1 1963 133 EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN PAIN IMPACT AND BRAIN AGING IN MIDDLE TO OLDER AGE INDIVIDUALS WITH KNEE PAIN. CHRONIC MUSCULOSKELETAL PAIN IS A HEALTH BURDEN THAT MAY ACCELERATE THE AGING PROCESS. ACCELERATED BRAIN AGING AND EPIGENETIC AGING HAVE SEPARATELY BEEN OBSERVED IN THOSE WITH CHRONIC PAIN. HOWEVER, IT IS UNKNOWN WHETHER THESE BIOLOGICAL MARKERS OF AGING ARE ASSOCIATED WITH EACH OTHER IN THOSE WITH CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND BRAIN AGING IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS (57.91 +/- 8.04 Y) 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 AN MRI SCAN. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AND BRAIN AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD, RESPECTIVELY). THERE WAS A SIGNIFICANT MAIN EFFECT FOR PAIN IMPACT GROUP (F (2,167) = 3.847, P = 0.023, ROTATIONAL ENERGY = 1 / 2IOMEGA2 = 0.038, ANCOVA) ON BRAIN-PAD AND DNAMGRIMAGE-DIFFERENCE (F (2,167) = 6.800, P = 0.001, I = MK2 = 0.075, ANCOVA) AFTER CONTROLLING FOR COVARIATES. DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD WERE MODESTLY CORRELATED (R =0.198; P =0.010). EXPLORATORY ANALYSIS REVEALED THAT DNAMGRIMAGE-DIFFERENCE MEDIATED GCPS PAIN IMPACT, GCPS PAIN SEVERITY, AND PAIN-RELATED DISABILITY SCORES ON BRAIN-PAD. BASED UPON THE CURRENT STUDY FINDINGS, WE SUGGEST THAT PAIN COULD BE A DRIVER FOR ACCELERATED BRAIN AGING VIA EPIGENOME INTERACTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2 4912  54 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3 1964  60 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  181  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5 3162  42 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 1782  40 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 OR >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	

7 1645  47 DOES THE EPIGENETIC CLOCK GRIMAGE PREDICT MORTALITY INDEPENDENT OF GENETIC INFLUENCES: AN 18 YEAR FOLLOW-UP STUDY IN OLDER FEMALE TWIN PAIRS. BACKGROUND: EPIGENETIC CLOCKS ARE BASED ON DNA METHYLATION (DNAM). IT HAS BEEN SUGGESTED THAT THESE CLOCKS ARE USEABLE MARKERS OF BIOLOGICAL AGING AND PREMATURE MORTALITY. BECAUSE GENETIC FACTORS EXPLAIN VARIATIONS IN BOTH EPIGENETIC AGING AND MORTALITY, THIS ASSOCIATION COULD ALSO BE EXPLAINED BY SHARED GENETIC FACTORS. WE INVESTIGATED THE INFLUENCE OF GENETIC AND LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, CHRONIC DISEASES, BODY MASS INDEX) AND EDUCATION ON THE ASSOCIATION OF ACCELERATED EPIGENETIC AGING WITH MORTALITY USING A LONGITUDINAL TWIN DESIGN. UTILIZING A PUBLICLY AVAILABLE ONLINE TOOL, WE CALCULATED THE EPIGENETIC AGE USING TWO EPIGENETIC CLOCKS, HORVATH DNAMAGE AND DNAM