ON PHYSICAL FUNCTION MEASURES KNOWN TO PREDICT HEALTH SPAN AND MORTALITY. 2022 10 3648 29 INCREASED RELATIVE ABUNDANCE OF RUMINOCCOCUS IS ASSOCIATED WITH REDUCED CARDIOVASCULAR RISK IN AN OBESE POPULATION. BACKGROUND: OBESITY IS A COMPLEX DISEASE WITH UNDERLYING GENETIC, ENVIRONMENTAL, PSYCHOLOGICAL, PHYSIOLOGICAL, MEDICAL, AND EPIGENETIC FACTORS. OBESITY CAN CAUSE VARIOUS DISORDERS, INCLUDING CARDIOVASCULAR DISEASES (CVDS), THAT ARE AMONG THE MOST PREVALENT CHRONIC CONDITIONS IN QATAR. RECENT STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT ROLES OF THE GUT MICROBIOME IN IMPROVING THE PATHOLOGY OF VARIOUS DISEASES, INCLUDING OBESITY. THUS, IN THIS STUDY, WE AIMED TO INVESTIGATE THE EFFECTS OF DIETARY INTAKE AND GUT MICROBIAL COMPOSITION IN MODULATING THE RISK OF CVD DEVELOPMENT IN OBESE QATARI ADULTS. METHODS: WE ENROLLED 46 ADULT SUBJECTS (18-65 YEARS OF AGE) WHO WERE CLASSIFIED BASED ON THEIR CVD RISK SCORES, CALCULATED USING THE FRAMINGHAM FORMULA, INTO A CVD NO-RISK GROUP (SCORE OF <10%, N = 36) AND CVD RISK GROUP (SCORE OF >/=10%, N = 10). FOR EACH STUDY SUBJECT, WE MEASURED THE GUT MICROBIAL COMPOSITION WITH A 16S RDNA SEQUENCING METHOD THAT TARGETED THE V3-V4 REGION USING ILLUMINA MISEQ, AND THEIR NUTRITIONAL STATUS WAS RECORDED BASED ON 24-H DIETARY RECALL. DIETARY INTAKE, BACTERIAL TAXA SUMMARY, DIVERSITY INDEX, MICROBIAL MARKERS, PATHWAY ANALYSIS, AND NETWORK CORRELATION WERE DETERMINED FOR THE STUDY SUBJECTS. RESULTS: THE CVD RISK GROUP SHOWED A LOWER INTAKE OF VITAMIN D, REDUCED RELATIVE ABUNDANCE OF GENERA RUMINOCOCCUS AND BIFIDOBACTERIUM, NO CHANGE IN BACTERIAL DIVERSITY, AND HIGHER LEVELS OF TAURINE, HYPOTAURINE, AND LIPOIC ACID METABOLISM THAN THE CVD NO-RISK GROUP. BESIDES, THE RELATIVE ABUNDANCE OF GENUS RUMINOCOCCUS WAS POSITIVELY CORRELATED WITH THE INTAKE OF PROTEIN, MONOUNSATURATED FAT, VITAMIN A, AND VITAMIN D. CONCLUSION: TAKEN TOGETHER, OUR RESULTS SUGGEST THAT THE GENUS RUMINOCOCCUS COULD BE USED AS A MICROBIAL MARKER, AND ITS REDUCED RELATIVE ABUNDANCE COULD MEDIATE THE RISK OF CVDS IN THE OBESE QATARI POPULATION. 2022 11 686 23 BRAIN-SPECIFIC GENES CONTRIBUTE TO CHRONIC BUT NOT TO ACUTE BACK PAIN. INTRODUCTION: BACK PAIN IS THE LEADING CAUSE OF DISABILITY WORLDWIDE. ALTHOUGH MOST BACK PAIN CASES ARE ACUTE, 20% OF ACUTE PAIN PATIENTS EXPERIENCE CHRONIC BACK PAIN SYMPTOMS. IT IS UNCLEAR WHETHER ACUTE PAIN AND CHRONIC PAIN HAVE SIMILAR OR DISTINCT UNDERLYING GENETIC MECHANISMS. OBJECTIVES: TO CHARACTERIZE THE MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO ACUTE AND CHRONIC PAIN STATES. METHODS: CROSS-SECTIONAL OBSERVATIONAL GENOME-WIDE ASSOCIATION STUDY. RESULTS: A TOTAL OF 375,158 INDIVIDUALS FROM THE