1  1169 108 CONTRIBUTION OF GENETIC, EPIGENETIC AND TRANSCRIPTOMIC DIFFERENCES TO TWIN DISCORDANCE IN MULTIPLE SCLEROSIS. EVALUATION OF: BARANZINI SE, MUDGE J, VAN VELKINBURGH JC ET AL. GENOME, EPIGENOME AND RNA SEQUENCES OF MONOZYGOTIC TWINS DISCORDANT FOR MULTIPLE SCLEROSIS. NATURE 464, 1351-1356 (2010). MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CNS. GENETICALLY IDENTICAL (MONOZYGOTIC) TWINS HAVE A CONCORDANCE RATE FOR MS OF APPROXIMATELY 30%, LENDING SUPPORT TO THE NOTION THAT THE DISEASE HAS A COMPLEX ETIOLOGY, DEVELOPING AS A RESULT OF GENETIC AND ENVIRONMENTAL FACTORS AND THEIR INTERACTIONS. HOWEVER, RECENT STUDIES HAVE HIGHLIGHTED THE FACT THAT MONOZYGOTIC TWINS MIGHT NOT ACTUALLY BE GENETICALLY IDENTICAL. IN AN EFFORT TO SEE IF THIS CAN EXPLAIN MS TWIN DISCORDANCE, BARANZINI AND COLLEAGUES SEQUENCED THE GENOME FROM A PAIR OF MONOZYGOTIC TWINS DISCORDANT FOR MS, AND ALSO EXAMINED DNA METHYLATION AND GENE EXPRESSION ACROSS THE GENOME IN THIS TWIN PAIR AND AN ADDITIONAL TWO MORE TWIN PAIRS. NO CONSISTENT DIFFERENCES IN DNA SEQUENCE, DNA METHYLATION OR GENE EXPRESSION WERE FOUND. HERE WE PUT THESE FINDINGS INTO CONTEXT AND DISCUSS THEIR SIGNIFICANCE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  4256  36 METHYLOMIC MARKERS OF PERSISTENT CHILDHOOD ASTHMA: A LONGITUDINAL STUDY OF ASTHMA-DISCORDANT MONOZYGOTIC TWINS. BACKGROUND: ASTHMA IS THE MOST COMMON CHRONIC INFLAMMATORY DISORDER IN CHILDREN. THE AETIOLOGY OF ASTHMA PATHOLOGY IS COMPLEX AND HIGHLY HETEROGENEOUS, INVOLVING THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS THAT IS HYPOTHESIZED TO INVOLVE EPIGENETIC PROCESSES. OUR AIM WAS TO EXPLORE WHETHER METHYLOMIC VARIATION IN EARLY CHILDHOOD IS ASSOCIATED WITH DISCORDANCE FOR ASTHMA SYMPTOMS WITHIN MONOZYGOTIC (MZ) TWIN PAIRS RECRUITED FROM THE ENVIRONMENTAL RISK (E-RISK) LONGITUDINAL TWIN STUDY. WE ALSO AIMED TO IDENTIFY DIFFERENCES IN DNA METHYLATION THAT ARE ASSOCIATED WITH ASTHMA THAT DEVELOPS IN CHILDHOOD AND PERSISTS INTO EARLY ADULTHOOD AS THESE MAY REPRESENT USEFUL PROGNOSTIC BIOMARKERS. RESULTS: WE EXAMINED GENOME-WIDE PATTERNS OF DNA METHYLATION IN BUCCAL CELL SAMPLES COLLECTED FROM 37 MZ TWIN PAIRS DISCORDANT FOR ASTHMA AT AGE 10. DNA METHYLATION AT INDIVIDUAL CPG SITES DEMONSTRATED SIGNIFICANT VARIABILITY WITHIN DISCORDANT MZ TWIN PAIRS WITH THE TOP-RANKED NOMINALLY SIGNIFICANT DIFFERENTIALLY METHYLATED POSITION (DMP) LOCATED IN THE HGSNAT GENE. WE STRATIFIED OUR ANALYSIS BY ASSESSING DNA METHYLATION DIFFERENCES IN A SUB-GROUP OF MZ TWIN PAIRS WHO REMAINED PERSISTENTLY DISCORDANT FOR ASTHMA AT AGE 18. THE TOP-RANKED NOMINALLY SIGNIFICANT DMP ASSOCIATED WITH PERSISTING ASTHMA IS LOCATED IN THE VICINITY OF THE HLX GENE, WHICH HAS BEEN PREVIOUSLY IMPLICATED IN CHILDHOOD ASTHMA. CONCLUSIONS: WE IDENTIFIED DNA METHYLATION DIFFERENCES ASSOCIATED WITH CHILDHOOD ASTHMA IN PERIPHERAL DNA SAMPLES FROM DISCORDANT MZ TWIN PAIRS. OUR DATA SUGGEST THAT DIFFERENCES IN DNA METHYLATION ASSOCIATED WITH CHILDHOOD ASTHMA WHICH PERSISTS INTO EARLY ADULTHOOD ARE DISTINCT FROM THOSE ASSOCIATED WITH ASTHMA WHICH REMITS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3  5222  29 PRIMARY BILIARY CIRRHOSIS: FAMILY STORIES. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC IMMUNE-MEDIATED CHOLESTATIC LIVER DISEASE OF UNKNOWN AETIOLOGY WHICH AFFECTS MOSTLY WOMEN IN MIDDLE AGE. FAMILIAL PBC IS WHEN PBC AFFECTS MORE THAN ONE MEMBER OF THE SAME FAMILY, AND DATA SUGGEST THAT FIRST-DEGREE RELATIVES OF PBC PATIENTS HAVE AN INCREASED RISK OF DEVELOPING THE DISEASE. MOST OFTEN, THESE FAMILIAL CLUSTERS INVOLVE MOTHER-DAUGHTER PAIRS, WHICH IS CONSISTENT WITH THE FEMALE PREPONDERANCE OF THE DISEASE. THESE CLUSTERS PROVIDE EVIDENCE TOWARDS A GENETIC BASIS UNDERLYING PBC. HOWEVER, CLUSTERS OF NONRELATED INDIVIDUALS HAVE ALSO BEEN REPORTED, GIVING STRENGTH TO AN ENVIRONMENTAL COMPONENT. TWIN STUDIES HAVE DEMONSTRATED A HIGH CONCORDANCE FOR PBC IN MONOZYGOTIC TWINS AND A LOW CONCORDANCE AMONG DIZYGOTIC TWINS. IN CONCLUSION, STUDIES OF PBC IN FAMILIES CLEARLY DEMONSTRATE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF THE DISEASE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  2192  35 EPIGENETIC METHODS AND TWIN STUDIES. GENOMIC PREDISPOSITION FAILS TO FULLY EXPLAIN THE ONSET OF COMPLEX