1 3383 161 HNF1B NEPHROPATHY HAS A SLOW-PROGRESSIVE PHENOTYPE IN CHILDHOOD-WITH THE EXCEPTION OF VERY EARLY ONSET CASES: RESULTS OF THE GERMAN MULTICENTER HNF1B CHILDHOOD REGISTRY. BACKGROUND: HNF1B GENE MUTATIONS ARE AN IMPORTANT CAUSE OF BILATERAL (CYSTIC) DYSPLASIA IN CHILDREN, COMPLICATED BY CHRONIC RENAL INSUFFICIENCY. THE CLINICAL VARIABILITY, THE ABSENCE OF GENOTYPE-PHENOTYPE CORRELATIONS, AND LIMITED LONG-TERM DATA RENDER COUNSELING OF AFFECTED FAMILIES DIFFICULT. METHODS: LONGITUDINAL DATA OF 62 CHILDREN PROBANDS WITH GENETICALLY PROVEN HNF1B NEPHROPATHY WAS OBTAINED IN A MULTICENTER APPROACH. GENETIC FAMILY CASCADE SCREENING WAS PERFORMED IN 30/62 CASES. RESULTS: EIGHTY-SEVEN PERCENT OF PATIENTS HAD BILATERAL DYSPLASIA, 74% VISIBLE BILATERAL, AND 16% UNILATERAL RENAL CYSTS AT THE END OF OBSERVATION. CYST DEVELOPMENT WAS NON-PROGRESSIVE IN 72% WITH A MEAN GLOMERULAR FILTRATION RATE (GFR) LOSS OF - 0.33 ML/MIN/1.73M(2) PER YEAR (+/- 8.9). IN PATIENTS WITH AN INCREASE IN CYST NUMBER, THE ANNUAL GFR REDUCTION WAS - 2.8 ML/MIN/1.73M(2) (+/- 13.2), IN THE TOTAL COHORT - 1.0 ML/MIN/1.73M(2) (+/-10.3). A SUBSET OF HNF1B PATIENTS DIFFERS FROM THIS GROUP AND DEVELOPS END STAGE RENAL DISEASE (ESRD) AT VERY EARLY AGES < 2 YEARS. HYPERURICEMIA (37%) WAS A FREQUENT FINDING AT YOUNG AGE (MEDIAN 1 YEAR), WHEREAS HYPOMAGNESEMIA (24%), ELEVATED LIVER ENZYMES (21%), AND HYPERGLYCEMIA (8%) SHOWED AN INCREASED INCIDENCE IN THE TEENAGED CHILD. GENETIC ANALYSIS REVEALED NO GENOTYPE-PHENOTYPE CORRELATIONS BUT A SIGNIFICANT PARENT-OF-ORIGIN EFFECT WITH A PREPONDERANCE OF 81% OF MATERNAL INHERITANCE IN DOMINANT CASES. CONCLUSIONS: IN MOST CHILDREN, HNF1B NEPHROPATHY HAS A NON-PROGRESSIVE COURSE OF CYST DEVELOPMENT AND A SLOW-PROGRESSIVE COURSE OF KIDNEY FUNCTION. A SUBGROUP OF PATIENTS DEVELOPED ESRD AT VERY YOUNG AGE < 2 YEARS REQUIRING SPECIAL MEDICAL ATTENTION. THE PARENT-OF-ORIGIN EFFECT SUGGESTS AN INFLUENCE OF EPIGENETIC MODIFIERS IN HNF1B DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2 1537  32 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  274  28 AGE-RELATED CHANGES IN DNA METHYLATION AFFECT RENAL HISTOLOGY AND POST-TRANSPLANT FIBROSIS. DURING AGEING, KIDNEY FUNCTION DECREASES DUE TO RENAL TUBULAR ATROPHY, INTERSTITIAL FIBROSIS, GLOMERULOSCLEROSIS AND ARTERIOSCLEROSIS. RECENTLY, CHANGES IN DNA METHYLATION WERE SHOWN TO CONTRIBUTE TO VARIOUS AGEING PROCESSES. HOWEVER, IT IS UNKNOWN WHETHER SUCH CHANGES ALSO CONTRIBUTE TO AGE-RELATED KIDNEY DYSFUNCTION. TO ASSESS