UK BIOBANK COHORT WERE INCLUDED IN THE DISCOVERY OF GENOME-WIDE ASSOCIATION STUDY. OF THOSE, 70,633 (19%) AND 32,209 (9%) INDIVIDUALS MET THE DEFINITION OF CHRONIC AND ACUTE BACK PAIN, RESPECTIVELY. A TOTAL OF 355 SINGLE NUCLEOTIDE POLYMORPHISM GROUPED INTO 13 LOCI REACHED THE GENOME-WIDE SIGNIFICANCE THRESHOLD (5X10(-8)) FOR CHRONIC BACK PAIN, BUT NONE FOR ACUTE. OF THESE, 7 LOCI WERE REPLICATED IN THE NORD-TRONDELAG HEALTH STUDY (HUNT) COHORT (19,760 CHRONIC LOW BACK PAIN CASES AND 28,674 PAIN-FREE CONTROLS). SINGLE NUCLEOTIDE POLYMORPHISM HERITABILITY WAS 4.6% (P=1.4X10(-78)) FOR CHRONIC BACK PAIN AND 0.81% (P=1.4X10-8) FOR ACUTE BACK PAIN. SIMILAR DIFFERENCES IN HERITABILITY ESTIMATES BETWEEN ACUTE AND CHRONIC BACK PAIN WERE FOUND IN THE HUNT COHORT: 3.4% (P=0.0011) AND 0.6% (P=0.851), RESPECTIVELY. PATHWAY ANALYSES, TISSUE-SPECIFIC HERITABILITY ENRICHMENT ANALYSES, AND EPIGENETIC CHARACTERIZATION SUGGEST A SUBSTANTIAL GENETIC CONTRIBUTION TO CHRONIC BUT NOT ACUTE BACK PAIN FROM THE LOCI PREDOMINANTLY EXPRESSED IN THE CENTRAL NERVOUS SYSTEM. CONCLUSION: CHRONIC BACK PAIN IS SUBSTANTIALLY MORE HERITABLE THAN ACUTE BACK PAIN. THIS HERITABILITY IS MOSTLY ATTRIBUTED TO GENES EXPRESSED IN THE BRAIN. 2022 12 1541 23 DNA METHYLATION IN GENES OF LONGEVITY-REGULATING PATHWAYS: ASSOCIATION WITH OBESITY AND METABOLIC COMPLICATIONS. AGING IS THE MAIN RISK FACTOR FOR MOST CHRONIC DISEASES. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION (DNAM) PLAYS A PIVOTAL ROLE IN THE REGULATION OF PHYSIOLOGICAL RESPONSES THAT CAN VARY ALONG LIFESPAN. THE AIM OF THIS RESEARCH WAS TO ANALYZE THE ASSOCIATION BETWEEN LEUKOCYTE DNAM IN GENES INVOLVED IN LONGEVITY AND THE OCCURRENCE OF OBESITY AND RELATED METABOLIC ALTERATIONS IN AN ADULT POPULATION. SUBJECTS FROM THE MENA COHORT (N=474) WERE CATEGORIZED ACCORDING TO AGE (<45 VS 45>) AND THE PRESENCE OF METABOLIC ALTERATIONS: INCREASED WAIST CIRCUMFERENCE, HYPERCHOLESTEROLEMIA, INSULIN RESISTANCE, AND METABOLIC SYNDROME. THE METHYLATION LEVELS OF 58 CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE STRONGLY CORRELATED (FDR-ADJUSTED< 0.0001) WITH BMI. FIFTEEN OF THEM WERE DIFFERENTIALLY METHYLATED (P<0.05) BETWEEN YOUNGER AND OLDER SUBJECTS THAT EXHIBITED AT LEAST ONE METABOLIC ALTERATION. SIX OF THESE CPG SITES, LOCATED AT MTOR (CG08862778), ULK1 (CG07199894), ADCY6 (CG11658986), IGF1R (CG01284192), CREB5 (CG11301281), AND RELA (CG08128650), WERE COMMON TO THE METABOLIC TRAITS, AND CREB5, RELA, AND ULK1 WERE STATISTICALLY ASSOCIATED WITH AGE. IN SUMMARY, LEUKOCYTE DNAM LEVELS OF SEVERAL CPG SITES LOCATED AT GENES INVOLVED IN LONGEVITY-REGULATING PATHWAYS WERE ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME TRAITS, SUGGESTING A ROLE OF DNAM IN AGING-RELATED METABOLIC ALTERATIONS. 