DISEASES, WHICH IS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELING, AND NON-CODING RNA, ARE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. AUTOIMMUNE DISEASES NOW INCLUDE ALMOST 100 CONDITIONS AND ARE ESTIMATED TO CUMULATIVELY AFFECT UP TO 5% OF THE WORLD POPULATION WITH A HEALTHCARE EXPENDITURE SUPERIOR TO CANCER WORLDWIDE. MANY ADVANCES IN MEDICINE HAVE BEEN MADE TO TREAT THESE CONDITIONS BUT THERE ARE STILL GAPS, AND AN INNOVATIVE AND EFFICIENT THERAPY IS NEEDED. SYSTEMIC AUTOIMMUNE DISEASES INCLUDE RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, SJOGREN SYNDROME, POLYMYOSITIS, AND DERMATOMYOSITIS. MONOZYGOTIC TWINS DISCORDANT FOR ANY DISEASE OFFER AN IDEAL STUDY DESIGN AS THEY ARE MATCHED FOR MANY FACTORS, INCLUDING GENETIC VARIATION AND THIS IS A REAL ADVANTAGE FOR EPIGENETICS STUDY. WE WILL HEREIN DISCUSS THE AVAILABLE DATA IN THE EPIGENETIC DIFFERENCES LEADING TO DISEASE DISCORDANCE IN MZ TWINS FOR SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AND SYSTEMIC SCLEROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  4775  43 NUCLEIC ACID-SENSING AND INTERFERON-INDUCIBLE PATHWAYS SHOW DIFFERENTIAL METHYLATION IN MZ TWINS DISCORDANT FOR LUPUS AND OVEREXPRESSION IN INDEPENDENT LUPUS SAMPLES: IMPLICATIONS FOR PATHOGENIC MECHANISM AND DRUG TARGETING. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, AUTOIMMUNE INFLAMMATORY DISEASE WITH GENOMIC AND NON-GENOMIC CONTRIBUTIONS TO RISK. WE HYPOTHESIZE THAT EPIGENETIC FACTORS ARE A SIGNIFICANT CONTRIBUTOR TO SLE RISK AND MAY BE INFORMATIVE FOR IDENTIFYING PATHOGENIC MECHANISMS AND THERAPEUTIC TARGETS. TO TEST THIS HYPOTHESIS WHILE CONTROLLING FOR GENETIC BACKGROUND, WE PERFORMED AN EPIGENOME-WIDE ANALYSIS OF DNA METHYLATION IN GENOMIC DNA FROM WHOLE BLOOD IN THREE PAIRS OF FEMALE MONOZYGOTIC (MZ) TWINS OF EUROPEAN ANCESTRY, DISCORDANT FOR SLE. RESULTS WERE REPLICATED ON THE SAME ARRAY IN FOUR CELL TYPES FROM A SET OF FOUR DANISH FEMALE MZ TWIN PAIRS DISCORDANT FOR SLE. GENES IMPLICATED BY THE EPIGENETIC ANALYSES WERE THEN EVALUATED IN 10 INDEPENDENT SLE GENE EXPRESSION DATASETS FROM THE GENE EXPRESSION OMNIBUS (GEO). THERE WERE 59 DIFFERENTIALLY METHYLATED LOCI BETWEEN UNAFFECTED AND AFFECTED MZ TWINS IN WHOLE BLOOD, INCLUDING 11 NOVEL LOCI. ALL BUT TWO OF THESE LOCI WERE HYPOMETHYLATED IN THE SLE TWINS RELATIVE TO THE UNAFFECTED TWINS. THE GENES HARBORING THESE HYPOMETHYLATED LOCI EXHIBITED INCREASED EXPRESSION IN MULTIPLE INDEPENDENT DATASETS OF SLE PATIENTS. THIS PATTERN WAS LARGELY CONSISTENT REGARDLESS OF DISEASE ACTIVITY, CELL TYPE, OR RENAL TISSUE TYPE. THE GENES PROXIMAL TO CPGS EXHIBITING DIFFERENTIAL METHYLATION (DM) IN THE SLE-DISCORDANT MZ TWINS AND EXHIBITING DIFFERENTIAL EXPRESSION (DE) IN INDEPENDENT SLE GEO COHORTS (DM-DE GENES) CLUSTERED INTO TWO PATHWAYS: THE NUCLEIC ACID-SENSING PATHWAY AND THE TYPE I INTERFERON PATHWAY. THE DM-DE GENES WERE ALSO INFORMATICALLY QUERIED FOR POTENTIAL GENE-DRUG INTERACTIONS, YIELDING A LIST OF 41 DRUGS INCLUDING A KNOWN SLE THERAPY. THE DM-DE GENES DELINEATE TWO IMPORTANT BIOLOGIC PATHWAYS THAT ARE NOT ONLY REFLECTIVE OF THE HETEROGENEITY OF SLE BUT MAY ALSO CORRELATE WITH DISTINCT IFN RESPONSES THAT DEPEND ON THE SOURCE, TYPE, AND LOCATION OF NUCLEIC ACID MOLECULES AND THE ACTIVATED RECEPTORS IN INDIVIDUAL PATIENTS. CELL- AND TISSUE-SPECIFIC ANALYSES WILL BE CRITICAL TO THE UNDERSTANDING OF GENETIC FACTORS DYSREGULATING THE NUCLEIC ACID-SENSING AND IFN PATHWAYS AND WHETHER THESE FACTORS COULD BE APPROPRIATE TARGETS FOR THERAPEUTIC INTERVENTION.	2021	
                                                                                                                                                                                                                                                                                                                            
