1 1760 111 EARLY PREDICTORS OF ASTHMA AND ALLERGY IN CHILDREN: THE ROLE OF EPIGENETICS. PURPOSE OF REVIEW: ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NONCOMMUNICABLE DISEASES OF CHILDHOOD. ALTHOUGH EPIDEMIOLOGIC STUDIES SUGGEST THAT ASTHMA BEGINS IN THE PRESCHOOL YEARS, THE LACK OF FIRM DIAGNOSTIC CRITERIA TO DISTINGUISH CHILDREN WHO WILL WHEEZE ONLY TRANSIENTLY DURING EARLY-LIFE LOWER RESPIRATORY ILLNESSES FROM CHILDREN WHO WILL WHEEZE PERSISTENTLY AND DEVELOP ASTHMA PREVENTS PINPOINTING THE TIME AT WHICH DISEASE TRULY BEGINS. EPIGENETIC MECHANISMS LINK GENE REGULATION TO ENVIRONMENTAL CUES AND DEVELOPMENTAL TRAJECTORIES. THIS ARTICLE REVIEWS, THE SEARCH FOR EPIGENETIC PREDICTORS OF ASTHMA AND/OR ALLERGY THAT CAN BE IDENTIFIED ALREADY AT BIRTH AND/OR IN EARLY LIFE. RECENT FINDINGS: DNA METHYLATION SIGNATURES ASSOCIATED WITH ASTHMA AND/OR ALLERGY AT BIRTH, AND TIME-DEPENDENT DNA METHYLATION SIGNATURES ASSOCIATED WITH ALLERGIC DISEASE PHENOTYPES IN EARLY LIFE HAVE BEEN IDENTIFIED. SUMMARY: THE IDENTIFICATION OF EARLY EPIGENETIC PREDICTORS OF ALLERGIC DISEASES POINTS TO A POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN REGULATING THE INCEPTION OF AND THE SUSCEPTIBILITY TO THESE DISEASES. PREDICTIVE SIGNATURES TO MORE ACCURATELY ESTIMATE A CHILD'S RISK FOR ASTHMA AND ALLERGY MAY IMPROVE CHILDHOOD ASTHMA DIAGNOSIS. MOREOVER, UNDERSTANDING THE BIOLOGICAL IMPLICATIONS OF THESE SIGNATURES MAY HELP ELUCIDATE NOVEL DISEASE PATHWAYS AND ENDOTYPES. 2015 2 2530 58 EPIGENETICS IN ALLERGIC DISEASES. PURPOSE OF REVIEW: ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC DISEASES OF CHILDHOOD, AFFECTING MORE THAN 7 MILLION CHILDREN IN THE UNITED STATES. EPIDEMIOLOGICAL EVIDENCE SUPPORTS THE IDEA THAT THE INCEPTION OF ALLERGIC DISEASES IS TYPICALLY BEFORE THE PRESCHOOL YEARS, EVEN WHEN CHRONIC SYMPTOMS DO NOT EMERGE UNTIL ADULTHOOD. THE ROLE OF EPIGENETIC MECHANISMS (PARTICULARLY DNA METHYLATION) IN ALLERGIC DISEASE IS UNDER ACTIVE INVESTIGATION BECAUSE THESE MECHANISMS ARE KNOWN TO BE AT THE INTERFACE OF GENE REGULATION, ENVIRONMENTAL STIMULI, AND DEVELOPMENTAL PROCESSES, ALL OF WHICH ARE ESSENTIAL FOR THE PATHOGENESIS FOR ASTHMA AND ALLERGY. THIS ARTICLE SPECIFICALLY REVIEWS GENOME-WIDE DNA METHYLATION STUDIES IN ALLERGIC DISEASE. RECENT FINDINGS: DIFFERENTIAL DNA METHYLATION AT SPECIFIC REGIONS APPEARS TO BE ASSOCIATED WITH CONCURRENT ALLERGIC DISEASE. A FEW STUDIES HAVE IDENTIFIED METHYLATION SIGNATURES PREDICTIVE OF DISEASE. SUMMARY: DNA METHYLATION SIGNATURES HAVE BEEN SHOWN TO BE ASSOCIATED WITH SEVERAL ALLERGIC DISEASE PHENOTYPES, TYPICALLY CONCURRENTLY WITH DISEASE. THE FEW THAT HAVE BEEN FOUND TO PRECEDE DIAGNOSIS ARE ESPECIALLY INTERESTING BECAUSE THEY HIGHLIGHT AN EARLY TRAJECTORY TO DISEASE. 2015 3 2160 45 EPIGENETIC MECHANISMS IN ASTHMA. ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NONCOMMUNICABLE DISEASES OF CHILDHOOD, BUT THE UNDERLYING PATHOGENETIC MECHANISMS ARE POORLY UNDERSTOOD. BECAUSE EPIGENETIC MECHANISMS LINK GENE REGULATION TO ENVIRONMENTAL CUES AND DEVELOPMENTAL TRAJECTORIES, THEIR CONTRIBUTION TO ASTHMA AND ALLERGY PATHOGENESIS IS UNDER ACTIVE INVESTIGATION. DNA METHYLATION SIGNATURES ASSOCIATED WITH CONCURRENT DISEASE AND WITH THE DEVELOPMENT OF ASTHMA DURING CHILDHOOD ASTHMA HAVE BEEN IDENTIFIED, BUT THEIR SIGNIFICANCE IS NOT EASILY INTERPRETABLE. ON THE OTHER HAND, THE CHARACTERIZATION OF EARLY EPIGENETIC PREDICTORS OF ASTHMA POINTS TO A POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN REGULATING THE INCEPTION OF, AND THE SUSCEPTIBILITY TO, THIS DISEASE. 2016 4 6303 43 THE PUZZLE OF IMMUNE PHENOTYPES OF CHILDHOOD ASTHMA. ASTHMA REPRESENTS THE MOST COMMON CHRONIC CHILDHOOD DISEASE WORLDWIDE. WHEREAS PRESCHOOL CHILDREN PRESENT WITH WHEEZING TRIGGERED BY DIFFERENT FACTORS (MULTITRIGGER AND VIRAL WHEEZE), CLINICAL ASTHMA MANIFESTATION IN SCHOOL CHILDREN HAS PREVIOUSLY BEEN CLASSIFIED AS ALLERGIC AND NON-ALLERGIC ASTHMA. FOR BOTH, THE UNDERLYING IMMUNOLOGICAL MECHANISMS ARE NOT YET UNDERSTOOD IN DEPTH IN CHILDREN. TREATMENT IS STILL PRESCRIBED REGARDLESS OF UNDERLYING MECHANISMS, AND CHILDREN ARE NOT ALWAYS TREATED SUCCESSFULLY. THIS REVIEW SUMMARIZES RECENT KEY FINDINGS ON THE COMPLEX MECHANISMS OF THE DEVELOPMENT AND MANIFESTATION OF CHILDHOOD ASTHMA. WHEREAS TRADITIONAL CLASSIFICATION OF CHILDHOOD ASTHMA IS PRIMARILY BASED ON CLINICAL SYMPTOMS LIKE WHEEZING AND ATOPY, NOVEL APPROACHES TO SPECIFY ASTHMA PHENOTYPES ARE UNDER WAY AND FACE CHALLENGES SUCH AS INCLUDING THE STABILITY OF PHENOTYPES OVER TIME AND TRANSITION INTO ADULTHOOD. EPIDEMIOLOGICAL STUDIES ENCLOSE MORE INFORMATION ON THE PATIENT'S DISEASE HISTORY AND ENVIRONMENTAL INFLUENCES. LATEST STUDIES DEFINE ENDOTYPES BASED ON MOLECULAR AND CELLULAR MECHANISMS, FOR EXAMPLE DEFINING RISK AND PROTECTIVE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND NEW IMMUNE PHENOTYPES, SHOWING PROMISING RESULTS. ALSO, REGULATORY T CELLS AND RECENTLY DISCOVERED T HELPER CELL SUBTYPES SUCH AS TH9 AND TH17 CELLS WERE SHOWN TO BE IMPORTANT FOR THE DEVELOPMENT OF ASTHMA. INNATE LYMPHOID CELLS (ILC) COULD PLAY A CRITICAL ROLE IN ASTHMA PATIENTS AS THEY PRODUCE DIFFERENT CYTOKINES ASSOCIATED WITH ASTHMA. EPIGENETIC FINDINGS SHOWED DIFFERENT ACETYLATION AND METHYLATION PATTERNS FOR CHILDREN WITH ALLERGIC AND NON-ALLERGIC ASTHMA. ON A POSTTRANSCRIPTIONAL LEVEL, MIRNAS ARE REGULATING FACTORS IDENTIFIED TO DIFFER BETWEEN ASTHMA PATIENTS AND HEALTHY CONTROLS AND ALSO INDICATE DIFFERENCES WITHIN ASTHMA PHENOTYPES. METABOLOMICS IS ANOTHER EXCITING CHAPTER IMPORTANT FOR ENDOTYPING ASTHMATIC CHILDREN. DESPITE THE DEVELOPMENT OF NEW BIOMARKERS AND THE DISCOVERY OF NEW IMMUNOLOGICAL MOLECULES, THE COMPLEX PUZZLE OF CHILDHOOD ASTHMA IS STILL FAR FROM BEING COMPLETED. ADDRESSING THE CURRENT CHALLENGES OF DISTINCT CLINICAL ASTHMA AND WHEEZE PHENOTYPES, INCLUDING THEIR STABILITY AND UNDERLYING ENDOTYPES, INVOLVES ADDRESSING THE INTERPLAY OF INNATE AND ADAPTIVE IMMUNE REGULATORY MECHANISMS IN LARGE, INTERDISCIPLINARY COHORTS. 