THIS, WE PROFILED GENOME-WIDE CHANGES IN DNA METHYLATION (OVER 800 000 CPG SITES) IN 95 RENAL BIOPSIES OBTAINED PRIOR TO KIDNEY TRANSPLANTATION FROM DONORS AGED 16 TO 73 YEARS. DONOR AGE SIGNIFICANTLY ASSOCIATED WITH THE METHYLATION OF 92 778 CPGS (FALSE DISCOVERY RATE UNDER 0.05), CORRESPONDING TO 10 285 DIFFERENTIALLY METHYLATED REGIONS. THESE REGIONS WERE MOST FREQUENTLY LOCATED IN GENES INVOLVED IN THE WNT/BETA-CATENIN SIGNALING PATHWAY. USING AN INDEPENDENT COHORT OF 67 BIOPSIES, WE AUTONOMOUSLY VALIDATED THESE FINDINGS. INTERESTINGLY, THE METHYLATION STATUS OF THESE 92 778 AGE-RELATED CPGS WAS ASSOCIATED WITH GLOMERULOSCLEROSIS (34.4% OF CPGS AT A FALSE DISCOVERY RATE UNDER 0.05) AND INTERSTITIAL FIBROSIS (0.9%) AND GRAFT FUNCTION AT ONE YEAR AFTER TRANSPLANTATION, BUT NOT WITH TUBULAR ATROPHY AND ARTERIOSCLEROSIS. NO ASSOCIATION WAS OBSERVED WITH ANY OF THESE PATHOLOGIES AT THE TIME OF TRANSPLANTATION (0% AT A FALSE DISCOVERY RATE UNDER 0.05). THUS, AGE-ASSOCIATED CHANGES IN DNA METHYLATION AT THE TIME OF TRANSPLANTATION PREDICT FUTURE INJURY OF TRANSPLANTED KIDNEYS. SPECIFICALLY, OUR EPIGENOME-WIDE ASSOCIATION STUDY DEMONSTRATES THAT EPIGENETIC RENAL AGEING IS IMPLICATED IN PROGRESSIVE FIBROSIS IN BOTH THE GLOMERULUS AND THE INTERSTITIUM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4 3502  45 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  667  32 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023	

6 6080  36 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  177  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8 1519  29 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9 1271  31 CYTOSINE METHYLATION PREDICTS RENAL FUNCTION DECLINE IN AMERICAN INDIANS. DIABETIC NEPHROPATHY ACCOUNTS FOR MOST OF THE EXCESS MORTALITY IN INDIVIDUALS WITH DIABETES, BUT THE MOLECULAR MECHANISMS BY WHICH NEPHROPATHY DEVELOPS ARE LARGELY UNKNOWN. HERE WE TESTED CYTOSINE METHYLATION LEVELS AT 397,063 GENOMIC CPG SITES FOR ASSOCIATION WITH DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OVER A SIX YEAR PERIOD IN 181 DIABETIC PIMA INDIANS. METHYLATION LEVELS AT 77 SITES SHOWED SIGNIFICANT ASSOCIATION WITH EGFR DECLINE AFTER CORRECTION FOR MULTIPLE COMPARISONS. A MODEL INCLUDING METHYLATION LEVEL AT TWO PROBES (CG25799291 AND CG22253401) IMPROVED PREDICTION OF EGFR DECLINE IN ADDITION TO BASELINE EGFR AND THE ALBUMIN TO CREATININE RATIO WITH THE PERCENT OF VARIANCE EXPLAINED SIGNIFICANTLY IMPROVING FROM 23.1% TO 42.2%. CG22253401 WAS ALSO SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE IN A CASE-CONTROL STUDY DERIVED FROM THE CHRONIC RENAL INSUFFICIENCY COHORT. PROBES AT WHICH METHYLATION SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE WERE LOCALIZED TO GENE REGULATORY REGIONS AND ENRICHED FOR GENES WITH METABOLIC FUNCTIONS AND APOPTOSIS. THREE OF THE 77 PROBES THAT WERE ASSOCIATED WITH EGFR DECLINE IN BLOOD SAMPLES SHOWED DIRECTIONALLY CONSISTENT AND SIGNIFICANT ASSOCIATION WITH FIBROSIS IN MICRODISSECTED HUMAN KIDNEY TISSUE, AFTER CORRECTION FOR MULTIPLE COMPARISONS. THUS, CYTOSINE METHYLATION LEVELS MAY PROVIDE BIOMARKERS OF DISEASE PROGRESSION IN DIABETIC NEPHROPATHY AND EPIGENETIC VARIATIONS CONTRIBUTE TO THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 5186  31 PREMATURITY IN MICE LEADS TO REDUCTION IN NEPHRON NUMBER, HYPERTENSION, AND PROTEINURIA. THE NEPHRON NUMBER AT BIRTH IS A QUANTITATIVE TRAIT THAT CORRELATES INVERSELY WITH THE RISK OF HYPERTENSION AND CHRONIC KIDNEY DISEASE LATER IN LIFE. DURING KIDNEY DEVELOPMENT, THE NEPHRON NUMBER IS CONTROLLED BY MULTIPLE FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL MODIFIERS. PREMATURE BIRTH, WHICH REPRESENTS MORE THAN 12% OF ANNUAL LIVE BIRTHS IN THE UNITED STATES, HAS BEEN LINKED TO LOW NEPHRON NUMBER AND THE DEVELOPMENT OF HYPERTENSION LATER IN LIFE. IN THIS REPORT, WE DESCRIBE THE DEVELOPMENT OF A MOUSE MODEL OF PREMATURITY-INDUCED REDUCTION OF NEPHRON NUMBER. PREMATURE MICE, DELIVERED 1 AND 2 DAYS EARLY, HAVE 17.4 +/- 2.3% (N = 6) AND 23.6 +/- 2% (N = 10) FEWER NEPHRONS, RESPECTIVELY, WHEN COMPARED WITH FULL-TERM ANIMALS (12,252 +/- 571 NEPHRONS/KIDNEY, N = 10). AFTER 5 WEEKS OF AGE, THE MICE DELIVERED 2 DAYS PREMATURE SHOW LOWER REAL-TIME GLOMERULAR FILTRATION RATE (GFR, 283 +/- 13 VS 389 +/- 26 MUL/MIN). THE PREMATURE MICE ALSO DEVELOP HYPERTENSION (MEAN ARTERIAL PRESSURE [MAP], 134 +/- 18 VS 120 +/- 14 MM HG) AND ALBUMINURIA (286 +/- 83 VS 176 +/- 59 MUG ALBUMIN/MG CREATININE). THIS MOUSE MODEL PROVIDES A PROOF OF CONCEPT THAT PREMATURITY LEADS TO REDUCED NEPHRON NUMBER AND HYPERTENSION, AND THIS MODEL WILL BE USEFUL IN STUDYING THE PATHOPHYSIOLOGY OF PREMATURITY-INDUCED NEPHRON NUMBER REDUCTIONS AND HYPERTENSION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11 1345  28 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12 1585  27 DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC DIFFERENCES BETWEEN DIABETES PATIENTS WITH ESRD AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED POTENTIAL EPIGENETIC BIOMARKERS