2019 13 3050 16 GENOME-WIDE ASSOCIATION ANALYSES FOR LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE IDENTIFY NEW LOCI AND POTENTIAL DRUGGABLE TARGETS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY REDUCED LUNG FUNCTION AND IS THE THIRD LEADING CAUSE OF DEATH GLOBALLY. THROUGH GENOME-WIDE ASSOCIATION DISCOVERY IN 48,943 INDIVIDUALS, SELECTED FROM EXTREMES OF THE LUNG FUNCTION DISTRIBUTION IN UK BIOBANK, AND FOLLOW-UP IN 95,375 INDIVIDUALS, WE INCREASED THE YIELD OF INDEPENDENT SIGNALS FOR LUNG FUNCTION FROM 54 TO 97. A GENETIC RISK SCORE WAS ASSOCIATED WITH COPD SUSCEPTIBILITY (ODDS RATIO PER 1 S.D. OF THE RISK SCORE ( APPROXIMATELY 6 ALLELES) (95% CONFIDENCE INTERVAL) = 1.24 (1.20-1.27), P = 5.05 X 10(-49)), AND WE OBSERVED A 3.7-FOLD DIFFERENCE IN COPD RISK BETWEEN INDIVIDUALS IN THE HIGHEST AND LOWEST GENETIC RISK SCORE DECILES IN UK BIOBANK. THE 97 SIGNALS SHOW ENRICHMENT IN GENES FOR DEVELOPMENT, ELASTIC FIBERS AND EPIGENETIC REGULATION PATHWAYS. WE HIGHLIGHT TARGETS FOR DRUGS AND COMPOUNDS IN DEVELOPMENT FOR COPD AND ASTHMA (GENES IN THE INOSITOL PHOSPHATE METABOLISM PATHWAY AND CHRM3) AND DESCRIBE TARGETS FOR POTENTIAL DRUG REPOSITIONING FROM OTHER CLINICAL INDICATIONS. 2017 14 815 24 CHANGES IN THE EXPRESSION OF INFLAMMATORY AND EPIGENETIC-MODULATORY GENES AFTER AN INTENSIVE MEDITATION RETREAT. BACKGROUND: MEDITATION RETREATS ARE CHARACTERIZED BY INTENSIVE OR CONCENTRATED PERIODS OF MEDITATION PRACTICE, COMMONLY UNDERTAKEN IN A RESIDENTIAL SETTING. ALTHOUGH RESEARCH INDICATES THAT MEDITATION TRAINING CAN POSITIVELY INFLUENCE PHYSICAL AND MENTAL HEALTH OUTCOMES, THE BIOLOGICAL CONSEQUENCES OF MEDITATION RETREAT INTERVENTIONS ARE RELATIVELY UNDERSTUDIED. IN THIS STUDY, WE EXAMINED THE INFLUENCE OF A MONTH-LONG, SILENT MEDITATION RETREAT ON THE EXPRESSION OF GENES INVOLVED IN EPIGENETIC MODULATION AND IMMUNE PROCESSES. METHOD: WE ASSESSED GENE EXPRESSION CHANGES IN EXPERIENCED MEDITATORS ATTENDING A MONTH-LONG INSIGHT MEDITATION RETREAT (N = 28), AS COMPARED TO A COMMUNITY CONTROL GROUP (N = 34) OF EXPERIENCED PRACTITIONERS LIVING THEIR EVERYDAY LIVES. BLOOD SAMPLES WERE COLLECTED ON DAY TWO OF THE RETREAT (TIME 1) AND AGAIN 3 WEEKS LATER (TIME 2). CONTROL PARTICIPANTS WERE ALSO ASSESSED ACROSS A 3-WEEK INTERVAL, DURING WHICH THEY MAINTAINED THEIR REGULAR DAILY ROUTINES. RESULTS: AS COMPARED TO CONTROLS, RETREAT PARTICIPANTS SHOWED DIFFERENTIAL CHANGES IN THE EXPRESSION OF SEVERAL GENES INVOLVED IN CHROMATIN MODULATION AND INFLAMMATION. THE MOST SUBSTANTIVE FINDING WAS DOWNREGULATION OF THE TNF PATHWAY IN RETREAT PARTICIPANTS, WHICH WAS NOT OBSERVED IN CONTROLS. CONCLUSIONS: THESE FINDINGS INDICATE THAT MEDITATION RETREAT PARTICIPATION MAY INFLUENCE SOME OF THE INFLAMMATORY MECHANISMS INVOLVED IN THE DEVELOPMENT OF CHRONIC DISEASES, AND THAT THIS STYLE OF PSYCHOSOCIAL INTERVENTION MAY HAVE THERAPEUTIC POTENTIAL, PARTICULARLY IN EXPERIENCED PRACTITIONERS. 