Publications by authors named "Rachel S Kelly"

79 Publications

Metabolomic differences in lung function metrics: evidence from two cohorts.

Thorax 2021 Oct 14. Epub 2021 Oct 14.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Rationale: The biochemical mechanisms underlying lung function are incompletely understood.

Objectives: To identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery-the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk, n=10 460) and validation-the VA Normative Aging Study (NAS) metabolomic cohort (n=437).

Methods: We ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV) and the ratio of FEV to forced vital capacity (FEV/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05.

Measurements And Main Results: Of 156 metabolites that associated with FEV in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV and FEV/FVC.

Conclusions: The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216639DOI Listing
October 2021

Circulating levels of maternal vitamin D and risk of ADHD in offspring: results from the Vitamin D Antenatal Asthma Reduction Trial.

Int J Epidemiol 2021 Sep 17. Epub 2021 Sep 17.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the association between 25(OH)D during fetal development and risk of childhood ADHD.

Methods: Maternal plasma 25(OH)D was measured at 10-18 and 32-38 weeks of gestation, with sufficiency defined as 25(OH)D ≥ 30 ng/ml. Offspring ADHD status between ages 6-9 years was measured by parent report of clinical ADHD diagnosis among 680 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial. Association between maternal 25(OH)D and child ADHD was assessed using logistic regression, adjusting for maternal age, race and ethnicity. Effect modification by offspring sex was also assessed.

Results: No associations between maternal 25(OH)D at 10-18 weeks of gestation and offspring ADHD were observed. In the third trimester, we observed associations between maternal vitamin D sufficiency and offspring ADHD [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.26-0.84], in addition to maternal 25(OH)D sufficiency category, comparing the deficient (OR 0.34, 95% CI 0.12-0.94), insufficient (OR 0.41, 95% CI 0.15-1.10) and sufficient (OR 0.20, 95% CI 0.08-0.54) categories against highly deficient 25(OH)D, respectively. Stratified analyses revealed a protective association for sufficient maternal 25(OH)D and child ADHD among males (OR 0.47, 95% CI 0.23-0.94); the synergy index for additive effect modification of risk was 1.78 (95% CI 0.62-5.08).

Conclusions: Higher levels of maternal vitamin D in the third trimester are associated with lower risk of ADHD in offspring, with modest evidence for a stronger effect among male offspring. However, larger studies will be necessary to confirm these findings.
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http://dx.doi.org/10.1093/ije/dyab194DOI Listing
September 2021

Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent.

BMJ Open Diabetes Res Care 2021 08;9(1)

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Introduction: We investigated whether network analysis revealed clusters of coregulated metabolites associated with prevalent type 2 diabetes (T2D) among Puerto Rican adults.

Research Design And Methods: We used liquid chromatography-mass spectrometry to measure fasting plasma metabolites (>600) among participants aged 40-75 years in the Boston Puerto Rican Health Study (BPRHS; discovery) and San Juan Overweight Adult Longitudinal Study (SOALS; replication), with (n=357; n=77) and without (n=322; n=934) T2D, respectively. Among BPRHS participants, we used unsupervised partial correlation network-based methods to identify and calculate metabolite cluster scores. Logistic regression was used to assess cross-sectional associations between metabolite clusters and prevalent T2D at the baseline blood draw in the BPRHS, and significant associations were replicated in SOALS. Inverse-variance weighted random-effect meta-analysis was used to combine cohort-specific estimates.

Results: Six metabolite clusters were significantly associated with prevalent T2D in the BPRHS and replicated in SOALS (false discovery rate (FDR) <0.05). In a meta-analysis of the two cohorts, the OR and 95% CI (per 1 SD increase in cluster score) for prevalent T2D were as follows for clusters characterized primarily by glucose transport (0.21 (0.16 to 0.30); FDR <0.0001), sphingolipids (0.40 (0.29 to 0.53); FDR <0.0001), acyl cholines (0.35 (0.22 to 0.56); FDR <0.0001), sugar metabolism (2.28 (1.68 to 3.09); FDR <0.0001), branched-chain and aromatic amino acids (2.22 (1.60 to 3.08); FDR <0.0001), and fatty acid biosynthesis (1.54 (1.29 to 1.85); FDR <0.0001). Three additional clusters characterized by amino acid metabolism, cell membrane components, and aromatic amino acid metabolism displayed significant associations with prevalent T2D in the BPRHS, but these associations were not replicated in SOALS.

Conclusions: Among Puerto Rican adults, we identified several known and novel metabolite clusters that associated with prevalent T2D.
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http://dx.doi.org/10.1136/bmjdrc-2021-002298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378385PMC
August 2021

Genomic-Metabolomic Associations Support the Role of and Glycerophospholipids in Age-Related Macular Degeneration.

Ophthalmol Sci 2021 Mar 19;1(1). Epub 2021 Mar 19.

Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.

Purpose: Large-scale genome-wide association studies (GWAS) have reported important single nucleotide polymorphisms (SNPs) with significant associations with age-related macular degeneration (AMD). However, their role in disease development remains elusive. This study aimed to assess SNP-metabolite associations (i.e., metabolite quantitative trait loci [met-QTL]) and to provide insights into the biological mechanisms of AMD risk SNPs.