GRIMAGE, IN 413 FINNISH TWIN SISTERS, AGED 63-76 YEARS, AT THE BEGINNING OF THE 18-YEAR MORTALITY FOLLOW-UP. EPIGENETIC AGE ACCELERATION WAS CALCULATED AS THE RESIDUALS FROM A LINEAR REGRESSION MODEL OF EPIGENETIC AGE ESTIMATED ON CHRONOLOGICAL AGE (AA(HORVATH), AA(GRIMAGE), RESPECTIVELY). COX PROPORTIONAL HAZARD MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS. RESULTS: THE RESULTS OF THE INDIVIDUAL-BASED ANALYSES SHOWED AN INCREASED MORTALITY HAZARD RATIO (HR) OF 1.31 (CI(95): 1.13-1.53) PER ONE STANDARD DEVIATION (SD) INCREASE IN AA(GRIMAGE). THE RESULTS INDICATED NO SIGNIFICANT ASSOCIATIONS OF AA(HORVATH) WITH MORTALITY. PAIRWISE MORTALITY ANALYSES SHOWED AN HR OF 1.50 (CI(95): 1.02-2.20) PER 1 SD INCREASE IN AA(GRIMAGE). HOWEVER, AFTER ADJUSTING FOR SMOKING, THE HR ATTENUATED SUBSTANTIALLY AND WAS STATISTICALLY NON-SIGNIFICANT (1.29; CI(95): 0.84-1.99). SIMILARLY, IN MULTIVARIABLE ADJUSTED MODELS THE HR (1.42-1.49) WAS NON-SIGNIFICANT. IN AA(HORVATH), THE NON-SIGNIFICANT HRS WERE LOWER AMONG MONOZYGOTIC PAIRS IN COMPARISON TO DIZYGOTIC PAIRS, WHILE IN AA(GRIMAGE) THERE WERE NO SYSTEMATIC DIFFERENCES BY ZYGOSITY. FURTHER, THE PAIRWISE ANALYSIS IN QUARTILES SHOWED THAT THE INCREASED WITHIN PAIR DIFFERENCE IN AA(GRIMAGE) WAS ASSOCIATED WITH A HIGHER ALL-CAUSE MORTALITY RISK. CONCLUSIONS: IN CONCLUSION, THE FINDINGS SUGGEST THAT DNAM GRIMAGE IS A STRONG PREDICTOR OF MORTALITY INDEPENDENT OF GENETIC INFLUENCES. SMOKING, WHICH IS KNOWN TO ALTER DNAM LEVELS AND IS BUILT INTO THE DNAM GRIMAGE ALGORITHM, ATTENUATED THE ASSOCIATION BETWEEN EPIGENETIC AGING AND MORTALITY RISK.	2021	
                                                                                                                                                                                                                                                                                                                          
8 1962  48 EPIGENETIC AGING IS ASSOCIATED WITH CLINICAL AND EXPERIMENTAL PAIN IN COMMUNITY-DWELLING OLDER ADULTS. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, WHICH HAS MOTIVATED RESEARCH EFFORTS TO IDENTIFY "AGING BIOMARKERS." AGING BIOMARKERS ARE USED TO CALCULATE BIOLOGICAL AGE, WHICH ARE BETTER PREDICTORS OF DISEASE RISK AND RESIDUAL LIFESPAN WHEN COMPARED TO CHRONOLOGICAL AGE ALONE. EMERGING EVIDENCE USING THE EPIGENETIC CLOCK AS AN AGING BIOMARKER SUPPORTS HIGHLY RELIABLE INDIVIDUALIZED PREDICTIONS ABOUT FUTURE HEALTH. THIS STUDY AIMED TO DETERMINE WHETHER AN EPIGENETIC AGING BIOMARKER WAS ASSOCIATED WITH CHRONIC PAIN IN OLDER ADULTS (60-83 YEARS OLD). A SUBSET OF PARTICIPANTS (N = 29) IN THE NEUROMODULATORY EXAMINATION OF PAIN AND MOBILITY ACROSS THE LIFESPAN STUDY UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOLOGICAL, COGNITIVE, AND PAIN ASSESSMENTS. WE ESTIMATED HORVATH'S EPIGENETIC CLOCK AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE THAT HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK. OLDER INDIVIDUALS WITHOUT CHRONIC PAIN (N = 9) HAD SIGNIFICANTLY "YOUNGER" EPIGENETIC AGE COMPARED TO THOSE WITH CHRONIC PAIN (N = 20, P < 0.05). OLDER EPIGENETIC AGE WAS ASSOCIATED WITH GREATER PAIN DURING DAILY ACTIVITIES (R = 0.494, P = 0.010) AND ANATOMICAL PAIN SITES (R = 0.741, P < 0.001) BUT NOT PAIN FREQUENCY/DURATION. AN OLDER EPIGENETIC AGE WAS ALSO ASSOCIATED WITH HIGHER VIBRATORY DETECTION THRESHOLDS (R = 0.490, P = 0.021), HEAT PAIN THRESHOLDS (R = -0.478, P = 0.028), AND PRESSURE PAIN THRESHOLDS AT THE TRAPEZIUS (R = -0.571, P = 0.006) BUT NOT THERMAL DETECTION, PRESSURE PAIN AT THE QUADRICEPS OR PAIN INHIBITION (P'S > 0.05). EPIGENETIC AGING WAS ASSOCIATED WITH GREATER EMOTIONAL STABILITY (R = -0.461, P = 0.027), CONSCIENTIOUSNESS (R = -0.549, P = 0.007), AND LOWER EXTRAVERSION (R = 0.414, P = 0.049) BUT NOT DEPRESSION OR AFFECT (P'S > 0.05). EPIGENETIC AGING WAS ALSO ASSOCIATED WITH LOWER EPISODIC (R = -0.698, P = 0.001) AND WORKING MEMORY (R = -0.760, P < 0.001). OUR FINDINGS SUGGEST THAT CHRONIC PAIN IS ASSOCIATED WITH ACCELERATED EPIGENETIC AGING IN HEALTHY, COMMUNITY-DWELLING OLDER INDIVIDUALS, AND FUTURE STUDIES WITH LARGER SAMPLES ARE NEEDED TO CONFIRM OUR FINDINGS. AN AGING BIOMARKER SUCH AS THE EPIGENETIC CLOCK MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2019	
                                                                                                                                                                                                                                                                                                                                
9 5757  54 SOCIOECONOMIC STATUS, KNEE PAIN, AND EPIGENETIC AGING IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. CHRONIC MUSCULOSKELETAL PAIN IS OFTEN ASSOCIATED WITH LOWER SOCIOECONOMIC STATUS (SES). SES CORRELATES WITH PSYCHOLOGICAL AND ENVIRONMENTAL CONDITIONS THAT COULD CONTRIBUTE TO THE DISPROPORTIONATE BURDEN OF CHRONIC STRESS. CHRONIC STRESS CAN INDUCE CHANGES IN GLOBAL DNA METHYLATION AND GENE EXPRESSION, WHICH INCREASES RISK OF CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND SES IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW, AND ANSWERED DEMOGRAPHIC QUESTIONS PERTAINING TO SES. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE) AND THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AGE (DNAMGRIMAGE-DIFF). OVERALL, THE MEAN DNAMGRIMAGE WAS 60.3 (+/-7.6), AND THE AVERAGE DNAMGRIMAGE-DIFF WAS 2.4 YEARS (+/-5.6 YEARS). THOSE EXPERIENCING HIGH-IMPACT PAIN EARNED LESS INCOME AND HAD LOWER EDUCATION LEVELS COMPARED TO BOTH LOW-IMPACT AND NO PAIN GROUPS. DIFFERENCES IN DNAMGRIMAGE-DIFF ACROSS PAIN GROUPS WERE FOUND, WHEREBY INDIVIDUALS WITH HIGH-IMPACT PAIN HAD ACCELERATED EPIGENETIC AGING ( APPROXIMATELY 5 YEARS) COMPARED TO LOW-IMPACT PAIN AND NO PAIN CONTROL GROUPS (BOTH APPROXIMATELY 1 YEAR). OUR MAIN FINDING WAS THAT EPIGENETIC AGING MEDIATED THE ASSOCIATIONS OF INCOME AND EDUCATION WITH PAIN IMPACT, AS SUCH THE RELATIONSHIP BETWEEN SES AND PAIN OUTCOMES MAY OCCUR THROUGH POTENTIAL INTERACTIONS WITH THE EPIGENOME REFLECTIVE OF ACCELERATED CELLULAR AGING. PERSPECTIVE: SOCIOECONOMIC STATUS (SES) HAS PREVIOUSLY BEEN IMPLICATED IN THE PAIN EXPERIENCE. THE PRESENT MANUSCRIPT AIMS TO PRESENT A POTENTIAL SOCIAL-BIOLOGICAL LINK BETWEEN SES AND PAIN VIA ACCELERATED EPIGENETIC AGING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 6156  27 THE GENETIC INFLUENCE ON THE CORTICAL PROCESSING OF EXPERIMENTAL PAIN AND THE MODERATING EFFECT OF PAIN STATUS. BACKGROUND: RESEARCH SUGGESTS THAT THE COMT VAL(158)MET, BDNF VAL(66)MET AND OPRM1 A(118)G POLYMORPHISMS MODERATE THE EXPERIENCE OF PAIN. IN ORDER TO OBTAIN EXPERIMENTAL CONFIRMATION AND EXTENSION OF FINDINGS, CORTICAL PROCESSING OF EXPERIMENTALLY-INDUCED PAIN WAS USED. METHOD: A SAMPLE OF 78 INDIVIDUALS WITH CHRONIC LOW BACK PAIN COMPLAINTS AND 37 HEALTHY CONTROLS UNDERWENT EEG REGISTRATION. EVENT-RELATED POTENTIALS WERE MEASURED IN RESPONSE TO ELECTRICAL NOCICEPTIVE STIMULI AND MODERATION BY COMT VAL(158)MET, BDNF VAL(66)MET AND OPRM1 A(118)G POLYMORPHISMS WAS ASSESSED. RESULTS: GENETIC VARIATION DID NOT HAVE A DIRECT EFFECT ON CORTICAL PROCESSING OF EXPERIMENTAL PAIN. HOWEVER, GENETIC EFFECTS (COMT VAL(158)MET AND BDNF VAL(66)MET) ON EXPERIMENTAL PAIN WERE MODERATED BY THE PRESENCE OF CHRONIC PAIN. IN THE PRESENCE OF CHRONIC PAIN, THE COMT MET ALLELE AND THE BDNF MET ALLELE AUGMENTED CORTICAL PAIN PROCESSING, WHILST REDUCING PAIN PROCESSING IN PAIN-FREE CONTROLS. NO SIGNIFICANT EFFECTS WERE FOUND CONCERNING THE OPRM1 A(118)G POLYMORPHISM. CONCLUSIONS: THE CURRENT STUDY SUGGESTS THAT CHRONIC EXPERIENCE OF PAIN ENHANCES GENETIC SENSITIVITY TO EXPERIMENTALLY INDUCED MILDLY PAINFUL STIMULI, POSSIBLY THROUGH A PROCESS OF EPIGENETIC MODIFICATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11 3687  39 INFLAMMATION-RELATED GENES ARE ASSOCIATED WITH EPIGENETIC AGING IN HIV. CHRONIC INFLAMMATION IS CHARACTERISTIC OF BOTH HIV AND AGING ("INFLAMMAGING") AND MAY CONTRIBUTE TO THE ACCELERATED AGING OBSERVED IN PEOPLE LIVING WITH HIV (PLWH). WE EXAMINED WHETHER THREE INFLAMMATION-RELATED SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS) WERE RISK