6  2512  43 EPIGENETICS AND PRIMARY BILIARY CIRRHOSIS: A COMPREHENSIVE REVIEW AND IMPLICATIONS FOR AUTOIMMUNITY. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT DEVELOPS BASED UPON THE INTERACTION OF GENETIC AND ENVIRONMENTAL FACTORS. RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED DOZENS OF PREDISPOSING VARIANTS INCLUDING HLA, IL12A, AND CTLA4 BUT HAVE BEEN DISAPPOINTED IN IDENTIFYING A "SMOKING GUN." THESE DISCOVERIES HIGHLIGHT THE IMPORTANCE OF THE GENETIC BACKGROUND INVOLVED IN IMMUNOLOGICAL DYSREGULATION. ALTHOUGH CONCORDANCE RATE OF PBC IN MONOZYGOTIC (MZ) TWINS IS AMONG THE HIGHEST REPORTED IN AUTOIMMUNE DISORDERS, INCOMPLETE DISEASE CONCORDANCE IN TWINS ASSOCIATED WITH DIFFERENTIALLY EXPRESSED GENES HAS BEEN DEMONSTRATED. HOWEVER, LITTLE IS UNDERSTOOD ABOUT HOW ENVIRONMENTAL ASPECTS CONTRIBUTE TO THE DISEASE AND WHY MIDDLE-AGED WOMEN ARE MORE SUSCEPTIBLE. AS A RESULT, EPIGENETIC FACTORS, WHICH CONVERT SIGNALS INDICATING ENVIRONMENTAL CHANGES INTO DYNAMIC AND HERITABLE ALTERATIONS OF TRANSCRIPTIONAL POTENTIAL, ARE GETTING INCREASED ATTENTION BY RESEARCHERS IN BOTH BASIC AND CLINICAL STUDIES. AMONG EPIGENETIC MECHANISMS, THE INSTABILITY AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY ACCOUNT FOR THE FEMALE PREPONDERANCE IN PBC. IN ADDITION, TRANSCRIPTIONAL REGULATION OF HISTONE MODIFICATION AND DNA METHYLATION UNDERSCORES POTENTIAL INVOLVEMENT IN DISEASE PATHOGENESIS. HIGH-THROUGHPUT TECHNIQUES ARE BEING USED TO IDENTIFY EPIGENETIC REGULATORS. IN THIS REVIEW, WE ATTEMPT TO OUTLINE RECENT PROGRESS REGARDING EPIGENETICS IN PBC AND OTHER AUTOIMMUNE DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7   381  30 AN EPIGENOME-WIDE ASSOCIATION STUDY OF EARLY-ONSET MAJOR DEPRESSION IN MONOZYGOTIC TWINS. MAJOR DEPRESSION (MD) IS A DEBILITATING MENTAL HEALTH CONDITION WITH PEAK PREVALENCE OCCURRING EARLY IN LIFE. GENOME-WIDE EXAMINATION OF DNA METHYLATION (DNAM) OFFERS AN ATTRACTIVE COMPLEMENT TO STUDIES OF ALLELIC RISK GIVEN IT CAN REFLECT THE COMBINED INFLUENCE OF GENES AND ENVIRONMENT. THE CURRENT STUDY USED MONOZYGOTIC TWINS TO IDENTIFY DIFFERENTIALLY AND VARIABLY METHYLATED REGIONS OF THE GENOME THAT DISTINGUISH TWINS WITH AND WITHOUT A LIFETIME HISTORY OF EARLY-ONSET MD. THE SAMPLE INCLUDED 150 CAUCASIAN MONOZYGOTIC TWINS BETWEEN THE AGES OF 15 AND 20 (73% FEMALE; MAGE = 17.52 SD = 1.28) WHO WERE ASSESSED DURING A DEVELOPMENTAL STAGE CHARACTERIZED BY RELATIVELY DISTINCT NEUROPHYSIOLOGICAL CHANGES. ALL TWINS WERE GENERALLY HEALTHY AND CURRENTLY FREE OF MEDICATIONS WITH PSYCHOTROPIC EFFECTS. DNAM WAS MEASURED IN PERIPHERAL BLOOD CELLS USING THE INFINIUM HUMAN BEADCHIP 450 K ARRAY. MD ASSOCIATIONS WITH EARLY-ONSET MD WERE DETECTED AT 760 DIFFERENTIALLY AND VARIABLY METHYLATED PROBES/REGIONS THAT MAPPED TO 428 GENES. GENES AND GENOMIC REGIONS INVOLVED NEURAL CIRCUITRY FORMATION, PROJECTION, FUNCTIONING, AND PLASTICITY. GENE ENRICHMENT ANALYSES IMPLICATED GENES RELATED TO NEURON STRUCTURES AND NEURODEVELOPMENTAL PROCESSES INCLUDING CELL-CELL ADHESION GENES (E.G., PCDHA GENES). GENES PREVIOUSLY IMPLICATED IN MOOD AND PSYCHIATRIC DISORDERS AS WELL AS CHRONIC STRESS (E.G., NRG3) ALSO WERE IDENTIFIED. DNAM REGIONS ASSOCIATED WITH EARLY-ONSET MD WERE FOUND TO OVERLAP GENETIC LOCI IDENTIFIED IN THE LATEST PSYCHIATRIC GENOMICS CONSORTIUM META-ANALYSIS OF DEPRESSION. UNDERSTANDING THE TIME COURSE OF EPIGENETIC INFLUENCES DURING EMERGING ADULTHOOD MAY CLARIFY DEVELOPMENTAL PHASES WHERE CHANGES IN THE DNA METHYLOME MAY MODULATE INDIVIDUAL DIFFERENCES IN MD RISK.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  2142  45 EPIGENETIC INVESTIGATION OF VARIABLY X CHROMOSOME INACTIVATED GENES IN MONOZYGOTIC FEMALE TWINS DISCORDANT FOR PRIMARY BILIARY CIRRHOSIS. PRIMARY BILIARY CIRRHOSIS (PBC) IS AN AUTOIMMUNE CHRONIC CHOLESTATIC LIVER DISEASE WITH A STRONG GENETIC SUSCEPTIBILITY DUE TO THE HIGH CONCORDANCE IN MONOZYGOTIC (MZ) TWINS AND A STRIKING FEMALE PREDOMINANCE. WOMEN WITH PBC MANIFEST AN ENHANCED X MONOSOMY RATE IN PERIPHERAL LYMPHOCYTES AND WE THUS HYPOTHESIZED AN X CHROMOSOME EPIGENETIC COMPONENT TO EXPLAIN PBC FEMALE PREVALENCE. WHILE MOST GENES ON THE FEMALE INACTIVE X CHROMOSOME ARE SILENCED BY PROMOTER METHYLATION FOLLOWING X CHROMOSOME INACTIVATION (XCI), APPROXIMATELY 10% OF X- LINKED GENES EXHIBIT VARIABLE ESCAPE FROM XCI IN HEALTHY FEMALES. THIS STUDY WAS DESIGNED TO TEST THE HYPOTHESIS THAT SUSCEPTIBILITY TO PBC IS MODIFIED BY ONE OR MORE X-LINKED GENE WITH VARIABLE XCI STATUS. PERIPHERAL BLOOD MRNA AND DNA SAMPLES WERE OBTAINED FROM A UNIQUE COHORT OF MZ TWIN SETS DISCORDANT AND CONCORDANT FOR PBC. TRANSCRIPT LEVELS OF THE 125 VARIABLE XCI STATUS GENES WAS DETERMINED BY QUANTITATIVE RT-PCR