1 1423 196 DIFFERENTIAL DNA METHYLATION IN MONOZYGOTIC TWINS DISCORDANT FOR FEMALE SEXUAL FUNCTIONING. BACKGROUND: RESEARCH HAS REPEATEDLY SUGGESTED GENETIC AND ENVIRONMENTAL FACTORS IN THE ETIOLOGY UNDERLYING FEMALE SEXUAL DYSFUNCTION (FSD). BECAUSE SEXUAL FUNCTIONING IS A HIGHLY VARIABLE TRAIT, EPIGENETICS COULD PROVIDE A PROMISING APPROACH TO TACKLE THE ORIGINS OF FSD AND CONSEQUENTLY OFFER A STEP-CHANGE IN OUR UNDERSTANDING OF THESE PROBLEMS. AIM: TO IDENTIFY DIFFERENTIALLY METHYLATED CPG POSITIONS FOR SEXUAL FUNCTIONING IN A SAMPLE OF MONOZYGOTIC TWIN PAIRS DISCORDANT FOR SEXUAL FUNCTIONING. METHODS: THE SAMPLE CONSISTED OF 33 TRAIT-DISCORDANT MONOZYGOTIC TWIN PAIRS (MEAN AGE = 54.1 YEARS, SD = 9.05) FROM THE TWINS UK REGISTRY. PHENOTYPIC DATA ON SEXUAL DESIRE, AROUSAL, LUBRICATION, ORGASM, SATISFACTION, AND PAIN WERE COLLECTED USING THE FEMALE SEXUAL FUNCTION INDEX-LIFELONG (FSFI-LL). THE ILLUMINA INFINIUM HUMANMETHYLATION 450 DNA BEADCHIP WAS USED FOR EPIGENOME-WIDE ANALYSES OF DNA METHYLATION IN WHOLE-BLOOD SAMPLES. OUTCOMES: COMPARISON OF DNA METHYLATION PATTERNS ASSOCIATED WITH THE FSFI-LL TOTAL SCORE AND ITS SIX SUBDOMAINS. RESULTS: TWO DIFFERENTIALLY METHYLATED CPG POSITIONS (CG09580409 AND CG14734994) REACHING EXPERIMENT-WIDE STATISTICAL SIGNIFICANCE WERE FOUND FOR OVERALL SEXUAL FUNCTIONING, MAPPING TO MGC45800 AND THE THREONINE SYNTHASE-LIKE 2 GENE (THNSL2), RESPECTIVELY. FURTHERMORE, POTENTIAL BIOLOGICALLY RELEVANT CANDIDATES FOR SEXUAL DESIRE (CUB AND ZONA PELLUCIDA-LIKE DOMAINS 1, CUZD1) AND SATISFACTION (SOLUTE CARRIER FAMILY 6 MEMBER 19, SLC6A19) WERE IDENTIFIED. CLINICAL TRANSLATION: THNSL2 AND SLC6A19, WHICH HAVE BEEN LINKED TO WEIGHT AND ADIPOSITY, MIGHT REPRESENT NOVEL CANDIDATES FOR SEXUAL PROBLEMS IN WOMEN. STRENGTHS AND LIMITATIONS: THIS IS THE FIRST STUDY TO INVESTIGATE EPIGENETIC MECHANISMS UNDERLYING FSD. THE STUDY USED A RELATIVE SMALL SAMPLE OF MONOZYGOTIC FEMALE TWINS. THE CUTOFF TO DETERMINE DISCORDANCE IN SEXUAL PROBLEMS WAS CHOSEN BASED ON A 10% FSFI SCORE DIFFERENCE. THEREFORE, THE RESULTS HAVE TO BE INTERPRETED WITH CAUTION AND NEED REPLICATION IN LARGER CLINICAL SAMPLES. CONCLUSION: UNDERSTANDING HOW GENES AND ENVIRONMENT INTERACT TO INFLUENCE OUR SEXUALITY MIGHT INFORM CLINICAL PRACTICE AND LEAD TO NEW TREATMENTS FOR WOMEN EXPERIENCING FSD. BURRI A, LEUPIN M, SPECTOR T, MARINOVA Z. DIFFERENTIAL DNA METHYLATION IN MONOZYGOTIC TWINS DISCORDANT FOR FEMALE SEXUAL FUNCTIONING. J SEX MED 2017;14:1357-1364.	2017	

2 5001  39 PERINATAL RISK FACTORS IN TOURETTE'S AND CHRONIC TIC DISORDERS: A TOTAL POPULATION SIBLING COMPARISON STUDY. ADVERSE PERINATAL EVENTS MAY INCREASE THE RISK OF TOURETTE'S AND CHRONIC TIC DISORDERS (TD/CTD), BUT PREVIOUS STUDIES HAVE BEEN UNABLE TO CONTROL FOR UNMEASURED ENVIRONMENTAL AND GENETIC CONFOUNDING. WE AIMED TO PROSPECTIVELY INVESTIGATE POTENTIAL PERINATAL RISK FACTORS FOR TD/CTD, TAKING UNMEASURED FACTORS SHARED BETWEEN FULL SIBLINGS INTO ACCOUNT. A POPULATION-BASED BIRTH COHORT, CONSISTING OF ALL SINGLETONS BORN IN SWEDEN IN 1973-2003, WAS FOLLOWED UNTIL DECEMBER 2013. A TOTAL OF 3 026 861 INDIVIDUALS WERE IDENTIFIED, 5597 OF WHICH HAD A REGISTERED TD/CTD DIAGNOSIS. WE THEN STUDIED DIFFERENTIALLY EXPOSED FULL SIBLINGS FROM 947 942 FAMILIES; OF THESE, 3563 FAMILIES INCLUDED SIBLINGS THAT WERE DISCORDANT FOR TD/CTD. PERINATAL DATA WERE