FACTORS FOR ACCELERATED AGING AND HIV-ASSOCIATED, NON-AIDS (HANA) CONDITIONS AMONG PLWH. WE EXAMINED 155 POSTMORTEM CASES WITH HIV (MEAN AGE = 47.3, 81% MALE, 68% SELF-REPORTED WHITE) FROM THE NATIONAL NEUROAIDS TISSUE CONSORTIUM WHO HAD PRE-MORTEM NEUROBEHAVIORAL/MEDICAL/VIROLOGIC DATA AND EPIGENOMIC DATA FROM OCCIPITAL CORTEX TISSUE. ACCELERATED AGING WAS MEASURED ACCORDING TO THE EPIGENETIC CLOCK; AN AGING BIOMARKER BASED ON DNA METHYLATION LEVELS. PAST OR CURRENT AGE-ASSOCIATED HANA CONDITIONS INCLUDING CEREBROVASCULAR, LIVER AND KIDNEY DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CANCER, AND DIABETES WERE DETERMINED VIA SELF-REPORT. EPIGENETIC AGING Z-SCORES AND LIKELIHOOD OF PAST/CURRENT HANA CONDITIONS WERE COMPARED BETWEEN MAJOR ALLELE HOMOZYGOTES AND MINOR ALLELE CARRIERS FOR EACH SNP (IL-6 - 174G>C, IL-10 - 592C>A, TNF-ALPHA - 308 G>A) SEPARATELY. ANALYSES WERE ADJUSTED FOR RELEVANT DEMOGRAPHIC/CLINICAL FACTORS. EPIGENETIC AGING (E.G., HIGHER Z-SCORES) WAS SIGNIFICANTLY GREATER IN IL-6 C ALLELE CARRIERS (P = .002) AND IL-10 CC HOMOZYGOTES (P = .02) COMPARED TO OTHER GENOTYPE GROUPS. THE LIKELIHOOD OF ANY PAST/CURRENT HANA CONDITION DID NOT DIFFER BY IL-10 GENOTYPE BUT WAS 3.36 TIMES GREATER IN IL-6 C ALLELE CARRIERS VERSUS OTHERS (OR = 3.36, 95%CI = 1.09-10.34, P = .03). TNF-ALPHA GENOTYPE WAS NOT ASSOCIATED WITH EPIGENETIC AGING OR HANA CONDITIONS. IL-6 AND IL-10 SNPS MAY HELP TO IDENTIFY PLWH WHO ARE AT HIGH RISK FOR ACCELERATED AGING. THESE INSIGHTS INTO PATHOPHYSIOLOGICAL PATHWAYS MAY INFORM INTERVENTIONAL APPROACHES TO TREAT RAPID AGING AMONG PLWH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 5070  34 PHYSICAL ACTIVITY, TELEVISION VIEWING TIME, AND DNA METHYLATION IN PERIPHERAL BLOOD. INTRODUCTION: PHYSICAL ACTIVITY MAY AFFECT HEALTH VIA DNA METHYLATION. THE EPIGENETIC INFLUENCES OF SEDENTARY BEHAVIORS SUCH AS TELEVISION VIEWING ARE UNKNOWN. WE PERFORMED A GENOMEWIDE STUDY OF DNA METHYLATION IN PERIPHERAL BLOOD IN RELATION TO PHYSICAL ACTIVITY AND TELEVISION VIEWING TIME. METHODS: DNA METHYLATION WAS MEASURED USING THE ILLUMINA INFINIUM HUMANMETHYLATION450K BEADCHIP ARRAY IN BLOOD SAMPLES COLLECTED AT BASELINE (N = 5513) AND FOLLOW-UP (N = 1249) FROM PARTICIPANTS IN THE MELBOURNE COLLABORATIVE COHORT STUDY. AT BASELINE, TIMES PER WEEK OF LEISURE-TIME PHYSICAL ACTIVITY WERE SELF-REPORTED. AT FOLLOW-UP, THE INTERNATIONAL PHYSICAL ACTIVITY QUESTIONNAIRE WAS USED TO ASSESS MET-HOURS PER WEEK OF TOTAL AND LEISURE-TIME PHYSICAL ACTIVITY AND HOURS PER DAY OF TELEVISION VIEWING TIME. LINEAR MIXED MODELS WERE USED TO ASSESS ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY AND TELEVISION VIEWING MEASURES AND DNA METHYLATION AT INDIVIDUAL CPG SITES, ADJUSTED