ANALYSIS AND TWO GENES (CLIC2 AND PIN4) WERE IDENTIFIED AS CONSISTENTLY DOWNREGULATED IN THE AFFECTED TWIN OF DISCORDANT PAIRS. BOTH CLIC2 AND PIN4 DEMONSTRATED PARTIAL AND VARIABLE METHYLATION OF CPG SITES WITHIN 300 BP OF THE TRANSCRIPTION START SITE THAT DID NOT PREDICT THE XCI STATUS. PROMOTER METHYLATION OF CLIC2 MANIFESTED NO SIGNIFICANT DIFFERENCE BETWEEN SAMPLES AND NO SIGNIFICANT CORRELATION WITH TRANSCRIPT LEVELS. PIN4 METHYLATION SHOWED A POSITIVE TREND WITH TRANSCRIPTION IN ALL SAMPLES BUT NO DIFFERENTIAL METHYLATION WAS OBSERVED BETWEEN DISCORDANT TWINS. A GENETIC POLYMORPHISM AFFECTING THE NUMBER OF CPG SITES IN THE PIN4 PROMOTER DID NOT IMPACT METHYLATION OR TRANSCRIPT LEVELS IN A HETEROZYGOUS TWIN PAIR AND SHOWED A SIMILAR FREQUENCY IN INDEPENDENT SERIES OF UNRELATED PBC CASES AND CONTROLS. OUR RESULTS SUGGEST THAT EPIGENETIC FACTORS INFLUENCING PBC ONSET ARE MORE COMPLEX THAN METHYLATION DIFFERENCES AT X-LINKED PROMOTERS AND VARIABLY 3 INACTIVATED X-LINKED GENES MAY BE CHARACTERIZED BY PARTIAL PROMOTER METHYLATION AND BIALLELIC TRANSCRIPTION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  6598  26 TWINSUK: THE UK ADULT TWIN REGISTRY UPDATE. TWINSUK IS THE LARGEST COHORT OF COMMUNITY-DWELLING ADULT TWINS IN THE UK. THE REGISTRY COMPRISES OVER 14,000 VOLUNTEER TWINS (14,838 INCLUDING MIXED, SINGLE AND TRIPLETS); IT IS PREDOMINANTLY FEMALE (82%) AND MIDDLE-AGED (MEAN AGE 59). IN ADDITION, OVER 1800 PARENTS AND SIBLINGS OF TWINS ARE REGISTERED VOLUNTEERS. DURING THE LAST 27 YEARS, TWINSUK HAS COLLECTED NUMEROUS QUESTIONNAIRE RESPONSES, PHYSICAL/COGNITIVE MEASURES AND BIOLOGICAL MEASURES ON OVER 8500 SUBJECTS. DATA WERE COLLECTED ALONGSIDE FOUR COMPREHENSIVE PHENOTYPING CLINICAL VISITS TO THE DEPARTMENT OF TWIN RESEARCH AND GENETIC EPIDEMIOLOGY, KING'S COLLEGE LONDON. SUCH COLLECTION METHODS HAVE RESULTED IN VERY DETAILED LONGITUDINAL CLINICAL, BIOCHEMICAL, BEHAVIORAL, DIETARY AND SOCIOECONOMIC COHORT CHARACTERIZATION; IT PROVIDES A MULTIDISCIPLINARY PLATFORM FOR THE STUDY OF COMPLEX DISEASE DURING THE ADULT LIFE COURSE, INCLUDING THE PROCESS OF HEALTHY AGING. THE MAJOR STRENGTH OF TWINSUK IS THE AVAILABILITY OF SEVERAL 'OMIC' TECHNOLOGIES FOR A RANGE OF SAMPLE TYPES FROM PARTICIPANTS, WHICH INCLUDES GENOMEWIDE SCANS OF SINGLE-NUCLEOTIDE VARIANTS, NEXT-GENERATION SEQUENCING, METABOLOMIC PROFILES, MICROBIOMICS, EXOME SEQUENCING, EPIGENETIC MARKERS, GENE EXPRESSION ARRAYS, RNA SEQUENCING AND TELOMERE LENGTH MEASURES. TWINSUK FACILITATES AND ACTIVELY ENCOURAGES SHARING THE 'TWINSUK' RESOURCE WITH THE SCIENTIFIC COMMUNITY - INTERESTED RESEARCHERS MAY REQUEST DATA VIA THE TWINSUK WEBSITE (HTTP://TWINSUK.AC.UK/RESOURCES-FOR-RESEARCHERS/ACCESS-OUR-DATA/) FOR THEIR OWN USE OR FUTURE COLLABORATION WITH THE STUDY TEAM. IN ADDITION, FURTHER COHORT DATA COLLECTION IS PLANNED VIA THE WELLCOME OPEN RESEARCH GATEWAY (HTTPS://WELLCOMEOPENRESEARCH.ORG/GATEWAYS). THE CURRENT ARTICLE PRESENTS AN UP-TO-DATE REPORT ON THE APPLICATION OF TECHNOLOGICAL ADVANCES, NEW STUDY PROCEDURES IN THE COHORT AND FUTURE DIRECTION OF TWINSUK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10   463  30 ARE EPIGENETIC FACTORS IMPLICATED IN CHRONIC WIDESPREAD PAIN? BACKGROUND: CHRONIC WIDESPREAD MUSCULOSKELETAL PAIN (CWP) IS THE CARDINAL SYMPTOM OF FIBROMYALGIA AND AFFECTS ABOUT 12% OF THE GENERAL POPULATION. FAMILIAL AGGREGATION OF CWP HAS BEEN REPEATEDLY DEMONSTRATED WITH ESTIMATED HERITABILITIES OF AROUND 50%, INDICATING A GENETIC SUSCEPTIBILITY. THE OBJECTIVE OF THE STUDY WAS TO EXPLORE GENOME-WIDE DISEASE-DIFFERENTIALLY METHYLATED POSITIONS (DMPS) FOR CHRONIC WIDESPREAD PAIN (CWP) IN A SAMPLE OF UNRELATED INDIVIDUALS AND A SUBSAMPLE OF DISCORDANT MONOZYGOTIC (MZ) TWINS. METHODOLOGY/PRINCIPLE FINDINGS: A TOTAL OF N = 281 TWIN INDIVIDUALS FROM THE TWINSUK REGISTRY, INCLUDING N = 33 MZ TWINS DISCORDANT FOR SELF-REPORTED CWP, WERE PART OF THE DISCOVERY SAMPLE. THE REPLICATION SAMPLE INCLUDED 729 MEN AND 756 WOMEN FROM A SUBSAMPLE OF THE KORA S4 SURVEY-AN INDEPENDENT POPULATION-BASED COHORT FROM SOUTHERN GERMANY. EPIGENOME-WIDE ANALYSIS OF DNA METHYLATION WAS CONDUCTED USING THE ILLUMINA INFINIUM HUMANMETHYLATION 450 DNA BEADCHIP IN BOTH THE DISCOVERY AND REPLICATION SAMPLE. OF OUR 40 MAIN LOCI THAT WERE CARRIED FORWARD FOR