2022 15 4736 20 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE. 2017 16 177 20 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS. 2022 17 5845 24 STUDY PROTOCOL FOR THE EPIGENETIC CHARACTERIZATION OF ANGOR PECTORIS ACCORDING TO THE AFFECTED CORONARY COMPARTMENT: GLOBAL AND COMPREHENSIVE ASSESSMENT OF THE RELATIONSHIP BETWEEN INVASIVE CORONARY PHYSIOLOGY AND MICRORNAS. BACKGROUND: MICRORNAS (MIRNAS) ARE NONCODING RNAS INVOLVED IN POST-TRANSCRIPTIONAL GENETIC REGULATION WITH A PROPOSED ROLE IN INTERCELLULAR COMMUNICATION. MIRNAS ARE CONSIDERED PROMISING BIOMARKERS IN ISCHEMIC HEART DISEASE. INVASIVE PHYSIOLOGICAL EVALUATION ALLOWS A PRECISE ASSESSMENT OF EACH AFFECTED CORONARY COMPARTMENT. ALTHOUGH SOME STUDIES HAVE ASSOCIATED THE EXPRESSION OF CIRCULATING MIRNAS WITH INVASIVE PHYSIOLOGICAL INDEXES, THEIR GLOBAL RELATIONSHIP WITH CORONARY COMPARTMENTS HAS NOT BEEN ASSESSED. HERE, WE WILL EVALUATE CIRCULATING MIRNAS PROFILES ACCORDING TO THE CORONARY PATTERN OF THE VASCULAR COMPARTMENT AFFECTATION. STUDY AND DESIGN: THIS IS AN INVESTIGATOR-INITIATED, MULTICENTRE, DESCRIPTIVE STUDY TO BE CONDUCTED AT THREE CENTRES IN SPAIN (NCT05374694). THE STUDY WILL INCLUDE ONE HUNDRED CONSECUTIVE PATIENTS OLDER THAN 18 YEARS WITH CHEST PAIN OF PRESUMED CORONARY CAUSE UNDERGOING INVASIVE PHYSIOLOGICAL EVALUATION, INCLUDING FRACTIONAL FLOW RESERVE (FFR) AND INDEX OF MICROVASCULAR RESISTANCE (IMR). PATIENTS WILL BE INITIALLY CLASSIFIED INTO FOUR GROUPS, ACCORDING TO FFR AND IMR: MACROVASCULAR AND MICROVASCULAR AFFECTATION (FFR/=25), ISOLATED MACROVASCULAR AFFECTATION (FFR0.80 / IMR >/=25) AND NORMAL CORONARY INDEXES (FFR>0.80 / IMR<25). PATIENTS WITH ISOLATED MICROVASCULAR AFFECTATION OR NORMAL INDEXES WILL ALSO UNDERGO THE ACETYLCHOLINE TEST AND MAY BE RECLASSIFIED AS A FIFTH GROUP IN THE PRESENCE OF SPASM. A PANEL OF MIRNAS PREVIOUSLY ASSOCIATED WITH MOLECULAR MECHANISMS LINKED TO CHRONIC CORONARY SYNDROME WILL BE ANALYSED USING RT-QPCR. CONCLUSIONS: THE RESULTS OF THIS STUDY WILL IDENTIFY MIRNA PROFILES ASSOCIATED WITH PATTERNS OF CORONARY AFFECTATION AND WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE MECHANISTIC PATHWAYS OF CORONARY PATHOLOGY. 