Design: Cross-sectional multicenter study (Boston, Massachusetts, and Coimbra, Portugal).

Participants: Patients with AMD (n = 388) and control participants (n = 98) without any vitreoretinal disease (> 50 years).

Methods: Age-related macular degeneration grading was performed using color fundus photographs according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and evaluated with mass spectrometry for metabolomic profiling and Illumina OmniExpress for SNPs profiling. Analyses of met-QTL of endogenous metabolites were conducted using linear regression models adjusted for age, gender, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. Additionally, we analyzed the cumulative effect of AMD risk SNPs on plasma metabolites by generating genetic risk scores and assessing their associations with metabolites using linear regression models, accounting for the same covariates. Modeling was performed first for each cohort, and then combined by meta-analysis. Multiple comparisons were accounted for using the false discovery rate (FDR).

Main Outcome Measures: Plasma metabolite levels associated with AMD risk SNPs.

Results: After quality control, data for 544 plasma metabolites were included. Meta-analysis of data from all individuals (AMD patients and control participants) identified 28 significant met-QTL (β = 0.016-0.083; FDR q-value < 1.14 × 10), which corresponded to 5 metabolites and 2 genes: and . Polymorphisms in the gene were associated with phosphatidylethanolamine metabolites, which are glycerophospholipids, and polymorphisms in the gene with branched-chain amino acids. Similar results were observed when considering only patients with AMD. Genetic risk score-metabolite associations further supported a global impact of AMD risk SNPs on the plasma metabolome.

Conclusions: This study demonstrated that genomic-metabolomic associations can provide insights into the biological relevance of AMD risk SNPs. In particular, our results support that the gene and the glycerophospholipid metabolic pathway may play an important role in AMD, thus offering new potential therapeutic targets for this disease.
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http://dx.doi.org/10.1016/j.xops.2021.100017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353724PMC
March 2021

Metabolomic signatures of the short-term exposure to air pollution and temperature.

Environ Res 2021 10 24;201:111553. Epub 2021 Jun 24.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA; Channing Division of Network Medicine; Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02129, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Short-term exposures to air pollution and temperature have been reported to be associated with inflammation and oxidative stress. However, mechanistic understanding of the affected metabolic pathways is still lacking and literature on the short-term exposure of air-pollution on the metabolome is limited.

Objectives: We aimed to determine changes in the plasma metabolome and associated metabolic pathways related to short-term exposure to outdoor air pollution and temperature.

Methods: We performed mass-spectrometry based untargeted metabolomic profiling of plasma samples from a large and well-characterized cohort of men (Normative Aging Study) to identify metabolic pathways associated with short-term exposure to PM, NO, O, and temperature (one, seven-, and thirty-day average of address-specific predicted estimates). We used multivariable linear mixed-effect regression and independent component analysis (ICA) while simultaneously adjusting for all exposures and correcting for multiple testing.

Results: Overall, 456 white men provided 648 blood samples, in which 1158 metabolites were quantified, between 2000 and 2016. Average age and body mass index were 75.0 years and 27.7 kg/m, respectively. Only 3% were current smokers. In the adjusted models, NO, and temperature showed statistically significant associations with several metabolites (19 metabolites for NO and 5 metabolites for temperature). We identified six metabolic pathways (sphingolipid, butanoate, pyrimidine, glycolysis/gluconeogenesis, propanoate, and pyruvate metabolisms) perturbed with short-term exposure to air pollution and temperature. These pathways were involved in inflammation and oxidative stress, immunity, and nucleic acid damage and repair.

Conclusions: This is the first study to report an untargeted metabolomic signature of temperature exposure, the largest to report an untargeted metabolomic signature of air pollution, and the first to use ICA. We identified several significant plasma metabolites and metabolic pathways associated with short-term exposure to air pollution and temperature; using an untargeted approach. Those pathways were involved in inflammation and oxidative stress, immunity, and nucleic acid damage and repair. These results need to be confirmed by future research.
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http://dx.doi.org/10.1016/j.envres.2021.111553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478827PMC
October 2021

A strategy for advancing for population-based scientific discovery using the metabolome: the establishment of the Metabolomics Society Metabolomic Epidemiology Task Group.

Metabolomics 2021 05 2;17(5):45. Epub 2021 May 2.

Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Joondalup, 6027, Australia.

Metabolomic Epidemiology is a growing area of research within the metabolomics research community. In response to this, we describe the establishment of the Metabolomics Society Metabolomic Epidemiology Task Group. The overall mission of this group is to promote the growth and understanding of metabolomic epidemiology as an independent research discipline and to drive collaborative efforts that can shape the field. In this article we define metabolomic epidemiology and identify the key challenges that need to be addressed in order to advance population-based scientific discovery in metabolomics.
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http://dx.doi.org/10.1007/s11306-021-01789-0DOI Listing
May 2021

COMETS Analytics: An online tool for analyzing and meta-analyzing metabolomics data in large research consortia.

Am J Epidemiol 2021 Apr 22. Epub 2021 Apr 22.