COLLECTED FROM THE MEDICAL BIRTH REGISTER AND TD/CTD DIAGNOSES WERE COLLECTED FROM THE NATIONAL PATIENT REGISTER, USING A PREVIOUSLY VALIDATED ALGORITHM. IN THE FULLY ADJUSTED MODELS, IMPAIRED FETAL GROWTH, PRETERM BIRTH, BREECH PRESENTATION AND CESAREAN SECTION WERE ASSOCIATED WITH A HIGHER RISK OF TD/CTD, LARGELY INDEPENDENT FROM SHARED FAMILY CONFOUNDERS AND MEASURED COVARIATES. MATERNAL SMOKING DURING PREGNANCY WAS ASSOCIATED WITH RISK OF TD/CTD IN A DOSE-RESPONSE MANNER BUT THE ASSOCIATION WAS NO LONGER STATISTICALLY SIGNIFICANT IN THE SIBLING COMPARISON MODELS OR AFTER THE EXCLUSION OF COMORBID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER. A DOSE-RESPONSE RELATIONSHIP BETWEEN THE NUMBER OF ADVERSE PERINATAL EVENTS AND INCREASED RISK FOR TD/CTD WAS ALSO OBSERVED, WITH HAZARD RATIOS RANGING FROM 1.41 (95% CONFIDENCE INTERVAL (CI): 1.33-1.50) FOR ONE EVENT TO 2.42 (95% CI: 1.65-3.53) FOR FIVE OR MORE EVENTS. THESE RESULTS PAVE THE WAY FOR FUTURE GENE BY ENVIRONMENT INTERACTION AND EPIGENETIC STUDIES IN TD/CTD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3 1187  38 COPD GWAS VARIANT AT 19Q13.2 IN RELATION WITH DNA METHYLATION AND GENE EXPRESSION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AMONG THE MAJOR HEALTH BURDENS IN ADULTS. WHILE CIGARETTE SMOKING IS THE LEADING RISK FACTOR, A GROWING NUMBER OF GENETIC VARIATIONS HAVE BEEN DISCOVERED TO INFLUENCE DISEASE SUSCEPTIBILITY. EPIGENETIC MODIFICATIONS MAY MEDIATE THE RESPONSE OF THE GENOME TO SMOKING AND REGULATE GENE EXPRESSION. CHROMOSOME 19Q13.2 REGION IS ASSOCIATED WITH BOTH SMOKING AND COPD, YET ITS FUNCTIONAL ROLE IS UNCLEAR. OUR STUDY AIMED TO DETERMINE WHETHER RS7937 (RAB4B, EGLN2), A TOP GENETIC VARIANT IN 19Q13.2 REGION IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES OF COPD, IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD (N = 1490) AND GENE EXPRESSION IN BLOOD (N = 721) AND LUNGS (N = 1087). WE COMBINED GENETIC AND EPIGENETIC DATA FROM THE ROTTERDAM STUDY (RS) TO PERFORM THE EPIGENOME-WIDE ASSOCIATION ANALYSIS OF RS7937. FURTHER, WE USED GENETIC AND TRANSCRIPTOMIC DATA FROM BLOOD (RS) AND FROM LUNG TISSUE (LUNG EXPRESSION QUANTITATIVE TRAIT LOCI MAPPING STUDY), TO PERFORM THE TRANSCRIPTOME-WIDE ASSOCIATION STUDY OF RS7937. RS7937 WAS SIGNIFICANTLY (FDR < 0.05) AND CONSISTENTLY ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD AT 4 CPG SITES IN CIS, INDEPENDENT OF SMOKING. ONE METHYLATION SITE (CG11298343-EGLN2) WAS ALSO ASSOCIATED WITH COPD (P = 0.001). ADDITIONALLY, RS7937 WAS ASSOCIATED WITH GENE EXPRESSION LEVELS IN BLOOD IN CIS (EGLN2), 42% MEDIATED THROUGH CG11298343, AND IN LUNG TISSUE, IN CIS AND TRANS (NUMBL, EGLN2, DNMT3A, LOC101929709 AND PAK2). OUR RESULTS SUGGEST THAT CHANGES OF DNA METHYLATION AND GENE EXPRESSION MAY BE INTERMEDIATE STEPS BETWEEN GENETIC VARIANTS AND COPD, BUT FURTHER CAUSAL STUDIES IN LUNG TISSUE SHOULD CONFIRM THIS HYPOTHESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4 3078  48 GENOME-WIDE METHYLATION ANALYSIS OF A LARGE POPULATION SAMPLE SHOWS NEUROLOGICAL PATHWAYS INVOLVEMENT IN CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN. CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN (CWP), HAS A CONSIDERABLE HERITABLE COMPONENT, WHICH REMAINS TO BE EXPLAINED. EPIGENETIC FACTORS MAY CONTRIBUTE TO AND ACCOUNT FOR SOME OF THE HERITABILITY ESTIMATE. WE