2016 5 3580 36 IMPACT OF PERINATAL ENVIRONMENTAL TOBACCO SMOKE ON THE DEVELOPMENT OF CHILDHOOD ALLERGIC DISEASES. ALLERGIC DISEASES SUCH AS ASTHMA, ALLERGIC RHINITIS, ATOPIC DERMATITIS, AND FOOD ALLERGY, ARE MOST COMMON CHRONIC, NONCOMMUNICABLE DISEASES IN CHILDHOOD. IN THE PAST FEW DECADES, THE PREVALENCE HAS INCREASED ABRUPTLY WORLDWIDE. THERE ARE 2 POSSIBLE EXPLANATIONS FOR THE RISING PREVALENCE OF ALLERGIC DISEASES WORLDWIDE, THAT AN INCREASED DISEASE-AWARENESS OF PHYSICIAN, PATIENT, OR CAREGIVERS, AND AN ABRUPT EXPOSURE TO UNKNOWN HAZARDS. UNFORTUNATELY, THE UNDERLYING MECHANISMS REMAIN LARGELY UNKNOWN. DESPITE THE CONTINUING EFFORTS WORLDWIDE, THE ETIOLOGIES AND RISING PREVALENCE REMAIN UNCLEAR. THUS, IT IS IMPORTANT TO IDENTIFY AND CONTROL RISK FACTORS IN THE SUSCEPTIBLE INDIVIDUAL FOR THE BEST PREVENTION AND MANAGEMENT. GENETIC SUSCEPTIBILITY OR ENVIRONMENTS MAY BE A POTENTIAL BACKGROUND FOR THE DEVELOPMENT OF ALLERGIC DISEASE, HOWEVER THEY ALONE CANNOT EXPLAIN THE RISING PREVALENCE WORLDWIDE. THERE IS GROWING EVIDENCE THAT EPIGENETIC CHANGE DEPENDS ON THE GENE, ENVIRONMENT, AND THEIR INTERACTIONS, MAY INDUCE A LONG-LASTING ALTERED GENE EXPRESSION AND THE CONSEQUENT DEVELOPMENT OF ALLERGIC DISEASES. IN EPIGENETIC MECHANISMS, ENVIRONMENTAL TOBACCO SMOKE (ETS) EXPOSURE DURING CRITICAL PERIOD (I.E., DURING PREGNANCY AND EARLY LIFE) ARE CONSIDERED AS A POTENTIAL CAUSE OF THE DEVELOPMENT OF CHILDHOOD ALLERGIC DISEASES. HOWEVER, THE CAUSAL RELATIONSHIP IS STILL UNCLEAR. THIS REVIEW AIMED TO HIGHLIGHT THE IMPACT OF ETS EXPOSURE DURING THE PERINATAL PERIOD ON THE DEVELOPMENT OF CHILDHOOD ALLERGIC DISEASES AND TO PROPOSE A FUTURE RESEARCH DIRECTION. 2016 6 1757 29 EARLY ORIGINS OF ASTHMA (AND ALLERGY). ASTHMA IS THE MOST COMMON CHRONIC DISEASE STARTING IN CHILDHOOD AND PERSISTING INTO ADULTHOOD IN MANY CASES. DURING CHILDHOOD, DIFFERENT FORMS OF ASTHMA AND WHEEZING DISORDERS EXIST THAT CAN BE DISCRIMINATED BY THE MECHANISMS THEY ARE CAUSED BY. SPECIFIC GENETIC CONSTELLATIONS AND EXPOSURE AGAINST ENVIRONMENTAL FACTORS DURING EARLY CHILDHOOD AND IN UTERO PLAY A DECISIVE ROLE IN THE EARLY DEVELOPMENT OF THE DISEASE. EPIGENETIC MECHANISMS WHICH ARE MASTER REGULATORS OF GENE TRANSCRIPTION AND THUS GOVERN THE ACCESSIBILITY AND USE OF GENOME INFORMATION, HAVE RECENTLY BEEN IDENTIFIED AS A "THIRD POWER" DETERMINING MANY FEATURES IN THE EARLY DEVELOPMENT OF ASTHMA AND ALLERGY. 2016 7 2531 38 EPIGENETICS IN ASTHMA. PURPOSE OF REVIEW: ASTHMA IS ONE OF THE MOST COMMON CHRONIC RESPIRATORY DISEASES LINKED WITH INCREASED MORBIDITY AND HEALTHCARE UTILIZATION. THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES AND CAUSAL RELATIONSHIPS OF ASTHMA WITH EPIGENETIC MECHANISMS ARE PARTIALLY UNDERSTOOD. HERE WE REVIEW HUMAN STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA, WITH A SPECIAL FOCUS ON DNA METHYLATION. RECENT FINDINGS: EPIGENETIC STUDIES OF CHILDHOOD ASTHMA HAVE IDENTIFIED SPECIFIC METHYLATION SIGNATURES ASSOCIATED WITH ALLERGIC INFLAMMATION IN THE AIRWAY AND IMMUNE CELLS, DEMONSTRATING A REGULATORY ROLE FOR METHYLATION IN ASTHMA PATHOGENESIS. DESPITE THESE NOVEL FINDINGS, ADDITIONAL RESEARCH IN THE ROLE OF EPIGENETIC MECHANISMS UNDERLYING ASTHMA ENDOTYPES IS NEEDED. SIMILARLY, STUDIES OF HISTONE MODIFICATIONS ARE ALSO LACKING IN ASTHMA. FUTURE STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA WILL BENEFIT FROM DATA INTEGRATION IN WELL PHENOTYPED COHORTS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT LITERATURE ON EPIGENETIC STUDIES IN HUMAN ASTHMA, WITH SPECIAL EMPHASIS ON METHYLATION AND CHILDHOOD ASTHMA. 