REPLICATION, THREE CPGS REACHED SIGNIFICANT P-VALUES IN THE REPLICATION SAMPLE, INCLUDING MALATE DEHYDROGENASE 2 (MDH2; P-VALUE 0.017), TETRANECTIN (CLEC3B; P-VALUE 0.039), AND HEAT SHOCK PROTEIN BETA-6 (HSPB6; P-VALUE 0.016). THE ASSOCIATIONS BETWEEN THE COLLAGEN TYPE I, ALPHA 2 CHAIN (COL1A2) AND MONOAMINE OXIDASE B (MAOB) OBSERVED IN THE DISCOVERY SAMPLE-BOTH OF WHICH HAVE BEEN PREVIOUSLY REPORTED TO BE BIOLOGICAL CANDIDATES FOR PAIN-COULD NOT BE REPLICATED. CONCLUSION/SIGNIFICANCE: OUR RESULTS MAY SERVE AS A STARTING POINT TO ENCOURAGE FURTHER INVESTIGATION IN LARGE AND INDEPENDENT POPULATION-BASED COHORTS OF DNA METHYLATION AND OTHER EPIGENETIC CHANGES AS POSSIBLE DISEASE MECHANISMS IN CWP. ULTIMATELY, UNDERSTANDING THE KEY MECHANISMS UNDERLYING CWP MAY LEAD TO NEW TREATMENTS AND INFORM CLINICAL PRACTICE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  2075  36 EPIGENETIC DIFFERENCES IN INFLAMMATION GENES OF MONOZYGOTIC TWINS ARE RELATED TO PARENT-CHILD EMOTIONAL AVAILABILITY AND HEALTH. THE INFLAMMATORY RESPONSE IS AN IMMUNE DEFENSE ENGAGED IMMEDIATELY AFTER INJURY OR INFECTION. CHRONIC INFLAMMATION CAN BE DELETERIOUS FOR VARIOUS HEALTH OUTCOMES AND IS CHARACTERIZED BY HIGH LEVELS OF PRO-INFLAMMATORY MARKERS SUCH AS C-REACTIVE PROTEIN (CRP), INTERLEUKIN 6 (IL-6), AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA). A LARGE BODY OF RESEARCH DEMONSTRATES THESE INFLAMMATORY MARKERS ARE RESPONSIVE TO STRESS AND QUALITY OF SOCIAL RELATIONSHIPS THROUGHOUT THE LIFESPAN. FOR EXAMPLE, THE QUALITY OF THE EARLY PARENTAL BOND PREDICTS VARIOUS HEALTH OUTCOMES AND MAY BE DRIVEN BY CHANGES IN IMMUNE FUNCTION. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, MAY BE ONE MECHANISM BY WHICH EARLY SOCIAL EXPERIENCES SHAPE IMMUNE FUNCTIONING. THE PRESENT STUDY USED A MONOZYGOTIC TWIN DIFFERENCE DESIGN TO ASSESS IF MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR AND 2.5 YEARS PREDICTED IMMUNE GENE METHYLATION AT 8 YEARS OF AGE. FURTHER, WE ASSESSED IF INFLAMMATION GENE METHYLATION WAS RELATED TO GENERAL HEALTH PROBLEMS (E.G. INFECTIONS, ALLERGIES, ETC.). WE FOUND THAT MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR, BUT NOT 2.5 YEARS, WAS RELATED TO METHYLATION OF VARIOUS IMMUNE GENES IN MONOZYGOTIC TWINS. FURTHERMORE, TWIN PAIRS DISCORDANT IN HEALTH PROBLEMS HAVE MORE DIFFERENCE IN IMMUNE GENE METHYLATION COMPARED TO TWIN PAIRS CONCORDANT FOR HEALTH PROBLEMS, SUGGESTING THAT METHYLATION OF IMMUNE GENES MAY HAVE FUNCTIONAL CONSEQUENCES FOR GENERAL HEALTH. THESE RESULTS SUGGEST THAT THE EMOTIONAL COMPONENT OF ATTACHMENT QUALITY DURING INFANCY CONTRIBUTES TO IMMUNE EPIGENETIC PROFILES IN CHILDHOOD, WHICH MAY INFLUENCE GENERAL HEALTH.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12  5371  27 RECENT ADVANCES IN UNDERSTANDING THE GENETIC BASIS OF SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A POLYGENIC CHRONIC AUTOIMMUNE DISEASE LEADING TO MULTIPLE ORGAN DAMAGE. A LARGE HERITABILITY OF UP TO 66% IS ESTIMATED IN SLE, WITH ROUGHLY 180 REPORTED SUSCEPTIBILITY LOCI THAT HAVE BEEN IDENTIFIED MOSTLY BY GENOME-WIDE ASSOCIATION STUDIES (GWASS) AND ACCOUNT FOR APPROXIMATELY 30% OF GENETIC HERITABILITY. A VAST MAJORITY OF RISK VARIANTS RESIDE IN NON-CODING REGIONS, WHICH MAKES IT QUITE CHALLENGING TO INTERPRET THEIR FUNCTIONAL IMPLICATIONS IN THE SLE-AFFECTED IMMUNE SYSTEM, SUGGESTING THE IMPORTANCE OF UNDERSTANDING CELL TYPE-SPECIFIC EPIGENETIC REGULATION AROUND SLE GWAS VARIANTS. THE LATEST GENETIC STUDIES HAVE BEEN HIGHLY FRUITFUL AS SEVERAL DOZENS OF SLE LOCI WERE NEWLY DISCOVERED IN THE LAST FEW YEARS AND MANY LOCI HAVE COME TO BE UNDERSTOOD IN SYSTEMIC APPROACHES INTEGRATING GWAS SIGNALS WITH OTHER BIOLOGICAL RESOURCES. IN THIS REVIEW, WE SUMMARIZE SLE-ASSOCIATED GENETIC VARIANTS IN BOTH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) AND NON-MHC LOCI, EXAMINING POLYGENETIC RISK SCORES FOR SLE AND THEIR ASSOCIATIONS WITH CLINICAL FEATURES. FINALLY, VARIANT-DRIVEN PATHOGENETIC FUNCTIONS UNDERLYING GENETIC ASSOCIATIONS ARE DESCRIBED, COUPLED WITH DISCUSSION ABOUT CHALLENGES AND FUTURE DIRECTIONS IN GENETIC STUDIES ON SLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13  6761  35 X CHROMOSOME-WIDE ANALYSIS IDENTIFIES DNA METHYLATION SITES INFLUENCED BY CIGARETTE SMOKING. BACKGROUND: TOBACCO SMOKING IS A MAJOR CAUSE OF CHRONIC DISEASE WORLDWIDE. SMOKING MAY INDUCE CELLULAR AND MOLECULAR CHANGES INCLUDING EPIGENETIC MODIFICATION, WITH BOTH SHORT-TERM AND LONG-TERM MODIFICATION PATTERNS THAT MAY CONTRIBUTE TO PHENOTYPIC EXPRESSION OF DISEASES. RECENT EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED DOZENS OF SMOKING-RELATED DNA METHYLATION (DNAM) SITES. HOWEVER, THE X CHROMOSOMAL DNAM SITES HAVE BEEN LARGELY OVERLOOKED DUE TO A LACK OF AN ANALYTICAL FRAMEWORK FOR DEALING WITH THE SEX-DIMORPHIC DISTRIBUTION. TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES ON THE X CHROMOSOME, WE EXAMINED THE MODALITY OF EACH X CHROMOSOMAL DNAM SITE AND CONDUCTED A SEX-SPECIFIC ASSOCIATION STUDY OF CIGARETTE SMOKING. RESULTS: WE USED A DISCOVERY SAMPLE OF 139 MIDDLE-AGE TWINS, AND THREE REPLICATION SAMPLES OF 78 TWINS, 464 AND 333 UNRELATED INDIVIDUALS INCLUDING 47, 17, 22, AND 89 CURRENT SMOKERS, RESPECTIVELY. AFTER CORRECTION FOR MULTIPLE TESTING, THE TOP SMOKING-RELATED DNAM SITES IN BCOR AND TSC22D3 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, AMONG CURRENT SMOKERS. THESE SMOKING-ASSOCIATED SITES WERE REPLICATED WITH META-ANALYSIS P-VALUES OF 9.17 X 10(-12) AND 1.61 X 10(-9). FOR BOTH SITES, THE SMOKING EFFECTS ON METHYLATION LEVELS WERE LARGER IN MALES THAN THAT IN FEMALES. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING X CHROMOSOME METHYLATION PATTERNS AND THEIR ASSOCIATIONS WITH ENVIRONMENTAL EXPOSURES AND DISEASE PHENOTYPES AND DEMONSTRATE A ROBUST STATISTICAL METHODOLOGY FOR SUCH STUDY. EXISTING EWAS OF HUMAN DISEASES SHOULD INCORPORATE THE X CHROMOSOMAL SITES TO COMPLETE A COMPREHENSIVE EPIGENOME-WIDE SCAN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  3112  34 GEOEPIDEMIOLOGY AND (EPI-)GENETICS IN PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A RARE FEMALE PREPONDERANT CHRONIC AUTOIMMUNE CHOLESTATIC LIVER DISEASE, CHARACTERIZED BY INTRAHEPATIC DUCTOPENIA AND PROGRESSIVE FIBROSIS. DURING LAST DECADES INCIDENCE AND PREVALENCE SHOWED AN INCREASING RATE WHICH VARY WIDELY WORLDWIDE DEMONSTRATING AN IMPORTANT INTERACTION BETWEEN ENVIRONMENTAL AND GENETIC FACTORS. HERITABILITY SUGGESTED BY FAMILIAL OCCURRENCE AND MONOZYGOTIC TWINS CONCORDANCE HAVE BEEN CONFIRMED IN MORE STUDIES. EPIGENETICS MECHANISMS SUCH AS HISTONE MODIFICATION AND DNA METHYLATION CAN PARTIALLY EXPLAIN PREDISPOSITION AND INHERITANCE OF THIS DISEASE. NEVERTHELESS, AN ASSOCIATION WITH SPECIFIC CLASS II HUMAN LEUKOCYTE ANTIGEN (HLA) VARIANTS HAVE BEEN REPORTED, SHOWING AN INCREASE RISK IN SUSCEPTIBILITY. MORE RECENTLY, DATA REGARDING A STRONG PROTECTIVE ASSOCIATION BETWEEN PBC AND HLA ALLELES CONFIRMED THIS ASSOCIATION. AFTER RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS), A MORE INTRICATE INTERACTION BETWEEN PBC AND THE HLA REGION HAS BEEN SHOWN. FURTHERMORE, GWAS ALSO IDENTIFIED SEVERAL IMMUNE-RELATED-GENES IMPLICATED. MORE GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE ARE NEEDED TO REACH A COMPLETE AND SYSTEMATIC KNOWLEDGE OF THIS DISEASE. IN THIS REVIEW WE DISCUSS MORE RECENT ISSUED DATA ON GEOEPIDEMIOLOGY OF PBC AND THE ROLE OF (EPI-)GENETIC MECHANISMS IN ITS PATHOGENESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  3690  45 INFLAMMATORY BOWEL DISEASE: GENETICS, EPIGENETICS, AND PATHOGENESIS. INFLAMMATORY BOWEL DISEASES (IBDS) ARE COMPLEX, MULTIFACTORIAL DISORDERS CHARACTERIZED BY CHRONIC RELAPSING INTESTINAL INFLAMMATION. ALTHOUGH ETIOLOGY REMAINS LARGELY UNKNOWN, RECENT RESEARCH HAS SUGGESTED THAT GENETIC FACTORS, ENVIRONMENT, MICROBIOTA, AND IMMUNE RESPONSE ARE INVOLVED IN THE PATHOGENESIS. EPIDEMIOLOGICAL EVIDENCE FOR A GENETIC CONTRIBUTION IS DEFINED: 15% OF PATIENTS WITH CROHN'S DISEASE (CD) HAVE AN AFFECTED FAMILY MEMBER WITH IBD, AND TWIN STUDIES FOR CD HAVE SHOWN 50% CONCORDANCE IN MONOZYGOTIC TWINS COMPARED TO <10% IN DIZYGOTICS. THE MOST RECENT AND LARGEST GENETIC ASSOCIATION STUDIES, WHICH EMPLOYED GENOME-WIDE ASSOCIATION DATA FOR OVER 75,000 PATIENTS AND CONTROLS, IDENTIFIED 163 SUSCEPTIBILITY LOCI FOR IBD. MORE RECENTLY, A TRANS-ETHNIC ANALYSIS, INCLUDING OVER 20,000 INDIVIDUALS, IDENTIFIED AN ADDITIONAL 38 NEW IBD LOCI. ALTHOUGH MOST CASES ARE CORRELATED WITH POLYGENIC CONTRIBUTION TOWARD GENETIC SUSCEPTIBILITY, THERE IS A SPECTRUM OF RARE