ANALYSED EPIGENOME-WIDE METHYLATION USING MEDIPSEQ IN WHOLE BLOOD DNA FROM 1708 MONOZYGOTIC AND DIZYGOTIC CAUCASIAN TWINS HAVING CWP PREVALENCE OF 19.9%. LONGITUDINALLY STABLE METHYLATION BINS (LSBINS), WERE ESTABLISHED BY TESTING REPEATED MEASUREMENTS CONDUCTED >/=3 YEARS APART, N = 292. DNA METHYLATION VARIATION AT LSBINS WAS TESTED FOR ASSOCIATION WITH CWP IN A DISCOVERY SET OF 50 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR CWP, AND IN AN INDEPENDENT DATASET (N = 1608 TWINS), AND THE RESULTS FROM THE 2 SAMPLES WERE COMBINED USING FISHER METHOD. FUNCTIONAL INTERPRETATION OF THE MOST ASSOCIATED SIGNALS WAS BASED ON FUNCTIONAL GENOMIC ANNOTATIONS, GENE ONTOLOGY, AND PATHWAY ANALYSES. OF 723,029 SIGNALS IDENTIFIED AS LSBINS, 26,399 LSBINS DEMONSTRATED THE SAME DIRECTION OF ASSOCIATION IN BOTH DISCOVERY AND REPLICATION DATASETS AT NOMINAL SIGNIFICANCE (P </= 0.05). IN THE COMBINED ANALYSIS ACROSS 1708 INDIVIDUALS, WHEREAS NO LSBINS SHOWED GENOME-WIDE SIGNIFICANCE (P < 10-8), 24 SIGNALS REACHED P</=9E-5, AND THESE INCLUDED ASSOCIATION SIGNALS MAPPING IN OR NEAR TO IL17A, ADIPOR2, AND TNFRSF13B. BIOINFORMATICS ANALYSES OF THE ASSOCIATED METHYLATION BINS SHOWED ENRICHMENT FOR NEUROLOGICAL PATHWAYS IN CWP. WE ESTIMATE THAT THE VARIANCE EXPLAINED BY EPIGENETIC FACTORS IN CWP IS 6%. THIS, THE LARGEST STUDY TO DATE OF DNA METHYLATION IN CWP, POINTS TOWARDS EPIGENETIC MODIFICATION OF NEUROLOGICAL PATHWAYS IN CWP AND PROVIDES PROOF OF PRINCIPLE OF THIS METHOD IN TEASING APART THE COMPLEX RISK FACTORS FOR CWP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5 2626  41 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 4492  32 MONOZYGOTIC TWINS DISCORDANT FOR ROHHAD PHENOTYPE. RAPID-ONSET OBESITY WITH HYPOTHALAMIC DYSFUNCTION, HYPOVENTILATION, AND AUTONOMIC DYSREGULATION (ROHHAD) FALLS WITHIN A GROUP OF PEDIATRIC DISORDERS WITH BOTH RESPIRATORY CONTROL AND AUTONOMIC NERVOUS SYSTEM DYSREGULATION. CHILDREN WITH ROHHAD TYPICALLY PRESENT AFTER 1.5 YEARS OF AGE WITH RAPID WEIGHT GAIN AS THE INITIAL SIGN. SUBSEQUENTLY, THEY DEVELOP ALVEOLAR HYPOVENTILATION, AUTONOMIC NERVOUS SYSTEM DYSREGULATION, AND, IF UNTREATED, CARDIORESPIRATORY ARREST. TO OUR KNOWLEDGE, THIS IS THE FIRST REPORT OF DISCORDANT PRESENTATION OF ROHHAD IN MONOZYGOTIC TWINS. TWIN GIRLS, BORN AT TERM, HAD CONCORDANT GROWTH AND DEVELOPMENT UNTIL 8 YEARS OF AGE. FROM 8 TO 12 YEARS OF AGE, THE AFFECTED TWIN DEVELOPED FEATURES CHARACTERISTIC OF ROHHAD INCLUDING OBESITY, ALVEOLAR HYPOVENTILATION, SCOLIOSIS, HYPOTHALAMIC DYSFUNCTION (CENTRAL DIABETES INSIPIDUS, HYPOTHYROIDISM, PREMATURE PUBARCHE, AND GROWTH HORMONE DEFICIENCY), RIGHT PARASPINAL/THORACIC GANGLIONEUROBLASTOMA, SEIZURES, AND AUTONOMIC DYSREGULATION INCLUDING ALTERED PAIN PERCEPTION, LARGE AND SLUGGISHLY REACTIVE PUPILS, HYPOTHERMIA, AND PROFOUND BRADYCARDIA THAT REQUIRED A CARDIAC PACEMAKER. RESULTS OF GENETIC TESTING FOR PHOX2B (CONGENITAL CENTRAL HYPOVENTILATION SYNDROME DISEASE-DEFINING GENE) MUTATIONS WERE NEGATIVE. WITH EARLY RECOGNITION AND CONSERVATIVE MANAGEMENT, THE AFFECTED TWIN HAD EXCELLENT NEUROCOGNITIVE OUTCOME THAT MATCHED THAT OF THE UNAFFECTED TWIN. THE UNAFFECTED TWIN DEMONSTRATED RAPID WEIGHT GAIN LATER IN AGE BUT NOT DEVELOPMENT OF SIGNS/SYMPTOMS CONSISTENT WITH ROHHAD. THIS DISCORDANT TWIN PAIR DEMONSTRATES KEY FEATURES OF ROHHAD INCLUDING THE IMPORTANCE OF EARLY RECOGNITION (ESPECIALLY HYPOVENTILATION), COMPLEXITY OF SIGNS/SYMPTOMS AND CLINICAL COURSE, AND IMPORTANCE OF INITIATING COMPREHENSIVE, MULTISPECIALTY CARE. THESE CASES CONFOUND THE HYPOTHESIS OF A MONOGENIC ETIOLOGY FOR ROHHAD AND INDICATE ALTERNATIVE ETIOLOGIES INCLUDING AUTOIMMUNE OR EPIGENETIC PHENOMENON OR A COMBINATION OF GENETIC PREDISPOSITION AND ACQUIRED PRECIPITANT.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                   