2019 8 2651 44 EPIGENOMICS AND TRANSCRIPTOMICS IN THE PREDICTION AND DIAGNOSIS OF CHILDHOOD ASTHMA: ARE WE THERE YET? ASTHMA IS THE MOST COMMON NON-COMMUNICABLE CHRONIC DISEASE OF CHILDHOOD. DESPITE ITS HIGH PREVALENCE, TO DATE WE LACK METHODS THAT ARE BOTH EFFICIENT AND ACCURATE IN DIAGNOSING ASTHMA. MOST TRADITIONAL APPROACHES HAVE BEEN BASED ON GARNERING CLINICAL EVIDENCE, SUCH AS RISK FACTORS AND EXPOSURES. GIVEN THE HIGH HERITABILITY OF ASTHMA, MORE RECENT APPROACHES HAVE LOOKED AT GENETIC POLYMORPHISMS AS POTENTIAL "RISK FACTORS." HOWEVER, GENETIC VARIANTS EXPLAIN ONLY A SMALL PROPORTION OF ASTHMA RISK, AND HAVE BEEN LESS THAN OPTIMAL AT PREDICTING RISK FOR INDIVIDUAL SUBJECTS. EPIGENOMIC STUDIES OFFER SIGNIFICANT ADVANTAGES OVER PREVIOUS APPROACHES. EPIGENETIC REGULATION IS HIGHLY TISSUE-SPECIFIC, AND CAN INDUCE BOTH SHORT- AND LONG-TERM CHANGES IN GENE EXPRESSION. SUCH CHANGES CAN START IN UTERO, CAN VARY THROUGHOUT THE LIFE SPAN, AND IN SOME INSTANCES CAN BE PASSED ON FROM ONE GENERATION TO ANOTHER. MOST IMPORTANTLY, THE EPIGENOME CAN BE MODIFIED BY ENVIRONMENTAL FACTORS AND EXPOSURES, AND THUS EPIGENETIC AND TRANSCRIPTOMIC PROFILING MAY YIELD THE MOST ACCURATE RISK ESTIMATES FOR A GIVEN PATIENT BY INCORPORATING ENVIRONMENTAL (AND TREATMENT) EFFECTS THROUGHOUT THE LIFESPAN. HERE WE WILL REVIEW THE MOST RECENT ADVANCES IN THE USE OF EPIGENETIC AND TRANSCRIPTOMIC ANALYSIS FOR THE EARLY DIAGNOSIS OF ASTHMA AND ATOPY, AS WELL AS CHALLENGES AND FUTURE DIRECTIONS IN THE FIELD AS IT MOVES FORWARD. WE WILL PARTICULARLY FOCUS ON DNA METHYLATION, THE MOST STUDIED MECHANISM OF EPIGENETIC REGULATION. 2019 9 2492 29 EPIGENETICS AND CHILDHOOD ASTHMA: CURRENT EVIDENCE AND FUTURE RESEARCH DIRECTIONS. ASTHMA IS THE MOST COMMON CHRONIC DISEASE OF CHILDHOOD, AFFECTING ONE IN EIGHT CHILDREN IN THE USA AND WORLDWIDE. IT IS A COMPLEX DISEASE, INFLUENCED BY BOTH ENVIRONMENTAL EXPOSURES AND GENETIC FACTORS. ALTHOUGH EPIGENETIC MODIFICATIONS (DNA METHYLATION, HISTONE MODIFICATION AND MIRNA) CAN AFFECT TRANSCRIPTIONAL ACTIVITY IN MULTIPLE GENETIC PATHWAYS RELEVANT FOR ASTHMA DEVELOPMENT, VERY LIMITED WORK HAS BEEN CARRIED OUT SO FAR TO EXAMINE THE ROLE OF EPIGENETIC VARIATIONS ON ASTHMA DEVELOPMENT AND MANAGEMENT. THIS REVIEW PROVIDES A BRIEF OVERVIEW OF EPIGENETIC MODIFICATIONS, SUMMARIZES RECENT FINDINGS, AND DISCUSSES SOME OF THE MAJOR METHODOLOGICAL CONCERNS THAT ARE RELEVANT FOR ASTHMA EPIGENETICS. 2012 10 6735 40 WHAT HAVE MECHANISTIC STUDIES TAUGHT US ABOUT CHILDHOOD ASTHMA? CHILDHOOD ASTHMA IS A CHRONIC HETEROGENEOUS SYNDROME CONSISTING OF DIFFERENT DISEASE ENTITIES OR PHENOTYPES. THE IMMUNOLOGIC AND CELLULAR PROCESSES THAT OCCUR DURING ASTHMA DEVELOPMENT ARE STILL NOT FULLY UNDERSTOOD BUT REPRESENT DISTINCT ENDOTYPES. MECHANISTIC STUDIES HAVE EXAMINED THE ROLE OF GENE EXPRESSION, PROTEIN LEVELS, AND CELL TYPES IN EARLY LIFE DEVELOPMENT AND THE MANIFESTATION