GENETIC DISORDERS THAT CAN CONTRIBUTE TO EARLY-ONSET IBD (BEFORE 5 YEARS) OR VERY EARLY ONSET IBD (BEFORE 2 YEARS). GENETIC VARIANTS THAT CAUSE THESE DISORDERS HAVE A WIDE EFFECT ON GENE FUNCTION. THESE VARIANTS ARE SO RARE IN ALLELE FREQUENCY THAT THE GENETIC SIGNALS ARE NOT DETECTED IN GENOME-WIDE ASSOCIATION STUDIES OF PATIENTS WITH IBD. WITH RECENT ADVANCES IN SEQUENCING TECHNIQUES, ~50 GENETIC DISORDERS HAVE BEEN IDENTIFIED AND ASSOCIATED WITH IBD-LIKE IMMUNOPATHOLOGY. MONOGENIC DEFECTS HAVE BEEN FOUND TO ALTER INTESTINAL IMMUNE HOMEOSTASIS THROUGH MANY MECHANISMS. CANDIDATE GENE RESEQUENCING SHOULD BE CARRIED OUT IN EARLY-ONSET PATIENTS IN CLINICAL PRACTICE. THE EVIDENCE THAT GENETIC FACTORS CONTRIBUTE IN SMALL PART TO DISEASE PATHOGENESIS CONFIRMS THE IMPORTANT ROLE OF MICROBIAL AND ENVIRONMENTAL FACTORS. EPIGENETIC FACTORS CAN MEDIATE INTERACTIONS BETWEEN ENVIRONMENT AND GENOME. EPIGENETIC MECHANISMS COULD AFFECT DEVELOPMENT AND PROGRESSION OF IBD. EPIGENOMICS IS AN EMERGING FIELD, AND FUTURE STUDIES COULD PROVIDE NEW INSIGHT INTO THE PATHOGENESIS OF IBD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16   244  40 ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), ENVIRONMENT, EXPOSOME AND EPIGENETICS: A MOLECULAR PERSPECTIVE OF POSTNATAL NORMAL SPINAL GROWTH AND THE ETIOPATHOGENESIS OF AIS WITH CONSIDERATION OF A NETWORK APPROACH AND POSSIBLE IMPLICATIONS FOR MEDICAL THERAPY. GENETIC FACTORS ARE BELIEVED TO PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS). DISCORDANT FINDINGS FOR MONOZYGOTIC (MZ) TWINS WITH AIS SHOW THAT ENVIRONMENTAL FACTORS INCLUDING DIFFERENT INTRAUTERINE ENVIRONMENTS ARE IMPORTANT IN ETIOLOGY, BUT WHAT THESE ENVIRONMENTAL FACTORS MAY BE IS UNKNOWN. RECENT EVIDENCE FOR COMMON CHRONIC NON-COMMUNICABLE DISEASES SUGGESTS EPIGENETIC DIFFERENCES MAY UNDERLIE MZ TWIN DISCORDANCE, AND BE THE LINK BETWEEN ENVIRONMENTAL FACTORS AND PHENOTYPIC DIFFERENCES. DNA METHYLATION IS ONE IMPORTANT EPIGENETIC MECHANISM OPERATING AT THE INTERFACE BETWEEN GENOME AND ENVIRONMENT TO REGULATE PHENOTYPIC PLASTICITY WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. THE WORD EXPOSOME REFERS TO THE TOTALITY OF ENVIRONMENTAL EXPOSURES FROM CONCEPTION ONWARDS, COMPRISING FACTORS IN EXTERNAL AND INTERNAL ENVIRONMENTS. THE WORD EXPOSOME IS USED HERE ALSO IN RELATION TO PHYSIOLOGIC AND ETIOPATHOGENETIC FACTORS THAT AFFECT NORMAL SPINAL GROWTH AND MAY INDUCE THE DEFORMITY OF AIS. IN NORMAL POSTNATAL SPINAL GROWTH WE PROPOSE A NEW TERM AND CONCEPT, PHYSIOLOGIC GROWTH-PLATE EXPOSOME FOR THE NORMAL PROCESSES PARTICULARLY OF THE INTERNAL ENVIRONMENTS THAT MAY HAVE EPIGENETIC EFFECTS ON GROWTH PLATES OF VERTEBRAE. IN AIS, WE PROPOSE A NEW TERM AND CONCEPT PATHOPHYSIOLOGIC SCOLIOGENIC EXPOSOME FOR THE ABNORMAL PROCESSES IN MOLECULAR PATHWAYS PARTICULARLY OF THE INTERNAL ENVIRONMENT CURRENTLY EXPRESSED AS ETIOPATHOGENETIC HYPOTHESES; THESE ARE SUGGESTED TO HAVE DEFORMING EFFECTS ON THE GROWTH PLATES OF VERTEBRAE AT CELL, TISSUE, STRUCTURE AND/OR ORGAN LEVELS THAT ARE CONSIDERED TO BE EPIGENETIC. NEW RESEARCH IS REQUIRED FOR CHROMATIN MODIFICATIONS INCLUDING DNA METHYLATION IN AIS SUBJECTS AND VERTEBRAL GROWTH PLATES EXCISED AT SURGERY. IN ADDITION, CONSIDERATION IS NEEDED FOR A POSSIBLE NETWORK APPROACH TO ETIOPATHOGENESIS BY CONSTRUCTING AIS DISEASOMES. THESE APPROACHES MAY LEAD THROUGH SCREENING, GENETIC, EPIGENETIC, BIOCHEMICAL, METABOLIC PHENOTYPES AND PHARMACOGENOMIC RESEARCH TO IDENTIFY SUSCEPTIBLE INDIVIDUALS AT RISK AND MODULATE ABNORMAL MOLECULAR PATHWAYS OF AIS. THE POTENTIAL OF EPIGENETIC-BASED MEDICAL THERAPY FOR AIS CANNOT BE ASSESSED AT PRESENT, AND MUST AWAIT NEW RESEARCH DERIVED FROM THE EVALUATION OF EPIGENETIC CONCEPTS OF SPINAL GROWTH IN HEALTH AND DEFORMITY. THE TENETS OUTLINED HERE FOR AIS ARE APPLICABLE TO OTHER MUSCULOSKELETAL GROWTH DISORDERS INCLUDING INFANTILE AND JUVENILE IDIOPATHIC SCOLIOSIS.	2011	