7 4740  49 NOVEL GENETIC VARIANTS ASSOCIATED WITH CHRONIC KIDNEY DISEASE PROGRESSION. SIGNIFICANCE STATEMENT: EGFR SLOPE HAS BEEN USED AS A SURROGATE OUTCOME FOR PROGRESSION OF CKD. HOWEVER, GENETIC MARKERS ASSOCIATED WITH EGFR SLOPE AMONG PATIENTS WITH CKD WERE UNKNOWN. WE AIMED TO IDENTIFY GENETIC SUSCEPTIBILITY LOCI ASSOCIATED WITH EGFR SLOPE. A TWO-PHASE GENOME-WIDE ASSOCIATION STUDY IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN TPPP AND FAT1-LINC02374 , AND 22 OF THEM WERE USED TO DERIVE POLYGENIC RISK SCORES THAT MARK THE DECLINE OF EGFR BY DISRUPTING BINDING OF NEARBY TRANSCRIPTION FACTORS. THIS WORK IS THE FIRST TO IDENTIFY THE IMPACT OF TPPP AND FAT1-LINC02374 ON CKD PROGRESSION, PROVIDING PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD. BACKGROUND: THE INCIDENCE OF CKD IS ASSOCIATED WITH GENETIC FACTORS. HOWEVER, GENETIC MARKERS ASSOCIATED WITH THE PROGRESSION OF CKD HAVE NOT BEEN FULLY ELUCIDATED. METHODS: WE CONDUCTED A GENOME-WIDE ASSOCIATION STUDY AMONG 1738 PATIENTS WITH CKD, MAINLY FROM THE KOREAN COHORT STUDY FOR OUTCOMES IN PATIENTS WITH CKD. THE OUTCOME WAS EGFR SLOPE. WE PERFORMED A REPLICATION STUDY FOR DISCOVERED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITH P <10 -6 IN 2498 PATIENTS WITH CKD FROM THE CHRONIC RENAL INSUFFICIENCY COHORT STUDY. SEVERAL EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL) STUDIES, PATHWAY ENRICHMENT ANALYSES, EXPLORATION OF EPIGENETIC ARCHITECTURE, AND PREDICTING DISRUPTION OF TRANSCRIPTION FACTOR (TF) BINDING SITES EXPLORED POTENTIAL BIOLOGICAL IMPLICATIONS OF THE LOCI. WE DEVELOPED AND EVALUATED THE EFFECT OF POLYGENIC RISK SCORES (PRS) ON INCIDENT CKD OUTCOMES. RESULTS: SNPS IN TWO NOVEL LOCI, TPPP AND FAT1-LINC02374 , WERE REPLICATED (RS59402340 IN TPPP , PDISCOVERY =7.11X10 -7 , PCRIC =8.13X10 -4 , PMETA =7.23X10 -8 ; RS28629773 IN FAT1-LINC02374 , PDISCOVERY =6.08X10 -7 , PCRIC =4.33X10 -2 , PMETA =1.87X10 -7 ). THE EQTL STUDIES REVEALED THAT THE REPLICATED SNPS REGULATED THE EXPRESSION LEVEL OF NEARBY GENES ASSOCIATED WITH KIDNEY FUNCTION. FURTHERMORE, THESE SNPS WERE NEAR GENE ENHANCER REGIONS AND PREDICTED TO DISRUPT THE BINDING OF TFS. PRS BASED ON THE INDEPENDENTLY SIGNIFICANT TOP 22 SNPS WERE SIGNIFICANTLY ASSOCIATED WITH CKD OUTCOMES. CONCLUSIONS: THIS STUDY DEMONSTRATES THAT SNP MARKERS IN THE TPPP AND FAT1-LINC02374 LOCI COULD BE PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD.	2023	
                                                                       