FOR POTENTIAL CONFOUNDERS AND BATCH EFFECTS. RESULTS: AT FOLLOW-UP, TOTAL PHYSICAL ACTIVITY WAS ASSOCIATED WITH DNA METHYLATION AT CG10266336 (P = 6.0 X 10), ANNOTATED TO THE SAA2 GENE. WEAKER EVIDENCE OF ASSOCIATIONS (P < 1.0 X 10) WERE OBSERVED FOR AN ADDITIONAL 14 CPG SITES WITH TOTAL PHYSICAL ACTIVITY, FOR 7 CPG SITES WITH LEISURE-TIME PHYSICAL ACTIVITY, AND FOR 9 CPG SITES WITH TELEVISION VIEWING TIME. CHANGES IN LEISURE-TIME PHYSICAL ACTIVITY BETWEEN BASELINE AND FOLLOW-UP WERE ASSOCIATED WITH METHYLATION CHANGES (P < 0.05) AT FOUR OF THE SEVEN CPG SITES WITH WEAKER EVIDENCE OF CROSS-SECTIONAL ASSOCIATIONS WITH LEISURE-TIME PHYSICAL ACTIVITY. CONCLUSION: PHYSICAL ACTIVITY AND TELEVISION VIEWING MAY BE ASSOCIATED WITH BLOOD DNA METHYLATION, A POTENTIAL PATHWAY TO CHRONIC DISEASE DEVELOPMENT. FURTHER RESEARCH USING ACCELEROMETER DATA AND LARGER SAMPLE SIZES IS WARRANTED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13 1541  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 1529  31 DNA METHYLATION CHANGES IN WHOLE BLOOD AND CD16+ NEUTROPHILS IN RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IN WOMEN OF CHILDBEARING AGE. FOLATE, A WATER-SOLUBLE VITAMIN, IS A KEY SOURCE OF ONE-CARBON GROUPS FOR DNA METHYLATION, BUT STUDIES OF THE DNA METHYLATION RESPONSE TO SUPPLEMENTAL FOLIC ACID YIELD INCONSISTENT RESULTS. THESE STUDIES ARE COMMONLY CONDUCTED USING WHOLE BLOOD, WHICH CONTAINS A MIXED POPULATION OF WHITE BLOOD CELLS THAT HAVE BEEN SHOWN TO CONFOUND RESULTS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE IF CD16+ NEUTROPHILS MAY PROVIDE MORE SPECIFIC DATA THAN WHOLE BLOOD FOR IDENTIFYING DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION. THE STUDY WAS PERFORMED IN NORMAL WEIGHT (BMI 18.5 - 24.9 KG/M2) WOMEN (18 - 35 Y; N = 12), WITH BLOOD SAMPLES TAKEN BEFORE AND AFTER 8 WEEKS OF FOLIC ACID SUPPLEMENTATION AT 800 MUG/DAY. DNA METHYLATION PATTERNS FROM WHOLE BLOOD AND ISOLATED CD16+ NEUTROPHILS WERE MEASURED ACROSS >485,000 CPG SITES THROUGHOUT THE GENOME USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP. OVER THE COURSE OF THE 8-WEEK SUPPLEMENTATION, 6746 AND 7513 CPG SITES CHANGED (P < 0.05) IN WHOLE BLOOD AND CD16+ NEUTROPHILS, RESPECTIVELY. DNA METHYLATION DECREASED IN 68.4% (WHOLE BLOOD) AND 71.8% (CD16+ NEUTROPHILS) OF THESE SITES. THERE WERE ONLY 182 CPG SITES THAT CHANGED IN BOTH THE WHOLE BLOOD AND CD16+ NEUTROPHILS, 139 OF WHICH CHANGED IN THE SAME DIRECTION. THESE RESULTS SUGGEST THAT THE GENOME-WIDE DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IS DIFFERENT BETWEEN WHOLE BLOOD AND CD16+ NEUTROPHILS AND THAT A SINGLE WHITE BLOOD CELL TYPE MAY FUNCTION AS A MORE SPECIFIC EPIGENETIC REPORTER OF FOLATE STATUS THAN WHOLE BLOOD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15 2967  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  686  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