OF ASTHMA, MANY UNDER THE INFLUENCE OF ENVIRONMENTAL STIMULI, WHICH CAN BE BOTH PROTECTIVE AND RISK FACTORS FOR ASTHMA. GENETIC VARIANTS CAN REGULATE GENE EXPRESSION, CONTROLLED PARTLY BY DIFFERENT EPIGENETIC MECHANISMS. IN ADDITION, ENVIRONMENTAL FACTORS, SUCH AS LIVING SPACE, NUTRITION, AND SMOKING, CAN CONTRIBUTE TO THESE MECHANISMS. ALL OF THESE FACTORS PRODUCE MODIFICATIONS IN GENE EXPRESSION THAT CAN ALTER THE DEVELOPMENT AND FUNCTION OF IMMUNE AND EPITHELIAL CELLS AND SUBSEQUENTLY DIFFERENT TRAJECTORIES OF CHILDHOOD ASTHMA. THESE EARLY CHANGES IN A PARTIALLY IMMATURE IMMUNE SYSTEM CAN HAVE DRAMATIC EFFECTS (E.G., CAUSING DYSREGULATION), WHICH IN TURN CONTRIBUTE TO DIFFERENT DISEASE ENDOTYPES AND MAY HELP TO EXPLAIN DIFFERENTIAL RESPONSIVENESS TO ASTHMA TREATMENT. IN THIS REVIEW, WE SUMMARIZE PUBLISHED STUDIES THAT HAVE AIMED TO UNCOVER DISTINCT MECHANISMS IN CHILDHOOD ASTHMA, CONSIDERING GENETICS, EPIGENETICS, AND ENVIRONMENT. MOREOVER, A DISCUSSION OF NEW, POWERFUL TOOLS FOR SINGLE-CELL IMMUNOLOGIC ASSAYS FOR PHENOTYPIC AND FUNCTIONAL ANALYSIS IS INCLUDED, WHICH PROMISE NEW MECHANISTIC INSIGHTS INTO CHILDHOOD ASTHMA DEVELOPMENT AND THERAPEUTIC AND PREVENTIVE STRATEGIES. 2023 11 1640 25 DOES EPIGENETICS PLAY A ROLE IN HUMAN ASTHMA? ASTHMA AND OTHER ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NON-COMMUNICABLE DISEASES OF CHILDHOOD. ACCORDING TO THE WORLD HEALTH ORGANIZATION, ASTHMA AFFECTS >7.0 MILLION CHILDREN UNDER 18 IN THE UNITED STATES, WITH AN ECONOMIC BURDEN THAT IS ESTIMATED TO EXCEED THAT OF TUBERCULOSIS AND HIV/AIDS COMBINED. DESPITE MUCH RESEARCH, THE NATURAL HISTORY OF ASTHMA AND ITS PATHOGENESIS ARE STILL IN MANY WAYS ELUSIVE. THIS REVIEW DISCUSSES OUR CURRENT UNDERSTANDING OF THE ROLE EPIGENETIC PROCESSES PLAY IN ASTHMA PATHOGENESIS, FOCUSING ON GENOME-WIDE, POPULATION-BASED STUDIES. 2016 12 4063 33 MATERNAL AND CHILDHOOD ASTHMA: RISK FACTORS, INTERACTIONS, AND RAMIFICATIONS. ASTHMA IS EMERGING AS A PREMIER EXAMPLE OF A HEALTH RISK THAT CAN LARGELY BE MOLDED BY THE STATUS OF THE MOTHER AND THE ENVIRONMENTAL CONDITIONS ENCOUNTERED DURING SENSITIVE WINDOWS OF PRENATAL AND EARLY CHILDHOOD DEVELOPMENT. WHILE GENETIC BACKGROUND, ALLERGIC STATUS OF PARENTS, AND PREDISPOSITION FOR ATOPY AND INFLAMMATION PLAY A ROLE, EARLY-LIFE ENVIRONMENTAL CONDITIONS CAN COMPLETELY ALTER THE COURSE OF IMMUNE AND RESPIRATORY SYSTEM DEVELOPMENT. ENVIRONMENTALLY INDUCED ALTERATIONS THAT (1) MAINTAIN THE TH2 BIAS SEEN DURING GESTATION, (2) BLOCK THE MATURATION OF INNATE IMMUNE CELLS AND (3) CREATE INFLAMMATORY DYSFUNCTION IN THE INFANT PROVIDE THE FOUNDATION FOR CHILDHOOD ASTHMA. NO SINGLE RISK FACTOR CAN FULLY EXPLAIN THE INCREASED PREVALENCE OF ASTHMA IN RECENT DECADES BUT IT IS ASSUMED THAT THE RAPID INCREASE IS DUE TO ENVIRONMENTAL AND/OR EPIGENETIC CHANGES. WELL-ESTABLISHED AND SUSPECTED ENVIRONMENTAL RISK FACTORS COVER ALL CATEGORIES OF EARLY LIFE INTERACTIONS FROM DIET, EXPOSURE TO ENVIRONMENTAL CONTAMINANTS AND DRUGS, MATERNAL AND NEONATAL INFECTIONS, HYGIENE, TIMING OF VACCINATIONS AND EVEN THE MODE OF BIRTH DELIVERY. BECAUSE ASTHMA IS CONNECTED TO THE RISK OF SEVERAL COMORBID CHRONIC CONDITIONS, THE BENEFIT OF ASTHMA RISK REDUCTION AND PREVENTION IS GREATER THAN INITIALLY MAY BE APPARENT. THIS REVIEW DISCUSSES STRATEGIES TO OPTIMIZE PREVENTATIVE AND THERAPEUTIC OPTIONS ACROSS LIFE STAGES. 