8 1452  28 DISCORDANT INTESTINAL MALROTATION IN ADULT MONOZYGOTIC TWINS DISCOVERED INCIDENTALLY DURING LAPAROSCOPIC GASTRIC BYPASS: A CASE REPORT AND REVIEW OF THE LITERATURE. INTRODUCTION AND IMPORTANCE: INTESTINAL MALROTATION IS AN UNCOMMON ENTITY IN THE ADULT POPULATION; MORE SO IN MONOZYGOTIC TWINS, WHERE CONCORDANCE IS EXPECTED. IN LITERATURE, DISCORDANT INTESTINAL MALROTATION HAS ONLY BEEN DISCOVERED WHEN ONE TWIN BECAME SYMPTOMATIC, AND THE OTHER WAS SCREENED. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST DOCUMENTED CASE OF DISCORDANT ADULT TYPE INTESTINAL MALROTATION IN OTHERWISE ASYMPTOMATIC MONOZYGOTIC TWINS DISCOVERED INCIDENTALLY DURING LAPAROSCOPIC ROUX-EN-Y GASTRIC BYPASS (LRYGB). CASE PRESENTATION: TWINS A AND B MET THE NIH CRITERIA FOR BARIATRIC SURGERY, NEITHER HAVING SYMPTOMS OF ACUTE OR CHRONIC VOLVULUS OR HISTORY OF INTRAABDOMINAL SURGERY. TWIN A HAD A LRYGB PERFORMED BY A TRAINED BARIATRIC SURGEON, NOTING NO ANATOMIC ANOMALIES. 5 MONTHS LATER, TWIN B HAD LRYGB AND INTESTINAL MALROTATION WAS DIAGNOSED INCIDENTALLY. CLINICAL DISCUSSION: DIAGNOSIS OF INTESTINAL MALROTATION IS RARE IN ADULTS, USUALLY DISCOVERED AFTER BECOMING SYMPTOMATIC OR DURING ABDOMINAL IMAGING FOR ANOTHER INDICATION. TWO CASES OF DISCORDANT INTESTINAL MALROTATION IN MONOZYGOTIC TWINS HAVE BEEN DOCUMENTED, BOTH DISCOVERED WHEN ONE TWIN BECAME SYMPTOMATIC DUE TO ACUTE VOLVULUS, SUGGESTING EPIGENETIC PHENOMENA. WHEN DISCOVERED INCIDENTALLY DURING SURGERY, PATIENTS CAN SAFELY UNDERGO THEIR INTENDED PROCEDURE, BUT LITERATURE SUGGESTS PROPHYLACTIC DIVISION OF LADD'S BANDS, WHILE APPENDECTOMY IS LEFT TO THE DISCRETION OF THE SURGEON. CONCLUSIONS: INTESTINAL MALROTATION APPEARS TO BE ASSOCIATED WITH EPIGENETIC PHENOMENA AND IF DISCOVERED INCIDENTALLY DURING SURGERY, THE PROPOSED PROCEDURE CAN BE CARRIED OUT BY AN EXPERIENCED SURGEON, IN ADDITION TO DIVISION OF LADD'S BANDS AND APPENDECTOMY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9 4537  32 MULTIPLE SCLEROSIS SUSCEPTIBILITY AND THE X CHROMOSOME. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE COMPLEX TRAIT WITH STRONG EVIDENCE FOR A GENETIC COMPONENT. A FEMALE GENDER BIAS IS CLEAR BUT UNEXPLAINED AND A MATERNAL PARENT-OF-ORIGIN EFFECT HAS BEEN DESCRIBED. X-LINKED TRANSMISSION OF SUSCEPTIBILITY HAS BEEN PREVIOUSLY PROPOSED, BASED ON PEDIGREE, ASSOCIATION AND LINKAGE STUDIES. WE GENOTYPED 726 RELATIVE PAIRS INCLUDING 552 AFFECTED SIB-PAIRS FOR 22 X-CHROMOSOME MICROSATELLITE MARKERS AND A NOVEL DATASET OF 195 AUNT-UNCLE/NIECE-NEPHEW (AUNN) AFFECTED PAIRS FOR 18 MARKERS. PARENT-OF-ORIGIN EFFECTS WERE EXPLORED BY DIVIDING AUNN FAMILIES INTO LIKELY MATERNAL AND PATERNAL TRAIT TRANSMISSION. FOR THE SIB-PAIR DATASET WE WERE ABLE TO ESTABLISH EXCLUSION AT A LAMBDA S = 1.9 FOR ALL MARKERS USING AN EXCLUSION THRESHOLD OF LOD < OR = -2. SIMILARLY FOR THE AUNN DATASET, WE ESTABLISHED EXCLUSION AT LAMBDAAV = 1.9. FOR THE COMBINED DATASET WE ESTIMATE EXCLUSION OF LAMBDA = 1.6. WE DID NOT IDENTIFY SIGNIFICANT LINKAGE IN EITHER THE SIB-PAIRS OR THE AUNN DATASET NOR WHEN DATASETS WERE STRATIFIED FOR THE PRESENCE/ABSENCE OF THE HLA-DRB1*15 ALLELE OR FOR PATERNAL OR MATERNAL TRANSMISSION. THIS COMPREHENSIVE SCRUTINY OF THE X-CHROMOSOME SUGGESTS THAT IT IS UNLIKELY TO HARBOUR AN INDEPENDENT SUSCEPTIBILITY LOCUS OR ONE WHICH INTERACTS WITH THE HLA. COMPLEX INTERACTIONS INCLUDING EPIGENETIC ONES, AND MASKING BY BALANCED POLYMORPHISMS ARE MECHANISMS NOT EXCLUDED BY THE APPROACH TAKEN.