2023 18 4279 24 MICRONUCLEI, INFLAMMATION AND AUTO-IMMUNE DISEASE. AUTO-IMMUNE DISEASES (AUD) ARE CHARACTERIZED BY AN IMMUNE RESPONSE TO ANTIGENIC COMPONENTS OF THE HOST ITSELF. THE ETIOLOGY OF AUD IS NOT WELL UNDERSTOOD. THE AVAILABLE EVIDENCE POINTS TO AN INTERACTION BETWEEN GENETIC, EPIGENETIC, ENVIRONMENTAL, INFECTIOUS AND LIFE-STYLE FACTORS. AUD ARE MORE PREVALENT IN WOMEN THAN IN MEN; SEX HORMONES PLAY A CRUCIAL ROLE IN THIS SEX BIAS. MICRONUCLEI (MN) EMERGED AS A NEW PLAYER IN THE INDUCTION OF AUD, BASED ON THE CAPACITY OF DNA-SENSORS TO DETECT SELF-DNA THAT LEAKS INTO THE CYTOPLASM FROM DISRUPTED MN AND INDUCE THE CGAS-STING PATHWAY TRIGGERING AN INNATE AUTO-IMMUNE RESPONSE AND CHRONIC INFLAMMATION. IT WAS FOUND THAT INFLAMMATION CAN INDUCE MN AND MN CAN INDUCE INFLAMMATION, LEADING TO A VICIOUS INFLAMMATION-OXIDATIVE-DNA DAMAGE-MN-FORMATION-CHROMOTHRIPSIS CYCLE. MN ORIGINATING FROM SEX CHROMOSOME-LOSS MAY INDUCE INFLAMMATION AND AUD. WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES REPORTING MN IN PATIENTS WITH SYSTEMIC OR ORGAN-SPECIFIC AUD. A META-ANALYSIS WAS PERFORMED ON LYMPHOCYTE MN IN DIABETES MELLITUS (10 STUDIES, 457 PATIENTS/290 CONTROLS) AND BEHCET'S DISEASE (3 STUDIES, 100 PATIENTS/70 CONTROLS) AND FOR BUCCAL MN IN DIABETES MELLITUS (11 STUDIES, 507 PATIENTS/427 CONTROLS). A STATISTICALLY SIGNIFICANT INCREASE IN PATIENTS COMPARED TO CONTROLS WAS FOUND IN THE META-ANALYSES PROVIDING AN INDICATION OF AN ASSOCIATION BETWEEN MN AND AUD. A 36%-HIGHER MEAN-MRI IN BUCCAL CELLS (3.8+/-0.7) WAS FOUND COMPARED TO LYMPHOCYTES (2.8+/-0.7)(P = 0.01). THE META-MRI IN LYMPHOCYTES AND BUCCAL CELLS (1.7 AND 3.0 RESPECTIVELY) SUGGEST THAT BUCCAL CELLS MAY BE MORE SENSITIVE. TO ASSESS THEIR RELATIVE SENSITIVITY, STUDIES WITH MEASUREMENTS FROM THE SAME SUBJECTS WOULD BE DESIRABLE. IT IS IMPORTANT THAT FUTURE STUDIES (I) INVESTIGATE, IN WELL-DESIGNED POWERED STUDIES, THE PROSPECTIVE ASSOCIATION OF MN-FORMATION WITH AUD AND (II) EXPLORE THE MOLECULAR MECHANISMS BY WHICH CHROMOSOME SHATTERING IN MN AND THE RELEASE OF CHROMATIN FRAGMENTS FROM MN LEAD TO THE FORMATION OF AUTO-ANTIBODIES. 2020 19 6358 24 THE ROLE OF IL?16 GENE POLYMORPHISMS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS ONE OF THE MOST COMMON GYNECOLOGICAL DISEASES AFFECTING UP TO 10% OF THE FEMALE POPULATION OF CHILDBEARING AGE AND A MAJOR CAUSE OF PAIN AND INFERTILITY. IT IS INFLUENCED BY MULTIPLE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. INTERLEUKIN?16 (IL?16) IS A PROINFLAMMATORY CYTOKINE PLAYING A PIVOTAL ROLE IN MANY INFLAMMATORY AND AUTOIMMUNE DISEASES AS WELL AS IN THE PATHOGENESIS OF ENDOMETRIOSIS. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE ASSOCIATION OF TWO IL?16 GENE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), RS4072111 AND RS11556218, WITH THE RISK OF ENDOMETRIOSIS IN WOMEN FROM GREECE AS WELL AS TO GAIN INSIGHT ABOUT THE STRUCTURAL CONSEQUENCES OF THESE TWO EXONIC SNPS REGARDING DEVELOPMENT OF THE DISEASE. A TOTAL OF 159 WOMEN WITH ENDOMETRIOSIS (STAGES I?IV) HOSPITALIZED FOR ENDOMETRIOSIS, DIAGNOSED BY LAPAROSCOPIC INTERVENTION AND HISTOLOGICALLY CONFIRMED, AND 146 NORMAL CONTROLS WERE RECRUITED AND GENOTYPED. SUBJECTS WERE GENOTYPED USING A POLYMERASE CHAIN REACTION RESTRICTION FRAGMENT LENGTH POLYMORPHISM (PCR?RFLP) STRATEGY. A SIGNIFICANT ASSOCIATION WAS DETECTED REGARDING THE GG AND GT GENOTYPE AS WELL AS 'G' ALLELE OF RS11556218 IN PATIENTS WITH ENDOMETRIOSIS. THE RS4072111 SNP OF THE IL?16 GENE WAS NOT FOUND TO BE ASSOCIATED WITH AN INCREASED SUSCEPTIBILITY TO ENDOMETRIOSIS EITHER FOR ALL PATIENTS (STAGES I?IV) OR FOR STAGE III AND IV OF THE DISEASE ONLY. OUR RESULTS DEMONSTRATED THAT RS11556218 IS ASSOCIATED WITH ENDOMETRIOSIS IN GREEK WOMEN, PROBABLY BY RESULTING IN THE ABERRANT EXPRESSION OF IL?16, AS SUGGESTED BY THE BIOINFORMATICS ANALYSIS CONDUCTED ON THE SNP?DERIVED PROTEIN SEQUENCES, WHICH INDICATED A POSSIBLE ASSOCIATION BETWEEN MUTATION AND FUNCTIONAL MODIFICATION OF PRO?IL?16. 2018 20 5092 25 PLACENTAL EPIGENETIC MARKS RELATED TO GESTATIONAL WEIGHT GAIN REVEAL POTENTIAL GENES ASSOCIATED WITH OFFSPRING OBESITY PARAMETERS. OBJECTIVE: OFFSPRING EXPOSED TO GESTATIONAL OBESITY HAVE AN INCREASED RISK FOR CHRONIC DISEASES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETICS MAY PLAY A MECHANISTIC ROLE IN METABOLIC PROGRAMMING. THIS STUDY AIMED TO IDENTIFY PLACENTAL DNA METHYLATION MARKS ASSOCIATED WITH GESTATIONAL WEIGHT GAIN (GWG) AND TO STUDY THEIR ASSOCIATION WITH OFFSPRING OBESITY PARAMETERS AT SCHOOL AGE. METHODS: A GLOBAL METHYLATION ARRAY WAS PERFORMED IN 24 PLACENTAS FROM MOTHERS WITH DIFFERENT DEGREES OF GWG (SCREENING SAMPLE). THE METHYLATION PERCENTAGE OF FOUR CYTOSINE-GUANINE (CPG) SITES AND THE RELATIVE EXPRESSION OF THE RESPECTIVE ANNOTATED GENES WERE STUDIED IN 90 ADDITIONAL PLACENTAS (VALIDATION SAMPLE). ASSOCIATIONS OF THESE EPIGENETIC MARKS WITH CLINICAL PARAMETERS IN THE OFFSPRING AT 6 YEARS OF AGE WERE EXAMINED. RESULTS: THE SCREENING ANALYSIS IDENTIFIED 104 CPG SITES (97 GENES) ASSOCIATED WITH GWG. THE VALIDATION ANALYSIS OF FOUR SELECTED CPG SITES (ANNOTATING FOR FRAT1, SNX5, AND KCNK3 GENES) SHOWED THAT THE UPREGULATION OF SNX5 METHYLATION, THE DOWNREGULATION OF FRAT1 METHYLATION, AND KCNK3 UNDEREXPRESSION ASSOCIATED WITH AN ADVERSE METABOLIC PHENOTYPE IN CHILDREN OF WOMEN WITH INCREASED GWG. CONCLUSIONS: THESE RESULTS SUGGEST THAT PLACENTAL REGULATION OF FRAT1, SNX5, AND KCNK3 RELATES TO OBESITY PARAMETERS IN OFFSPRING EXPOSED TO EXCESSIVE GWG AND THEREBY COULD CONDITION THE RISK FOR FUTURE METABOLIC DISORDERS. 2023