FOR CHRONIC KIDNEY DISEASE PROGRESSION BY COMPARING SITE-SPECIFIC DNA METHYLATION LEVELS IN MORE THAN 14,000 GENES BETWEEN AFRICAN AMERICAN AND HISPANIC DIABETES PATIENTS WITH END STAGE RENAL DISEASE (ESRD) AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED 187 GENES THAT ARE DIFFERENTIALLY METHYLATED BETWEEN THE TWO GROUPS ON AT LEAST TWO CPG SITES IN EACH GENE IN DNA EXTRACTED FROM SALIVA. OF THE 187 GENES WHOSE MEAN METHYLATION LEVELS DIFFERED BETWEEN THE TWO GROUPS, 39 GENES, OR CLOSELY RELATED GENE FAMILY MEMBERS, HAVE BEEN REPORTED TO BE INVOLVED IN KIDNEY DEVELOPMENT OR DIABETIC NEPHROPATHY, PER SE, OR HAVE BEEN ASSOCIATED WITH DIALYSIS-INDUCED CHANGES IN GENE EXPRESSION IN PERIPHERAL BLOOD CELLS. THE FACT THAT SUCH A SUBSTANTIAL FRACTION (21%) OF THE 187 CANDIDATE GENES HAVE BEEN IMPLICATED PREVIOUSLY THROUGH GENOME ASSOCIATION OR TRANSCRIPTION PROFILING STUDIES SUGGESTS STRONGLY THAT THE DNA METHYLATION DIFFERENCES WE OBSERVE ARE ASSOCIATED WITH DISEASE PREDISPOSITION AND/OR TREATMENT. THE FACT THAT THESE NEPHROPATHY AND/OR DIALYSIS-ASSOCIATED DIFFERENCES BETWEEN PATIENTS WERE IDENTIFIED IN DNA EXTRACTED FROM SALIVA OFFERS PROOF-OF-PRINCIPLE THAT INTER-INDIVIDUAL EPIGENETIC DIFFERENCES MAY PROVE USEFUL AS PREDICTIVE BIOMARKERS OF DISEASE SUSCEPTIBILITY.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 2488  23 EPIGENETICALLY DYSREGULATED GENES AND PATHWAYS IMPLICATED IN THE PATHOGENESIS OF NON-SYNDROMIC HIGH MYOPIA. MYOPIA, COMMONLY REFERRED TO AS NEARSIGHTEDNESS, IS ONE OF THE MOST COMMON CAUSES OF VISUAL DISABILITY THROUGHOUT THE WORLD. IT AFFECTS MORE PEOPLE WORLDWIDE THAN ANY OTHER CHRONIC VISUAL IMPAIRMENT CONDITION. ALTHOUGH THE PREVALENCE VARIES AMONG VARIOUS ETHNIC GROUPS, THE INCIDENCE OF MYOPIA IS INCREASING IN ALL POPULATIONS ACROSS GLOBE. THUS, IT IS CONSIDERED A PRESSING PUBLIC HEALTH PROBLEM. BOTH GENETICS AND ENVIRONMENT PLAY A ROLE IN DEVELOPMENT OF MYOPIA. TO ELUCIDATE THE EPIGENETIC MECHANISM(S) UNDERLYING THE PATHOPHYSIOLOGY OF HIGH-MYOPIA, WE CONDUCTED METHYLATION PROFILING IN 18 CASES AND 18 MATCHED CONTROLS (AGED 4-12 YEARS), USING ILLUMINA METHYLATIONEPIC BEADCHIPS ARRAY. THE DEGREE OF MYOPIA WAS VARIABLE AMONG SUBJECTS, RANGING FROM -6 TO -15D. WE IDENTIFIED 1541 HYPERMETHYLATED CPGS, REPRESENTING 1745 GENES (2.0-FOLD OR HIGHER) (FALSE DISCOVERY RATE (FDR) P </= 0.05), MULTIPLE CPGS WERE P < 5 X 10(-8) WITH A RECEIVER OPERATING CHARACTERISTIC AREA UNDER THE CURVE (ROC-AUC) >/= 0.75 IN HIGH-MYOPIA SUBJECTS COMPARED TO