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  645  30 BIRTH DEFECTS IN GAZA: PREVALENCE, TYPES, FAMILIARITY AND CORRELATION WITH ENVIRONMENTAL FACTORS. THIS IS THE FIRST REPORT OF REGISTRATION AT BIRTH, AND OF INCIDENCE OF MAJOR STRUCTURAL BIRTH DEFECTS (BD) OBTAINED IN GAZA AT AL SHIFA HOSPITAL, WHERE 28% OF TOTAL BIRTHS IN GAZA STRIP OCCUR. DOCTORS REGISTERED 4,027 DELIVERIES, WITH A PROTOCOL COMPREHENSIVE OF CLINICAL, DEMOGRAPHIC, KIN AND ENVIRONMENTAL QUESTIONS. PREVALENCE OF BD IS 14/1,000, WITHOUT ASSOCIATION WITH INTERMARRIAGE OR GENDER OF THE CHILD. PREVALENCE OF LATE MISCARRIAGES AND STILL BIRTHS ARE RESPECTIVELY 23.3/1,000 AND 7.4/1,000, AND OF PREMATURE BIRTHS 19.6/1,000. COUPLES WITH A BD CHILD HAVE ABOUT 10 TIMES HIGHER FREQUENCY OF RECURRENCE OF A BD IN THEIR PROGENY THAN THOSE WITH NORMAL CHILDREN, BUT NONE OF THEIR 694 SIBLINGS AND ONLY 10/1,000 OF THEIR 1,423 PROGENY HAD BD, SIMILAR TO THE FREQUENCY IN GENERAL POPULATION. THESE DATA SUGGEST OCCURRENCE OF NOVEL GENETIC AND EPIGENETIC EVENTS IN DETERMINATION OF BD. CHILDREN WITH BD WERE BORN WITH HIGHER FREQUENCY (P < 0 001) IN FAMILIES WHERE ONE OR BOTH PARENTS WERE UNDER "WHITE PHOSPHORUS" ATTACK, THAT IN THE GENERAL POPULATION. BOMBING OF THE FAMILY HOME AND REMOVAL OF THE RUBBLE WERE ALSO FREQUENTLY REPORTED BY COUPLES WITH BD OCCURRENCE. THESE DATA SUGGESTS A CAUSATIVE/FAVORING ROLE OF ACUTE EXPOSURE OF PARENTS TO THE WEAPONS-ASSOCIATED CONTAMINANTS, AND/OR OF THEIR CHRONIC EXPOSURE FROM THEIR PERSISTENCE IN THE ENVIRONMENT ON THE EMBRYONIC DEVELOPMENT OF THEIR CHILDREN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 6835  27 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 2978  39 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	
                               
13 6632  31 UNDERSTANDING THE ROLE OF THE CHROMOSOME 15Q25.1 IN COPD THROUGH EPIGENETICS AND TRANSCRIPTOMICS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A MAJOR HEALTH BURDEN IN ADULTS AND CIGARETTE SMOKING IS CONSIDERED THE MOST IMPORTANT ENVIRONMENTAL RISK FACTOR OF COPD. CHROMOSOME 15Q25.1 LOCUS IS ASSOCIATED WITH BOTH COPD AND SMOKING. OUR STUDY AIMS AT UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION OF CHROMOSOME 15Q25.1 WITH COPD THROUGH EPIGENETIC AND TRANSCRIPTIONAL VARIATION IN A POPULATION-BASED SETTING. TO ASSESS IF COPD-ASSOCIATED VARIANTS IN 15Q25.1 ARE METHYLATION QUANTITATIVE TRAIT LOCI, EPIGENOME-WIDE ASSOCIATION ANALYSIS OF FOUR GENETIC VARIANTS, PREVIOUSLY ASSOCIATED WITH COPD (P < 5 X 10(-8)) IN THE 15Q25.1 LOCUS (RS12914385:C>T-CHRNA3, RS8034191:T>C-HYKK, RS13180:C>T-IREB2 AND RS8042238:C>T-IREB2), WAS PERFORMED IN THE ROTTERDAM STUDY (N = 1489). ALL FOUR VARIANTS WERE SIGNIFICANTLY ASSOCIATED (P < 1.4 X 10(-6)) WITH BLOOD DNA METHYLATION OF IREB2, CHRNA3 AND PSMA4, OF WHICH TWO, INCLUDING IREB2 AND PSMA4, WERE ALSO DIFFERENTIALLY METHYLATED IN COPD CASES AND CONTROLS (P < 0.04). FURTHER ADDITIVE AND MULTIPLICATIVE EFFECTS OF SMOKING WERE EVALUATED AND NO SIGNIFICANT EFFECT WAS OBSERVED. TO EVALUATE IF THESE FOUR GENETIC VARIANTS ARE EXPRESSION QUANTITATIVE TRAIT LOCI, TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS WAS PERFORMED IN 1087 LUNG SAMPLES. ALL FOUR VARIANTS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH DIFFERENTIAL EXPRESSION OF THE IREB2 3'UTR IN LUNG TISSUES (P < 5.4 X 10(-95)). WE CONCLUDE THAT REGULATORY MECHANISMS AFFECTING THE EXPRESSION OF IREB2 GENE, SUCH AS DNA METHYLATION, MAY EXPLAIN THE ASSOCIATION BETWEEN GENETIC VARIANTS IN CHROMOSOME 15Q25.1 AND COPD, LARGELY INDEPENDENT OF SMOKING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14 6911  33 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 3050  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16 3883  38 KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. BACKGROUND: A RECENT REVIEW BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) UPDATED THE ASSESSMENTS OF THE > 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912.	