Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic, highly fluorinated aliphatic compounds, commonly utilised in a wide variety of consumer products with diverse applications.

Summary: Background: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. Methods: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. Findings: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10−5), SLC8A1 (P-value = 3.9 × 10−5); and TENM4 (P-value = 4.9 × 10−5). Interpretation: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. Funding: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Prior studies of food allergy have identified metabolomic pathways involved in immune function and allergy that are associated with having food allergies, but there is limited data around oral immunotherapy (OIT), desensitization, and immune tolerance. We aim to characterize metabolomic changes during desensitization through OIT.

Environmental, genetic, and microbial factors are independently associated with childhood asthma. We aimed to determine the roles of environmental exposures and 17q21 locus genotype in the maturation of the early-life microbiome in childhood asthma. We analyzed fecal 16s rRNA sequencing at 3-6 months and 1 year of age to characterize microbial maturation of offspring of participants in the Vitamin D Antenatal Reduction Trial (VDAART). We determined associations of microbial maturation and environmental exposures in the mediation of asthma risk at age 3 years. We examined 17q21 genotype and microbial maturation associations with asthma risk in VDAART and sought replication of key results in the Copenhagen Prospective Studies on Childhood Asthma 2010 (COPSAC) cohort. Accelerated fecal microbial maturation at 3-6 months and delayed microbial maturation at 1 year of age were associated with asthma (p<0.001 in VDAART). In VDAART participants, fecal Bacteroides was reduced at age 3-6 months in association with subsequent asthma (p=0.006) and among subjects with lower microbial maturation at 1 year of age (q=0.009). Breastfeeding was associated with reduced asthma in VDAART participants, and 61% of the association between breastfeeding and asthma was mediated by microbial maturation at 3-6 months of age. In both VDAART and COPSAC cohorts, microbial maturation and 17q21 genotypes exhibited independent, additive effects on childhood asthma risk. The intestinal microbiome and its maturation mediates associations between environmental exposures including breastfeeding and asthma. The intestinal microbiome and 17q21 genotype appear to exert additive and independent effects on childhood asthma risk.

Background Sex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not been extensively analysed for atopy-related markers including allergy skin tests, IgE and eosinophils in asthmatic children. Methods We performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole-genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations. Results Single nucleotide polymorphism (SNP) rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (p interaction =9.08×10 −10 ) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (p interaction =0.0058). Gene expression of ZNF33B (zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys. Conclusions We report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role for ZNF33B should be studied further as an important driver of sex-divergent features of atopy in childhood asthma.

Background: MiRNAs and metabolites exhibit crucial inter-relationships. Metabolic stimuli influence miRNA expression, and miRNAs regulate diverse cellular processes, impacting metabolism. Despite identifying specific miRNAs and metabolites impacting childhood asthma, a global assessment of their inter-dependencies is lacking.Methods: In two childhood asthma cohorts (Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) with N = 1,121 and Childhood Asthma Management Program (CAMP) with NBaseline = 312 and NEnd of trial = 454), we conducted miRNAome-metabolome-wide association studies ('miR-metabo-WAS'). A meta-analysis revealed common contemporaneous associations (FDR≤ 0.05). Persistent miRNA-metabolome associations were assessed using baseline data from CAMP and metabolomic profiling at the trial's end. Causal effects of miRNA and metabolite pairs on clinical phenotypes (airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction) were evaluated through structural equation modeling with 1000 bootstraps (FDR ≤ 0.05).Findings: The meta-analysis found 369 significant contemporaneous associations (133 miRNAs, 60 metabolites). Identified were 13 central hub metabolites and four hub miRNAs. In CAMP, eight miRNA-metabolite associations persisted from baseline to trial end. Five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, 12,13-diHOME) served as primary mediators in 100 indirect miRNA-metabolite associations, collectively influencing peripheral blood eosinophilia, AHR, and airflow obstruction.Interpretation: The robust miRNA-metabolite association and significant indirect impact of miRNAs through five hub metabolites on various asthma metrics indicate integrated effects in asthma. These findings suggest miRNA regulation of metabolism and cellular functions influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma.Funding: This work was funded by NIH grants R01 HL139634 and R01 HL155742.Declaration of Interest: The authors declare no competing interests.Ethical Approval: CAMP was approved by the Mass General Brigham Healthcare institutional review board (Protocol#: 2000-P-001130/55), as well as all participating clinical centers and the data coordinating center. All participants gave informed consent.