CONTROLS. AMONG THESE, 48 CPGS HAD EXCELLENT CORRELATION (AUC >/= 0.90). HEREIN, WE PRESENT THE FIRST GENOME-WIDE DNA METHYLATION ANALYSIS IN A UNIQUE HIGH-MYOPIA COHORT, SHOWING EXTENSIVE AND DISCRETE METHYLATION CHANGES RELATIVE TO CONTROLS. THE GENES WE IDENTIFIED HOLD SIGNIFICANT POTENTIAL AS TARGETS FOR NOVEL THERAPEUTIC INTERVENTION EITHER ALONE, OR IN COMBINATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14 6817  41 [FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY: REPORT OF SEVEN PATIENTS]. BACKGROUND: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY IS THE THIRD MOST COMMON MUSCULAR DYSTROPHY WITH AN ESTIMATED PREVALENCE OF 1 PER 20.000 AND A NORMAL LIFE EXPECTANCY IN THE MAJORITY OF PATIENTS. HOWEVER, APPROXIMATELY 15% OF PATIENTS BECOME WHEELCHAIR BOUND IN THE COURSE OF THEIR LIFE. IT IS A HEREDITARY AUTOSOMAL DOMINANT DISEASE WITH HIGH (95%) PENETRANCE BY THE AGE OF 20, BUT WITH VARIABLE DEGREE OF PHENOTYPIC EXPRESSION EVEN IN THE SAME FAMILY GROUP. SYMPTOMS FREQUENTLY START IN THE SECOND DECADE OF LIFE, WITH FACIAL AND SCAPULAR WEAKNESS. AIM: TO REPORT THE CLINICAL FEATURES OF SEVEN PATIENTS WITH THE DISEASE, SEEN AT A PUBLIC HOSPITAL. MATERIAL AND METHODS: ANALYSIS OF SEVEN PATIENTS WITH GENETIC STUDY SEEN IN A PUBLIC HOSPITAL IN SANTIAGO. RESULTS: THE AGE OF PATIENTS FLUCTUATED FROM 18 TO 61 YEARS AND FOUR WERE FEMALES. THE MEAN AGE AT ONSET OF SYMPTOMS WAS 29 YEARS AND FOUR HAD A FAMILY HISTORY OF THE DISEASE. THE USUAL PRESENTING COMPLAINT WAS ARM OR SHOULDER ASYMMETRIC WEAKNESS. FOUR PATIENTS HAD BONE PAIN. FACIAL INVOLVEMENT WAS PRESENT IN FOUR. A GENETIC STUDY WAS DONE IN FIVE PATIENTS, THE OTHER TWO PATIENTS WERE RELATIVES, CONFIRMING THE CONTRACTION OR LOWER NUMBER OF REPETITIONS IN D4Z4 REGION. AFTER 12 YEARS OF FOLLOW UP ONLY 2 PATIENTS OLDER THAN 60 YEARS CANNOT WORK AND ONE FEMALE PATIENTS IS IN A SEMI DEPENDENT STATE AT THE AGE OF 30. CONCLUSIONS: THE CLINICAL WORKUP IN THE DIAGNOSIS AND THE TIMELY INDICATION OF GENETIC STUDIES ARE HIGHLIGHTED, TO AVOID UNNECESSARY AND INVASIVE PROCEDURES. THE VARIABILITY IN THE PHENOTYPIC EXPRESSION IN A SIMILAR GENETIC DEFECT IS DISCUSSED AND THE GENETIC OR EPIGENETIC MECHANISMS OF THIS MUSCULAR DYSTROPHY ARE DESCRIBED.