2016	
                                                                                                                                                                                                                                                   
17 6036  40 THE CHARACTERISTICS OF EXTRACHROMOSOMAL CIRCULAR DNA IN PATIENTS WITH END-STAGE RENAL DISEASE. BACKGROUND: END-STAGE RENAL DISEASE (ESRD) IS THE FINAL STAGE OF CHRONIC KIDNEY DISEASE (CKD). IN ADDITION TO THE STRUCTURALLY INTACT CHROMOSOME GENOMIC DNA, THERE IS A DOUBLE-STRANDED CIRCULAR DNA CALLED EXTRACHROMOSOMAL CIRCULAR DNA (ECCDNA), WHICH IS THOUGHT TO BE INVOLVED IN THE EPIGENETIC REGULATION OF HUMAN DISEASE. HOWEVER, THE FEATURES OF ECCDNA IN ESRD PATIENTS ARE BARELY KNOWN. IN THIS STUDY, WE IDENTIFIED ECCDNA FROM ESRD PATIENTS AND HEALTHY PEOPLE, AS WELL AS REVEALED THE CHARACTERISTICS OF ECCDNA IN PATIENTS WITH ESRD. METHODS: USING THE HIGH-THROUGHPUT CIRCLE-SEQUENCING TECHNIQUE, WE EXAMINED THE ECCDNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY PEOPLE (NC) (N = 12) AND ESRD PATIENTS (N = 16). WE ANALYZED THE LENGTH DISTRIBUTION, GENOME ELEMENTS, AND MOTIFS FEATURE OF ECCDNA IN ESRD PATIENTS. THEN, AFTER IDENTIFYING THE SPECIFIC ECCDNA IN ESRD PATIENTS, WE EXPLORED THE POTENTIAL FUNCTIONS OF THE TARGET GENES OF THE SPECIFIC ECCDNA. FINALLY, WE INVESTIGATED THE PROBABLE HUB ECCDNA USING ALGORITHMS. RESULTS: IN TOTAL, 14,431 AND 11,324 ECCDNAS WERE FOUND IN THE ESRD AND NC GROUPS, RESPECTIVELY, WITH SIZES RANGING FROM 0.01 KB TO 60 KB AT MOST. ADDITIONALLY, THE ESRD GROUP HAD A GREATER DISTRIBUTION OF ECCDNA ON CHROMOSOMES 4, 11, 13, AND 20. IN TWO GROUPS, WE ALSO DISCOVERED SEVERAL MOTIFS OF SPECIFIC ECCDNAS. FURTHERMORE, WE IDENTIFIED 13,715 SPECIFIC ECCDNAS IN THE ESRD GROUP AND 10,585 SPECIFIC ECCDNAS IN THE NC GROUP, BOTH OF WHICH WERE LARGELY ANNOTATED AS MRNA CATALOG. PATHWAY STUDIES USING GENE ONTOLOGY (GO) AND THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) SHOWED THAT THE SPECIFIC ECCDNA IN ESRD WAS MARKEDLY ENRICHED IN CELL JUNCTION AND COMMUNICATION PATHWAYS. FURTHERMORE, WE IDENTIFIED POTENTIALLY 20 HUB ECCDNA-TARGETING GENES FROM ALL ESRD-SPECIFIC ECCDNA-TARGETING GENES. ALSO, WE FOUND THAT 39 ECCDNA-TARGETING GENES WERE ASSOCIATED WITH ESRD, AND SOME OF THESE ECCDNAS MAY BE RELATED TO THE PATHOGENESIS OF ESRD. CONCLUSIONS: OUR FINDINGS REVEALED THE CHARACTERISTICS OF ECCDNA IN ESRD PATIENTS AND DISCOVERED POTENTIALLY HUB AND ESRD-RELEVANT ECCDNA-TARGETING GENES, SUGGESTING A NOVEL PROBABLE MECHANISM OF ESRD.	2023	
                                                                                                                                                                                        