17  6262  40 THE MULTIFACETED FUNCTIONAL ROLE OF DNA METHYLATION IN IMMUNE-MEDIATED RHEUMATIC DISEASES. GENOMIC PREDISPOSITION CANNOT EXPLAIN THE ONSET OF COMPLEX DISEASES, AS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELLING AND NON-CODING RNA, ARE CONSIDERED TO BE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. THE PARADIGMATIC CASES OF RHEUMATOID ARTHRITIS (RA), SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), SYSTEMIC SCLEROSIS (SSC), SJOGREN'S SYNDROME (SJS) AND TYPE-1 DIABETES (T1D) SHARE THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGEN INFLUENCED BY SEVERAL FACTORS, WITH A LARGELY INCOMPLETE ROLE OF INDIVIDUAL GENOMIC SUSCEPTIBILITY. THE MOST WIDELY INVESTIGATED EPIGENETIC MECHANISM IS DNA METHYLATION WHICH IS ASSOCIATED WITH GENE SILENCING AND IS DUE TO THE BINDING OF METHYL-CPG BINDING DOMAIN (MBD)-CONTAINING PROTEINS, SUCH AS MECP2, TO 5-METHYLCYTOSINE (5MC). INDEED, A CAUSAL RELATIONSHIP OCCURS BETWEEN DNA METHYLATION AND TRANSCRIPTION FACTORS OCCUPANCY AND RECRUITMENT AT SPECIFIC GENOMIC LOCUS. IN MOST CASES, THE RESULTS OBTAINED IN DIFFERENT STUDIES ARE CONTROVERSIAL IN TERMS OF DNA METHYLATION COMPARISON WHILE FASCINATING EVIDENCE COMES FROM THE COMPARISON OF THE EPIGENOME IN CLINICALLY DISCORDANT MONOZYGOTIC TWINS. IN THIS MANUSCRIPT, WE WILL REVIEW THE MECHANISMS OF EPIGENETICS AND DNA METHYLATION CHANGES IN SPECIFIC IMMUNE-MEDIATED RHEUMATIC DISEASES TO HIGHLIGHT REMAINING UNMET NEEDS AND TO IDENTIFY POSSIBLE SHARED MECHANISMS BEYOND DIFFERENT TISSUE INVOLVEMENTS WITH COMMON THERAPEUTIC OPPORTUNITIES. KEY POINTS * DNA METHYLATION HAS A CRUCIAL ROLE IN REGULATING AND TUNING THE IMMUNE SYSTEM. * EVIDENCES SUGGEST THAT DYSREGULATION OF DNA METHYLATION IS PIVOTAL IN THE CONTEXT OF IMMUNE-MEDIATED RHEUMATIC DISEASES. * DNA METHYLATION DYSREGULATION IN FOXP3 AND INTERFERONS-RELATED GENES IS SHARED WITHIN SEVERAL AUTOIMMUNE DISEASES. * DNA METHYLATION IS AN ATTRACTIVE MARKER FOR DIAGNOSIS AND THERAPY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  2951  34 GENETIC AND EPIGENETIC EPIDEMIOLOGY OF CHRONIC WIDESPREAD PAIN. THE ETIOLOGY UNDERLYING CHRONIC WIDESPREAD PAIN (CWP) REMAINS LARGELY UNKNOWN. AN INTEGRATIVE BIOPSYCHOSOCIAL MODEL SEEMS TO YIELD THE MOST PROMISING EXPLANATIONS FOR THE PATHOGENESIS OF THE CONDITION, WITH GENETIC FACTORS ALSO CONTRIBUTING TO DISEASE DEVELOPMENT AND MAINTENANCE. HERE, WE CONDUCTED A SEARCH OF STUDIES INVESTIGATING THE GENETIC AND EPIGENETIC EPIDEMIOLOGY OF CWP THROUGH ELECTRONIC DATABASES INCLUDING WEB OF SCIENCE, MEDLINE, PUBMED, EMBASE, AND GOOGLE SCHOLAR. COMBINATIONS OF KEYWORDS INCLUDING CWP, CHRONIC PAIN, MUSCULOSKELETAL PAIN, GENETICS, EPIGENETICS, GENE, TWINS, SINGLE-NUCLEOTIDE POLYMORPHISM, GENOTYPE, AND ALLELES WERE USED. IN THE END, A TOTAL OF 15 PUBLICATIONS WERE CONSIDERED RELEVANT TO BE INCLUDED IN THIS REVIEW: EIGHT WERE TWIN STUDIES ON CWP, SIX WERE MOLECULAR GENETIC STUDIES ON CWP, AND ONE WAS AN EPIGENETIC STUDY ON CWP. THE FINDINGS SUGGEST GENETIC AND UNIQUE ENVIRONMENTAL FACTORS TO CONTRIBUTE TO CWP. VARIOUS CANDIDATES SUCH AS SEROTONIN-RELATED PATHWAY GENES WERE FOUND TO BE ASSOCIATED WITH CWP AND SOMATOFORM SYMPTOMS. HOWEVER, STUDIES SHOW SOME LIMITATIONS AND NEED REPLICATION. THE PRESENTED RESULTS FOR CWP COULD SERVE AS A TEMPLATE FOR GENETIC STUDIES ON OTHER CHRONIC PAIN CONDITIONS. ULTIMATELY, A MORE IN-DEPTH UNDERSTANDING OF DISEASE MECHANISMS WILL HELP WITH THE DEVELOPMENT OF MORE EFFECTIVE TREATMENT, INFORM NOSOLOGY, AND REDUCE THE STIGMA STILL LINGERING ON THIS DIAGNOSIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  6742  45 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM.	2012	
                                                                                                                                                                                                                                                                                
20  3209  18 HEALTH DISPARITIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE CHARACTERIZED BY AUTOANTIBODY PRODUCTION AND DIVERSE CLINICAL MANIFESTATIONS. THE MANY COMPLEX, OVERLAPPING, AND CLOSELY ASSOCIATED FACTORS THAT INFLUENCE SLE SUSCEPTIBILITY AND OUTCOMES INCLUDE ETHNIC DISPARITIES, LOW ADHERENCE TO MEDICATIONS, AND POVERTY, AND GEOGRAPHY. EPIGENETIC MECHANISMS MAY PROVIDE THE LINK BETWEEN THESE ENVIRONMENTAL EXPOSURES AND BEHAVIORS AND THE DISPROPORTIONATE BURDEN OF SLE SEEN IN ETHNIC MINORITIES. ATTENTION TO THESE MODIFIABLE SOCIAL DETERMINANTS OF HEALTH WOULD NOT ONLY IMPROVE OUTCOMES FOR VULNERABLE PATIENTS WITH SLE BUT LIKELY REDUCE SUSCEPTIBILITY TO SLE AS WELL THROUGH EPIGENETIC CHANGES.	2020