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 3568  29 IMPACT OF INFLAMMATION ON EPIGENETIC DNA METHYLATION - A NOVEL RISK FACTOR FOR CARDIOVASCULAR DISEASE? OBJECTIVE: THE LIFESPAN OF DIALYSIS PATIENTS IS AS SHORT AS IN PATIENTS WITH METASTATIC CANCER DISEASE, MAINLY DUE TO CARDIOVASCULAR DISEASE (CVD). DNA METHYLATION IS AN IMPORTANT CELLULAR MECHANISM MODULATING GENE EXPRESSION ASSOCIATED WITH AGEING, INFLAMMATION AND ATHEROSCLEROTIC PROCESSES. DESIGN: DNA METHYLATION WAS ANALYSED IN PERIPHERAL BLOOD LEUCOCYTES FROM THREE DIFFERENT GROUPS OF CHRONIC KIDNEY DISEASE (CKD) POPULATIONS (37 CKD STAGES 3 AND 4 PATIENTS, 98 CKD STAGE 5 PATIENTS AND 20 PREVALENT HAEMODIALYSIS PATIENTS). THIRTY-SIX HEALTHY SUBJECTS SERVED AS CONTROLS. CLINICAL CHARACTERISTICS (DIABETES MELLITUS, NUTRITIONAL STATUS AND PRESENCE OF CLINICAL CVD), INFLAMMATION AND OXIDATIVE STRESS BIOMARKERS, HOMOCYSTEINE AND GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES (DEFINED AS HPAII/MSPI RATIO BY THE LUMINOMETRIC METHYLATION ASSAY METHOD) WERE EVALUATED. CKD STAGE 5 PATIENTS (N=98) STARTING DIALYSIS TREATMENT WERE FOLLOWED FOR A PERIOD OF 36 +/- 2 MONTHS. RESULTS: INFLAMED PATIENTS HAD LOWER RATIOS OF HPAII/MSPI, INDICATING GLOBAL DNA HYPERMETHYLATION. ANALYSIS BY THE COX REGRESSION MODEL DEMONSTRATED THAT DNA HYPERMETHYLATION (HPAII/MSPI RATIO <MEDIAN) WAS SIGNIFICANTLY ASSOCIATED WITH BOTH ALL-CAUSE (RR 5.0; 95% CI: 1.7-14.8; P<0.01) AND CARDIOVASCULAR (RR 13.9; 95% CI: 1.8-109.3; P<0.05) MORTALITY, EVEN FOLLOWING THE ADJUSTMENT FOR AGE, CVD, DIABETES MELLITUS AND INFLAMMATION. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT GLOBAL DNA HYPERMETHYLATION IS ASSOCIATED WITH INFLAMMATION AND INCREASED MORTALITY IN CKD.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 6547  30 TRANSCRIPTOMICS OF LONG-TERM MEDITATION PRACTICE: EVIDENCE FOR PREVENTION OR REVERSAL OF STRESS EFFECTS HARMFUL TO HEALTH. BACKGROUND AND OBJECTIVES: STRESS CAN OVERLOAD ADAPTIVE MECHANISMS, LEADING TO EPIGENETIC EFFECTS HARMFUL TO HEALTH. RESEARCH ON THE REVERSAL OF THESE EFFECTS IS IN ITS INFANCY. EARLY RESULTS SUGGEST SOME MEDITATION TECHNIQUES HAVE HEALTH BENEFITS THAT GROW WITH REPEATED PRACTICE. THIS STUDY FOCUSED ON POSSIBLE TRANSCRIPTOMIC EFFECTS OF 38 YEARS OF TWICE-DAILY TRANSCENDENTAL MEDITATION((R)) (TM((R))) PRACTICE. MATERIALS AND METHODS: FIRST, USING ILLUMINA((R)) BEADCHIP MICROARRAY TECHNOLOGY, DIFFERENCES IN GLOBAL GENE EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE SOUGHT BETWEEN HEALTHY PRACTITIONERS AND TIGHTLY MATCHED CONTROLS (N = 12, AGE 65). SECOND, THESE MICROARRAY RESULTS WERE VERIFIED ON A SUBSET OF GENES USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND WERE VALIDATED USING QPCR IN LARGER TM AND CONTROL GROUPS (N = 45, AGE 63). BIOINFORMATICS