2011 13 1409 33 DIETARY INTERVENTIONS AND NUTRITIONAL FACTORS IN THE PREVENTION OF PEDIATRIC ASTHMA. ASTHMA IS THE MOST FREQUENT CHRONIC DISEASE IN CHILDREN, AND ITS PATHOGENESIS INVOLVES GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE RAPID RISE IN THE PREVALENCE OF ASTHMA REGISTERED OVER THE LAST FEW DECADES HAS STRESSED THE NEED TO IDENTIFY THE ENVIRONMENTAL AND MODIFIABLE FACTORS ASSOCIATED WITH THE DEVELOPMENT OF THE DISEASE. IN PARTICULAR, THERE IS INCREASING INTEREST IN THE ROLE OF MODIFIABLE NUTRITIONAL FACTORS SPECIFIC TO BOTH THE PRENATAL AND POST-NATAL EARLY LIFE AS, DURING THIS TIME, THE IMMUNE SYSTEM IS PARTICULARLY VULNERABLE TO EXOGENOUS INTERFERENCES. SEVERAL DIETARY FACTORS, INCLUDING MATERNAL DIET DURING PREGNANCY, THE DURATION OF BREASTFEEDING, THE USE OF SPECIAL MILK FORMULAS, THE TIMING OF THE INTRODUCTION OF COMPLEMENTARY FOODS, AND PRENATAL AND EARLY LIFE SUPPLEMENTATION WITH VITAMINS AND PROBIOTICS/PREBIOTICS, HAVE BEEN ADDRESSED AS POTENTIAL TARGETS FOR THE PREVENTION OF ASTHMA. IN THIS REVIEW, WE OUTLINE RECENT FINDINGS ON THE POTENTIAL ROLE OF PRENATAL AND PERINATAL DIETARY AND NUTRITIONAL INTERVENTIONS FOR THE PRIMARY PREVENTION OF PEDIATRIC ASTHMA. MOREOVER, WE ADDRESSED UNMET NEEDS AND AREAS FOR FUTURE RESEARCH IN THE PREVENTION OF CHILDHOOD-ONSET ASTHMA. 2020 14 1546 34 DNA METHYLATION IN NASAL EPITHELIUM: STRENGTHS AND LIMITATIONS OF AN EMERGENT BIOMARKER FOR CHILDHOOD ASTHMA. ASTHMA IS ONE OF THE MOST WIDESPREAD CHRONIC RESPIRATORY CONDITIONS. THIS DISEASE PRIMARILY DEVELOPS IN CHILDHOOD AND IS INFLUENCED BY DIFFERENT FACTORS, MAINLY GENETICS AND ENVIRONMENTAL FACTORS. DNA METHYLATION IS AN EPIGENETIC MECHANISM WHICH MAY REPRESENT A BRIDGE BETWEEN THESE TWO FACTORS, PROVIDING A TOOL TO COMPREHEND THE INTERACTION BETWEEN GENETICS AND ENVIRONMENT. MOST EPIDEMIOLOGICAL STUDIES IN THIS FIELD HAVE BEEN CONDUCTED USING BLOOD SAMPLES, ALTHOUGH DNA METHYLATION MARKS IN BLOOD MAY NOT BE RELIABLE FOR DRAWING EXHAUSTIVE CONCLUSIONS ABOUT DNA METHYLATION IN THE AIRWAYS. BECAUSE OF THE ROLE OF NASAL EPITHELIUM IN ASTHMA AND THE TISSUE SPECIFICITY OF DNA METHYLATION, STUDYING THE RELATIONSHIP BETWEEN DNA METHYLATION AND CHILDHOOD ASTHMA MIGHT REVEAL CRUCIAL INFORMATION ABOUT THIS WIDESPREAD RESPIRATORY DISEASE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE CURRENT FINDINGS IN THIS FIELD OF RESEARCH. WE WILL PRESENT A VIEWPOINT OF SELECTED STUDIES, CONSIDER STRENGTHS AND LIMITATIONS, AND PROPOSE FUTURE RESEARCH IN THIS AREA. 2020 15 396 36 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014 16 602 34 BETTER UNDERSTANDING OF CHILDHOOD ASTHMA, TOWARDS PRIMARY PREVENTION - ARE WE THERE YET? CONSIDERATION OF PERTINENT LITERATURE. ASTHMA IS A CHRONIC DISEASE, CHARACTERIZED BY REVERSIBLE AIRWAY OBSTRUCTION, AIRWAY INFLAMMATION AND HYPER-REACTIVITY. THE PREVALENCE OF ASTHMA HAS RISEN DRAMATICALLY OVER