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	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18 2978  33 GENETIC ASSOCIATION AND EXPRESSION ANALYSES OF THE PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE (PIP5K1C) GENE IN ALCOHOL USE DISORDER-RELEVANCE FOR PAIN SIGNALING AND ALCOHOL USE. BACKGROUND: THE GENE ENCODING PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE (PIP5K1C) HAS BEEN RECENTLY IMPLICATED IN PAIN REGULATION. INTERESTINGLY, A RECENT CROSS-TISSUE AND CROSS-PHENOTYPIC EPIGENETIC ANALYSIS IDENTIFIED THE SAME GENE IN ALCOHOL USE DISORDER (AUD). GIVEN THE HIGH COMORBIDITY BETWEEN AUD AND CHRONIC PAIN, WE HYPOTHESIZED THAT GENETIC VARIATION IN PIP5K1C MIGHT CONTRIBUTE TO SUSCEPTIBILITY TO AUD. METHODS: WE CONDUCTED A CASE-CONTROL ASSOCIATION STUDY OF GENETIC VARIANTS IN PIP5K1C. ASSOCIATION ANALYSES OF 16 COMMON PIP5K1C SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WERE CONDUCTED IN CASES AND CONTROLS OF AFRICAN (427 CASES AND 137 CONTROLS) AND EUROPEAN ANCESTRY (488 CASES AND 324 CONTROLS) USING STANDARD METHODS. IN ADDITION, GIVEN THE PROMINENT ROLE OF THE OPIOID SYSTEM IN PAIN SIGNALING, WE INVESTIGATED THE EFFECTS OF ACUTE ALCOHOL EXPOSURE ON PIP5K1C EXPRESSION IN HUMANIZED TRANSGENIC MICE FOR THE MU-OPIOID RECEPTOR THAT INCLUDED THE OPRM1 A118G POLYMORPHISM, A WIDELY USED MOUSE MODEL TO STUDY ANALGESIC RESPONSE TO OPIOIDS IN PAIN. PIP5K1C EXPRESSION WAS MEASURED IN THE THALAMUS AND BASOLATERAL AMYGDALA (BLA) IN MICE AFTER SHORT-TERM ADMINISTRATION (SINGLE 2 G/KG DOSE) OF ALCOHOL OR SALINE USING IMMUNOHISTOCHEMISTRY AND ANALYZED BY 2-WAY ANALYSIS OF VARIANCE. RESULTS: IN THE CASE-CONTROL ASSOCIATION STUDY USING AN NIAAA DISCOVERY SAMPLE, 8 SNPS IN PIP5K1C WERE SIGNIFICANTLY ASSOCIATED WITH AUD IN THE AFRICAN ANCESTRY (AA) GROUP (P < 0.05 AFTER CORRECTION; RS4807493, RS10405681, RS2074957, RS10432303, RS8109485, RS1476592, RS10419980, AND RS4432372). HOWEVER, A REPLICATION ANALYSIS USING AN INDEPENDENT SAMPLE (N = 3,801) FOUND NO SIGNIFICANT ASSOCIATIONS AFTER CORRECTION FOR MULTIPLE TESTING. IN THE HUMANIZED TRANSGENIC MOUSE MODEL WITH THE OPRM1 POLYMORPHISM, PIP5K1C EXPRESSION WAS SIGNIFICANTLY DIFFERENT BETWEEN ALCOHOL AND SALINE-TREATED MICE, REGARDLESS OF GENOTYPE, IN BOTH THE THALAMUS (P < 0.05) AND BLA (P < 0.01). CONCLUSIONS: OUR DISCOVERY SAMPLE SHOWS THAT GENETIC VARIANTS IN PIP5K1C ARE ASSOCIATED WITH AUD IN THE AA GROUP, AND ACUTE ALCOHOL EXPOSURE LEADS TO UP-REGULATION OF PIP5K1C, POTENTIALLY EXPLAINING A MECHANISM UNDERLYING THE INCREASED RISK FOR CHRONIC PAIN CONDITIONS IN INDIVIDUALS WITH AUD.	2018	
                                                                                                                                                                                                                                                                                                                                            