INVESTIGATION EMPLOYED INGENUITY((R)) PATHWAY ANALYSIS (IPA((R))), DAVID, GENOMATIX, AND R PACKAGES. RESULTS: THE 200 GENES AND LOCI FOUND TO MEET STRICT CRITERIA FOR DIFFERENTIAL EXPRESSION IN THE MICROARRAY EXPERIMENT SHOWED CONTRASTING PATTERNS OF EXPRESSION THAT DISTINGUISHED THE TWO GROUPS. DIFFERENTIAL EXPRESSION RELATING TO IMMUNE FUNCTION AND ENERGY EFFICIENCY WERE MOST APPARENT. IN THE TM GROUP, RELATIVE TO THE CONTROL, ALL 49 GENES ASSOCIATED WITH INFLAMMATION WERE DOWNREGULATED, WHILE GENES ASSOCIATED WITH ANTIVIRAL AND ANTIBODY COMPONENTS OF THE DEFENSE RESPONSE WERE UPREGULATED. THE LARGEST EXPRESSION DIFFERENCES WERE SHOWN BY SIX GENES RELATED TO ERYTHROCYTE FUNCTION THAT APPEARED TO REFLECT A CONDITION OF LOWER ENERGY EFFICIENCY IN THE CONTROL GROUP. RESULTS SUPPORTING THESE GENE EXPRESSION DIFFERENCES WERE OBTAINED WITH QPCR-MEASURED EXPRESSION BOTH IN THE WELL-MATCHED MICROARRAY GROUPS AND IN THE LARGER, LESS WELL-MATCHED GROUPS. CONCLUSIONS: THESE FINDINGS ARE CONSISTENT WITH PREDICTIONS BASED ON RESULTS FROM EARLIER RANDOMIZED TRIALS OF MEDITATION AND MAY PROVIDE EVIDENCE FOR STRESS-RELATED MOLECULAR MECHANISMS UNDERLYING REDUCTIONS IN ANXIETY, POST-TRAUMATIC STRESS DISORDER (PTSD), CARDIOVASCULAR DISEASE (CVD), AND OTHER CHRONIC DISORDERS AND DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 2079  28 EPIGENETIC DNA METHYLATION CHANGES ASSOCIATED WITH HEADACHE CHRONIFICATION: A RETROSPECTIVE CASE-CONTROL STUDY. BACKGROUND THE BIOLOGICAL MECHANISMS OF HEADACHE CHRONIFICATION ARE POORLY UNDERSTOOD. WE AIMED TO IDENTIFY CHANGES IN DNA METHYLATION ASSOCIATED WITH THE TRANSFORMATION FROM EPISODIC TO CHRONIC HEADACHE. METHODS PARTICIPANTS WERE RECRUITED FROM THE POPULATION-BASED NORWEGIAN HUNT STUDY. THIRTY-SIX FEMALE HEADACHE PATIENTS WHO TRANSFORMED FROM EPISODIC TO CHRONIC HEADACHE BETWEEN BASELINE AND FOLLOW-UP 11 YEARS LATER WERE MATCHED AGAINST 35 CONTROLS WITH EPISODIC HEADACHE. DNA METHYLATION WAS QUANTIFIED AT 485,000 CPG SITES, AND CHANGES IN METHYLATION LEVEL AT THESE SITES WERE COMPARED BETWEEN CASES AND CONTROLS BY LINEAR REGRESSION ANALYSIS. DATA WERE ANALYZED IN TWO STAGES (STAGES 1 AND 2) AND IN A COMBINED META-ANALYSIS. RESULTS NONE OF THE TOP 20 CPG SITES IDENTIFIED IN STAGE 1 REPLICATED IN STAGE 2 AFTER MULTIPLE TESTING CORRECTION. IN THE COMBINED META-ANALYSIS THE STRONGEST ASSOCIATED CPG SITES WERE RELATED TO SH2D5 AND NPTX2, TWO BRAIN-EXPRESSED GENES INVOLVED IN THE REGULATION OF SYNAPTIC PLASTICITY. FUNCTIONAL ENRICHMENT