THE PAST DECADE, AFFECTING AROUND 300,000,000 PEOPLE. THE ETIOLOGY IS MULTIFACTORIAL, WITH GENETIC, EPIGENETIC, DEVELOPMENTAL AND ENVIRONMENTAL FACTORS PLAYING A ROLE. A COMPLEX INTERACTION BETWEEN THE INTRAUTERINE ENVIRONMENT, THE DEVELOPING IMMUNE SYSTEM, THE INFANT'S MICROBIOME AND INFECTIOUS ORGANISMS MAY LEAD TO THE DEVELOPMENT OF ALLERGIC SENSITIZATION AND ASTHMA. THUS, A LARGE NUMBER OF STUDIES HAVE INVESTIGATED THE RISK FACTORS FOR CHILDHOOD ASTHMA, WITH A METICULOUS SEARCH OF MODIFIABLE FACTORS THAT COULD AID IN PRIMARY PREVENTION. WE PRESENT A CURRENT LITERATURE REVIEW FROM 2014-2017, AS WELL AS OLDER CLASSIC PUBLICATIONS, ON THE PATHOGENESIS AND THE POTENTIAL MODIFIABLE FACTORS FOR PRIMARY PREVENTION OF ASTHMA. NO IDEAL PREVENTIVE MEASURE HAS YET BEEN FOUND. RATHER, CREATING FAVORABLE PRENATAL AND POSTNATAL ENVIRONMENTS, MINIMAL EXPOSURE TO HOSTILE ENVIRONMENTAL FACTORS, PREVENTION OF INFECTIONS IN EARLY LIFE, ALLERGIC DESENSITIZATION AND NUTRITIONAL MODIFICATIONS COULD POSSIBLY REDUCE ASTHMA INCEPTION. IN THE ERA OF PERSONALIZED MEDICINE, IDENTIFYING INDIVIDUAL RISK FACTORS AND TAILORING SPECIFIC PREVENTIVE MEASURES IS WARRANTED. 2017 17 6808 24 [EPIGENETICS IN ALLERGIC DISEASES AND ASTHMA]. ALLERGIC DISEASES AND ASTHMA ARE THE RESULT OF COMPLEX INTERACTIONS BETWEEN GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. ASTHMA IS ONE OF THE MOST PREVALENT CHRONIC DISEASE AMONG CHILDREN. IN THIS ARTICLE WE REVIEW SOME ENVIRONMENTAL FACTORS LIKE: ALLERGEN EXPOSITION, TOBACCO, BACTERIA, MICROBIAL COMPONENTS, DIET, OBESITY AND STRESS, WHICH INFLUENCES DURING INTRAUTERINE AND INFANCY LIFE IN THE EPIGENETIC REGULATION OF ASTHMA AND ALLERGIC DISEASES. THE REVIEW HAS BEEN DONE IN THREE MODELS: IN-VITRO, ANIMAL AND HUMAN. 2016 18 530 33 ASTHMA. ASTHMA IS THE MOST COMMON INFLAMMATORY DISEASE OF THE LUNGS. THE PREVALENCE OF ASTHMA IS INCREASING IN MANY PARTS OF THE WORLD THAT HAVE ADOPTED ASPECTS OF THE WESTERN LIFESTYLE, AND THE DISEASE POSES A SUBSTANTIAL GLOBAL HEALTH AND ECONOMIC BURDEN. ASTHMA INVOLVES BOTH THE LARGE-CONDUCTING AND THE SMALL-CONDUCTING AIRWAYS, AND IS CHARACTERIZED BY A COMBINATION OF INFLAMMATION AND STRUCTURAL REMODELLING THAT MIGHT BEGIN IN UTERO. DISEASE PROGRESSION OCCURS IN THE CONTEXT OF A DEVELOPMENTAL BACKGROUND IN WHICH THE POSTNATAL ACQUISITION OF ASTHMA IS STRONGLY LINKED WITH ALLERGIC SENSITIZATION. MOST ASTHMA CASES FOLLOW A VARIABLE COURSE, INVOLVING VIRAL-INDUCED WHEEZING AND ALLERGEN SENSITIZATION, THAT IS ASSOCIATED WITH VARIOUS UNDERLYING MECHANISMS (OR ENDOTYPES) THAT CAN DIFFER BETWEEN INDIVIDUALS. EACH SET OF ENDOTYPES, IN TURN, PRODUCES SPECIFIC ASTHMA CHARACTERISTICS THAT EVOLVE ACROSS THE LIFECOURSE OF THE PATIENT. STRONG GENETIC AND ENVIRONMENTAL DRIVERS OF ASTHMA INTERCONNECT THROUGH NOVEL EPIGENETIC MECHANISMS THAT OPERATE PRENATALLY AND THROUGHOUT CHILDHOOD. ASTHMA CAN SPONTANEOUSLY REMIT OR BEGIN DE NOVO IN ADULTHOOD, AND THE FACTORS THAT LEAD TO THE EMERGENCE AND REGRESSION OF ASTHMA, IRRESPECTIVE OF AGE, ARE POORLY UNDERSTOOD. NONETHELESS, THERE IS MOUNTING EVIDENCE THAT SUPPORTS A PRIMARY ROLE FOR STRUCTURAL CHANGES