19 3050  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20 4986  29 PATIENT-REPORTED SYMPTOM OUTCOMES AND MICROSATELLITE INSTABILITY IN PATIENTS WITH METASTATIC COLORECTAL CANCER. BACKGROUND: THE SURVIVAL OF PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IS INFLUENCED BY THE GENETIC AND EPIGENETIC CHANGES THAT MIGHT INFLUENCE THE PATIENT EXPERIENCE OF SYMPTOM BURDEN. UNDERSTANDING THE ASSOCIATION OF MOLECULAR CHANGES WITH THE SYMPTOM BURDEN COULD HELP CLINICIANS GAIN INSIGHT INTO THE MOLECULAR BASIS OF SYMPTOM BURDEN AND IMPROVE TREATMENT TOLERANCE. TO DATE, NO STUDIES HAVE COMPARED THE PATIENT-REPORTED SYMPTOM BURDEN WITH THESE MOLECULAR SUBSETS AMONG PATIENTS WITH MCRC. PATIENTS AND METHODS: WE RECRUITED PATIENTS WITH MCRC THAT WAS REFRACTORY TO >/= 1 LINE OF THERAPY WHO HAD BEEN ENROLLED IN THE ASSESSMENT OF TARGETED THERAPIES AGAINST COLORECTAL CANCER TRIAL AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. ALL PATIENTS COMPLETED A BASELINE GASTROINTESTINAL SYMPTOM INVENTORY (MD ANDERSON SYMPTOM INVENTORY, GASTROINTESTINAL). THE SYMPTOM BURDEN ACROSS KEY DEMOGRAPHIC VARIABLES AND MOLECULAR CHANGES, INCLUDING CRC-ASSOCIATED MUTATIONS, MICROSATELLITE INSTABILITY (MSI) STATUS, AND THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WERE COMPARED USING CHI(2) TESTS. ASSOCIATION OF THE SYMPTOM BURDEN WITH OVERALL SURVIVAL WAS EXAMINED USING COX REGRESSION MODELS. RESULTS: PATIENTS WITH AN MSI-HIGH (MSI-H) PHENOTYPE REPORTED GREATER PAIN (ODDS RATIO [OR], 3.06; 95% CONFIDENCE INTERVAL [CI], 1.61-5.84), FATIGUE (OR, 2.78; 95% CI, 1.41-5.49), SLEEP (OR, 2.52; 95% CI, 1.32-4.08); AND DROWSINESS (OR, 2.51; 95% CI, 1.32-4.78) COMPARED WITH MICROSATELLITE STABLE PATIENTS. PATIENTS WITH AN MSI-H PHENOTYPE ALSO HAD GREATER ODDS OF OVERALL SYMPTOM BURDEN (OR, 2.48; 95% CI, 1.29-4.74) COMPARED WITH MICROSATELLITE STABLE PATIENTS. THE CIMP-HIGH PATIENTS EXPERIENCED GREATER ODDS OF PAIN COMPARED WITH THE CIMP-NEGATIVE PATIENTS (OR, 1.72; 95% CI, 1.06-2.80). A GREATER OVERALL SYMPTOM BURDEN WAS ASSOCIATED WITH POOR OVERALL SURVIVAL (HAZARD RATIO, 1.42; 95% CI, 0.98-2.06]), ALTHOUGH THE DIFFERENCE WAS NOT SIGNIFICANT (P = .06). CONCLUSION: CORRELATION OF MSI-H-ASSOCIATED TUMOR FEATURES WITH THE SYMPTOM BURDEN COULD HELP PROVIDE A BETTER UNDERSTANDING OF UNDERLYING MECHANISMS ASSOCIATED WITH OUR FINDINGS.	2020