18 5092  41 PLACENTAL EPIGENETIC MARKS RELATED TO GESTATIONAL WEIGHT GAIN REVEAL POTENTIAL GENES ASSOCIATED WITH OFFSPRING OBESITY PARAMETERS. OBJECTIVE: OFFSPRING EXPOSED TO GESTATIONAL OBESITY HAVE AN INCREASED RISK FOR CHRONIC DISEASES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETICS MAY PLAY A MECHANISTIC ROLE IN METABOLIC PROGRAMMING. THIS STUDY AIMED TO IDENTIFY PLACENTAL DNA METHYLATION MARKS ASSOCIATED WITH GESTATIONAL WEIGHT GAIN (GWG) AND TO STUDY THEIR ASSOCIATION WITH OFFSPRING OBESITY PARAMETERS AT SCHOOL AGE. METHODS: A GLOBAL METHYLATION ARRAY WAS PERFORMED IN 24 PLACENTAS FROM MOTHERS WITH DIFFERENT DEGREES OF GWG (SCREENING SAMPLE). THE METHYLATION PERCENTAGE OF FOUR CYTOSINE-GUANINE (CPG) SITES AND THE RELATIVE EXPRESSION OF THE RESPECTIVE ANNOTATED GENES WERE STUDIED IN 90 ADDITIONAL PLACENTAS (VALIDATION SAMPLE). ASSOCIATIONS OF THESE EPIGENETIC MARKS WITH CLINICAL PARAMETERS IN THE OFFSPRING AT 6 YEARS OF AGE WERE EXAMINED. RESULTS: THE SCREENING ANALYSIS IDENTIFIED 104 CPG SITES (97 GENES) ASSOCIATED WITH GWG. THE VALIDATION ANALYSIS OF FOUR SELECTED CPG SITES (ANNOTATING FOR FRAT1, SNX5, AND KCNK3 GENES) SHOWED THAT THE UPREGULATION OF SNX5 METHYLATION, THE DOWNREGULATION OF FRAT1 METHYLATION, AND KCNK3 UNDEREXPRESSION ASSOCIATED WITH AN ADVERSE METABOLIC PHENOTYPE IN CHILDREN OF WOMEN WITH INCREASED GWG. CONCLUSIONS: THESE RESULTS SUGGEST THAT PLACENTAL REGULATION OF FRAT1, SNX5, AND KCNK3 RELATES TO OBESITY PARAMETERS IN OFFSPRING EXPOSED TO EXCESSIVE GWG AND THEREBY COULD CONDITION THE RISK FOR FUTURE METABOLIC DISORDERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 3907  37 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20 3505  34 IDENTIFICATION OF SEX-SPECIFIC DNA METHYLATION CHANGES DRIVEN BY SPECIFIC CHEMICALS IN CORD BLOOD IN A FAROESE BIRTH COHORT. FAROE ISLANDERS CONSUME MARINE FOODS CONTAMINATED WITH METHYLMERCURY (MEHG), POLYCHLORINATED BIPHENYLS (PCBS), AND OTHER TOXICANTS ASSOCIATED WITH CHRONIC DISEASE RISKS. DIFFERENTIAL DNA METHYLATION AT SPECIFIC CPG SITES IN CORD BLOOD MAY SERVE AS A SURROGATE BIOMARKER OF HEALTH IMPACTS FROM CHEMICAL EXPOSURES. WE AIMED TO IDENTIFY KEY ENVIRONMENTAL CHEMICALS IN CORD BLOOD ASSOCIATED WITH DNA METHYLATION CHANGES IN A POPULATION WITH ELEVATED EXPOSURE TO CHEMICAL MIXTURES. WE STUDIED 72 PARTICIPANTS OF A FAROESE BIRTH COHORT RECRUITED BETWEEN 1986 AND 1987 AND FOLLOWED UNTIL ADULTHOOD. THE CORD BLOOD DNA METHYLOME WAS PROFILED USING INFINIUM HUMANMETHYLATION450 BEADCHIPS. WE DETERMINED THE ASSOCIATIONS OF CPG SITE CHANGES WITH CONCENTRATIONS OF MEHG, MAJOR PCBS, OTHER ORGANOCHLORINE COMPOUNDS [HEXACHLOROBENZENE (HCB), P,P'-DICHLORODIPHENYLDICHLOROETHYLENE (P,P'-DDE) AND P,P'-DICHLORODIPHENYLTRICHLOROETHANE], AND PERFLUOROALKYL SUBSTANCES. IN A COMBINED SEX ANALYSIS, AMONG THE 16 CHEMICALS STUDIED, PCB CONGENER 105 (CB-105) EXPOSURE WAS ASSOCIATED WITH THE MAJORITY OF DIFFERENTIALLY METHYLATED CPG SITES (214 OUT OF A TOTAL OF 250). IN FEMALE-ONLY ANALYSIS, ONLY 73 CB-105 ASSOCIATED CPG SITES WERE DETECTED, 44 OF WHICH WERE MAPPED TO GENES IN THE ELAV1-ASSOCIATED CANCER NETWORK. IN MALES-ONLY, METHYLATION CHANGES WERE SEEN FOR PERFLUOROOCTANE SULFONATE, HCB, AND P,P'-DDE IN 10,598, 1,238, AND 1,473 CPG SITES, RESPECTIVELY, 15% OF WHICH WERE ENRICHED IN CYTOBANDS OF THE X-CHROMOSOME ASSOCIATED WITH NEUROLOGICAL DISORDERS. IN THIS MULTIPLE-POLLUTANT AND GENOME-WIDE STUDY, WE IDENTIFIED KEY EPIGENETIC TOXICANTS. THE SIGNIFICANT ENRICHMENT OF SPECIFIC X-CHROMOSOME SITES IN MALES IMPLIES POTENTIAL SEX-SPECIFIC EPIGENOME RESPONSES TO PRENATAL CHEMICAL EXPOSURES.	2018