IN THE AIRWAYS WITH ASTHMA ACQUISITION, ON WHICH ALTERED INNATE IMMUNE MECHANISMS AND MICROBIOTA INTERACTIONS ARE SUPERIMPOSED. ON THE BASIS OF THE IDENTIFICATION OF NEW CAUSATIVE PATHWAYS, THE SUBPHENOTYPING OF ASTHMA ACROSS THE LIFECOURSE OF PATIENTS IS PAVING THE WAY FOR MORE-PERSONALIZED AND PRECISE PATHWAY-SPECIFIC APPROACHES FOR THE PREVENTION AND TREATMENT OF ASTHMA, CREATING THE REAL POSSIBILITY OF TOTAL PREVENTION AND CURE FOR THIS CHRONIC INFLAMMATORY DISEASE. 2015 19 1938 40 EPIDEMIOLOGIC EVIDENCE FOR ASSOCIATION BETWEEN ADVERSE ENVIRONMENTAL EXPOSURES IN EARLY LIFE AND EPIGENETIC VARIATION: A POTENTIAL LINK TO DISEASE SUSCEPTIBILITY? A GROWING BODY OF EVIDENCE SUGGESTS THAT THE RISK OF DEVELOPMENT AND PROGRESSION OF A VARIETY OF HUMAN CHRONIC DISEASES DEPENDS ON EPIGENETIC MODIFICATIONS TRIGGERED BY ENVIRONMENTAL CUES DURING EARLY LIFE SENSITIVE STAGES. EXPOSURES TO ENVIRONMENTAL FACTORS SUCH AS ADVERSE NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL CONDITIONS, AS WELL AS POLLUTANTS AND SUBSTANCE ABUSE IN EARLY LIFE, HAVE BEEN SHOWN TO BE IMPORTANT DETERMINANTS OF EPIGENETIC PROGRAMMING OF CHRONIC PATHOLOGICAL CONDITIONS IN HUMAN POPULATIONS. OVER THE PAST YEARS, IT HAS BECOME INCREASINGLY CLEAR DUE TO THE EPIGENOME-WIDE ASSOCIATION STUDIES (EWASS) THAT EARLY LIFE ADVERSE ENVIRONMENTAL EVENTS MAY TRIGGER WIDESPREAD AND PERSISTENT ALTERATIONS IN TRANSCRIPTIONAL PROFILING. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED UNDERLYING THESE ASSOCIATIONS. IN THIS CONTEXT, DNA METHYLATION IS THE MOST INTENSIVELY STUDIED EPIGENETIC PHENOMENON. IN THIS REVIEW, THE CLINICAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE ROLE OF EPIGENETIC FACTORS IN MEDIATING THE LINK BETWEEN EARLY LIFE EXPERIENCES AND LONG-TERM HEALTH OUTCOMES ARE SUMMARIZED. 2015 20 6877 31 [REASONS FOR THE DEVELOPMENT OF ALLERGIES IN CHILDREN]. ALLERGIES ARE ONE OF THE MOST COMMON CHRONIC DISEASES IN CHILDHOOD, CONTRIBUTING TO A TREMENDOUS MEDICAL AND ECONOMICAL BURDEN IN HEALTH CARE SYSTEMS OF MOST INDUSTRIALIZED COUNTRIES. THE DEVELOPMENT OF ALLERGIES IS DEPENDENT ON A COMPLEX INTERACTION OF-AMONG OTHERS-ENVIRONMENTAL FACTORS, NUTRITION, GENETIC AND EPIGENETIC MECHANISMS AS WELL AS THE MICROBIOME. THESE DIVERSE FACTORS CAN INFLUENCE EARLY LIFE IMMUNE REGULATION INCLUDING INNATE AND ADAPTIVE IMMUNE MECHANISMS IN A COMPLEX FASHION. IN CASE OF ANY CHILDHOOD ALLERGIES HAVE INCREASED SIGNIFICANTLY IN PAST DECADES. IN ADDITION TO ENVIRONMENTAL FACTORS AND NUTRITION, GENETIC AND EPIGENETIC MECHANISMS AS WELL AS THE MICROBIOME OF CHILDREN PLAY AN IMPORTANT ROLE. OF RELEVANCE IS THE WAY IN WHICH THESE DIVERSE FACTORS INFLUENCE EARLY IMMUNE DEVELOPMENT OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS OF CHILDREN. THEIR COMPLEX REGULATION IS DECISIVE FOR WHETHER OR NOT A CHILD DEVELOPS AN ALLERGY THAT MANIFESTS IN MOST CASES AS ATOPIC DERMATITIS, BRONCHIAL ASTHMA, OR ALLERGIC RHINO CONJUNCTIVITIS, OR WHETHER A CHILD DEVELOPS AN IMMUNE TOLERANCE. THESE INFLUENCES CAN BEGIN PRENATALLY, ALREADY SETTING THE COURSE FOR LATER IMMUNE SYSTEM DEVELOPMENT AND OCCURRENCE OF DISEASE. 2019