Background: Eicosanoids are a group of bioactive lipid mediators that have an established pathophysiological role in atopic diseases. However, the role of eicosanoids in early life prior to onset of disease is less well studied. Objectives: To investigate the association between urinary eicosanoids in early life and development of atopic disease in childhood. Methods: We measured concentrations of 21 urinary eicosanoids at age 1 year in children from the COPSAC2010 cohort (n=450). Clinical data on development of atopic disease were collected prospectively, including wheeze, asthma, atopic dermatitis, and allergic rhinitis until 10 years of age. Results: Confounder adjusted models showed higher concentrations of thromboxane metabolites at age 1 year were associated with increased risk of concurrent recurrent wheeze (cases=43, aOR=2.05 [1.11-4.02], p=0.03) and concurrent atopic dermatitis (cases=51, aOR=2.24 [1.38-3.67], p=0.001). Higher thromboxane concentrations were also associated with increased risk of developing atopic dermatitis at age 1-10 years(repeated measurement (GEE) aOR=1.72 [1.15-2.56], p=0.0007). Higher concentrations of PGDs (GEE aOR=1.65 [1.1-2.48], p=0.01), lower PGFs (GEE aOR=0.67 [0.44-1], p=0.05) and isoprostanes concentrations (GEE aOR=0.66 [0.44-0.99], p=0.047) were associated with increased risk of asthma at age 1-10 years. Further, higher thromboxane concentrations were positively associated with type 2 inflammation biomarkers including FeNO, blood eosinophils and allergic sensitization. Conclusions: This exploratory study suggests that early life perturbations in urinary eicosanoids herald the onset of atopic disease in childhood.

ABSTRACTIt has been widely recognized that a critical time window for neurodevelopment occurs in early life, and that the host’s gut microbiome plays an important role in neurodevelopment. While murine models have demonstrated that the maternal gut microbiome also influences offspring brain development, for humans it is still unclear if the critical time window for the association between the gut microbiome and neurodevelopment is prenatal, postnatal or both. Here we leverage a large-scale human study and compare the associations between the gut microbiota and metabolites from mothers and their children with the children’s neurodevelopment. We show, for the first time, that the maternal gut microbiome is more relevant than the children’s gut microbiome to the children’s neurodevelopment in the first year of life. Interestingly, the roles of the same taxa with respect to neurodevelopment can be opposite at the two stages of fetal neurodevelopment. These findings shed light on potential therapeutic interventions to prevent neurodevelopmental disorders.

IntroductionOlder adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults.MethodsA genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases.ResultsIn 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six nearPTCHD4validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10−5were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci forCPED1,CRADDandDSTfor the OCS burst outcome andGM2A,SNW1,CACNA1C,DPH1, andRPS10for the asthma-related exacerbation outcome.ConclusionsMultiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, includingPTCHD4.

Background: Recurrent respiratory infections are a leading cause of morbidity and mortality in children; endogenous steroids may impact childhood respiratory infection proneness (CRIP). Aim: To understand the associations between endogenous steroid profiles and CRIP. Methods: Two pre-birth cohorts were analyzed using a discovery and replication approach: the VDAART discovery population (n=421; NCT00920621) included children with metabolomic profiling at ages 1 and 6 years; and the COPSAC replication population (n=481; NCT00798226) at ages 1.5 and 6 years. Plasma metabolomic profiling was performed by Metabolon (NC, USA) using UPLC-MS/MS. The cumulative number of respiratory infections (e.g., URIs, LRIs) that occurred during the study period was recorded, and Poisson regression was used to evaluate associations between 18 steroid metabolites and the cumulative number of respiratory infections (referred to as CRIP). Results: Poisson regression analysis demonstrated inverse associations between steroid metabolites and CRIP at a nominal significance threshold in VDAART at age 1 year (P-values: 0.0127-2.33x10-12). Four of these associations replicated in COPSAC at age 18 months (P-values: 0.022-1.55x10-3). In a follow-up inquiry at age 6, reduced steroid levels were associated with increased CRIP in both cohorts. Significant inverse associations were observed for 12 metabolites in VDAART (P-values: 0.035-4.05x10-5) and 14 metabolites in COPSAC at age 6 years (P-values: 0.018-4.28x10-9). Conclusions: These results suggested that reduced steroid levels in infancy and age 6 are associated with increased occurrence of respiratory infections.