ANALYSIS POINTED TO PROCESSES INCLUDING CALCIUM ION BINDING AND ESTROGEN RECEPTOR PATHWAYS. CONCLUSION IN THIS FIRST GENOME-WIDE STUDY OF DNA METHYLATION IN HEADACHE CHRONIFICATION SEVERAL POTENTIALLY IMPLICATED LOCI AND PROCESSES WERE IDENTIFIED. THE STUDY EXEMPLIFIES THE USE OF PROSPECTIVELY COLLECTED POPULATION COHORTS TO SEARCH FOR EPIGENETIC MECHANISMS OF DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18 6311  23 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19 1444  30 DIFFERENTIALLY HYPOMETHYLATED CELL-FREE DNA AND CORONARY COLLATERAL CIRCULATION. BACKGROUND: THE FACTORS AFFECTING CARDIOPROTECTIVE COLLATERAL CIRCULATION ARE STILL INCOMPLETELY UNDERSTOOD. RECENTLY, CHARACTERISTICS, SUCH AS CPG METHYLATION OF CELL-FREE DNA (CFDNA), HAVE BEEN REPORTED AS MARKERS WITH CLINICAL UTILITY. THE AIM OF THIS STUDY WAS TO EVALUATE WHETHER CFDNA METHYLATION PATTERNS ARE ASSOCIATED WITH THE GRADE OF CORONARY COLLATERAL CIRCULATION (CCC). RESULT: IN THIS CASE-CONTROL STUDY, CLINICAL AND ANGIOGRAPHIC DATA WERE OBTAINED FROM 143 PATIENTS (MEAN AGE, 58 YEARS, MALE 71%) WITH CHRONIC TOTAL CORONARY OCCLUSION. ENZYMATIC METHYL-SEQUENCING (EM-SEQ) LIBRARIES WERE PREPARED USING THE CFDNA EXTRACTED FROM THE PLASMA. DATA WERE PROCESSED TO OBTAIN THE AVERAGE METHYLATION FRACTION (AMF) TABLES OF GENOMIC REGIONS FROM WHICH BLACKLISTED REGIONS WERE REMOVED. UNSUPERVISED ANALYSIS OF THE OBTAINED AMF VALUES SHOWED THAT SOME OF THE CHANGES IN METHYLATION WERE DUE TO CCC. THROUGH RANDOM FOREST PREPARATION PROCESS, 256 DIFFERENTIALLY METHYLATED REGION (DMR) CANDIDATES SHOWING STRONG ASSOCIATION WITH CCC WERE SELECTED. A RANDOM FOREST CLASSIFIER WAS THEN CONSTRUCTED, AND THE AREA UNDER THE CURVE OF THE RECEIVER OPERATING CHARACTERISTIC CURVE INDICATED AN APPROPRIATE PREDICTIVE FUNCTION FOR CCC. FINALLY, 20 DMRS WERE IDENTIFIED TO HAVE SIGNIFICANTLY DIFFERENT AMF VALUES BETWEEN THE GOOD AND POOR CCC GROUPS. PARTICULARLY, THE GOOD CCC GROUP EXHIBITED HYPOMETHYLATED DMRS. PATHWAY ANALYSIS REVEALED FIVE PATHWAYS, INCLUDING TGF-BETA SIGNALING, TO BE ASSOCIATED WITH GOOD CCC. CONCLUSION: THESE DATA HAVE DEMONSTRATED THAT DIFFERENTIAL HYPOMETHYLATION WAS IDENTIFIED IN DOZENS OF CFDNA REGIONS IN PATIENTS WITH GOOD CCC. OUR RESULTS SUPPORT THE CLINICAL UTILITY OF NONINVASIVELY OBTAINED EPIGENETIC SIGNATURES FOR PREDICTING COLLATERAL CIRCULATION IN PATIENTS WITH VASCULAR DISEASES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20 5638  27 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013