Biomedical Informatics Department, The Ohio State University College of Medicine, Columbus, Ohio, United States.

Consortium-based research is crucial for producing reliable high-quality findings but existing tools for consortium studies have important drawbacks with respect to data protection, ease of deployment, and analytical rigor. To address these concerns, we developed COnsortium of METabolomics Studies (COMETS) Analytics to support and streamline consortium-based analyses of metabolomics and other omics data. The application requires no specialized expertise and can be run locally to guarantee data protection or through a web-based server for convenience and speed. Unlike other web-based tools, COMETS Analytics enables standardized models to be run across all cohorts, using an algorithmic, reproducible approach to diagnose, document, and fix model issues. This eliminates the time-consuming and potentially error-prone step of manually customizing models by cohort, helping to accelerate consortium-based projects and enhancing analytical reproducibility. We demonstrated that the application scales well by performing two data analyses in 45 cohort studies that together comprised measurements of 4,647 metabolites in up to 134,742 participants. COMETS Analytics performed well in this test, as judged by the minimal errors that analysts had in preparing data inputs and the successful execution of all models attempted. As metabolomics gathers momentum among biomedical and epidemiological researchers, COMETS Analytics may be a useful tool for facilitating large-scale consortium-based research.
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http://dx.doi.org/10.1093/aje/kwab120DOI Listing
April 2021

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04;77(16):2040-2052

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
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http://dx.doi.org/10.1016/j.jacc.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065203PMC
April 2021

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze.

Eur Respir J 2021 09 23;58(3). Epub 2021 Sep 23.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

Background: Prenatal vitamin D supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D supplementation against offspring asthma/recurrent wheeze.

Methods: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D supplementation placebo.

Results: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC).

Conclusion: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D supplementation against offspring asthma/recurrent wheeze.
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http://dx.doi.org/10.1183/13993003.02012-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410880PMC
September 2021

Ambient PM species and ultrafine particle exposure and their differential metabolomic signatures.

Environ Int 2021 06 24;151:106447. Epub 2021 Feb 24.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02129, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.

Background: The metabolomic signatures of short- and long-term exposure to PM have been reported and linked to inflammation and oxidative stress. However, little is known about the relative contribution of the specific PM species (hence sources) that drive these metabolomic signatures.

Objectives: We aimed to determine the relative contribution of the different species of PM exposure to the perturbed metabolic pathways related to changes in the plasma metabolome.

Methods: We performed mass-spectrometry based metabolomic profiling of plasma samples among men from the Normative Aging Study to identify metabolic pathways associated with PM species. The exposure windows included short-term (one, seven-, and thirty-day moving average) and long-term (one year moving average). We used linear mixed-effect regression with subject-specific intercepts while simultaneously adjusting for PM, NO, O, temperature, relative humidity, and covariates and correcting for multiple testing. We also used independent component analysis (ICA) to examine the relative contribution of patterns of PM species.

Results: Between 2000 and 2016, 456 men provided 648 blood samples, in which 1158 metabolites were quantified. We chose 305 metabolites for the short-term and 288 metabolites for the long-term exposure in this analysis that were significantly associated (p-value < 0.01) with PM to include in our PM species analysis. On average, men were 75.0 years old and their body mass index was 27.7 kg/m. Only 3% were current smokers. In the adjusted models, ultrafine particles (UFPs) were the most significant species of short-term PM exposure followed by nickel, vanadium, potassium, silicon, and aluminum. Black carbon, vanadium, zinc, nickel, iron, copper, and selenium were the significant species of long-term PM exposure. We identified several metabolic pathways perturbed with PM species including glycerophospholipid, sphingolipid, and glutathione. These pathways are involved in inflammation, oxidative stress, immunity, and nucleic acid damage and repair. Results were overlapped with the ICA.

Conclusions: We identified several significant perturbed plasma metabolites and metabolic pathways associated with exposure to PM species. These species are associated with traffic, fuel oil, and wood smoke. This is the largest study to report a metabolomic signature of PM species' exposure and the first to use ICA.
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http://dx.doi.org/10.1016/j.envint.2021.106447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994935PMC
June 2021

Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype.

Am J Respir Crit Care Med 2021 04;203(7):853-863

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital-University of Copenhagen, Gentofte, Denmark.

A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated. To study the sphingolipid-associated childhood asthma endotype using multiomic data. We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort. Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05. This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.
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http://dx.doi.org/10.1164/rccm.202008-3206OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017574PMC
April 2021

Maternal Metabolome in Pregnancy and Childhood Asthma or Recurrent Wheeze in the Vitamin D Antenatal Asthma Reduction Trial.

Metabolites 2021 Jan 23;11(2). Epub 2021 Jan 23.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

The in utero environment during pregnancy has important implications for the developing health of the child. We aim to examine the potential impact of maternal metabolome at two different timepoints in pregnancy on offspring respiratory health in early life. In 685 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective associations between maternal metabolites at both baseline (10-18 weeks gestation) and third trimester (32-38 weeks gestation) and the risk of child asthma or recurrent wheeze by age three using logistic regression models accounting for confounding factors. Subgroup analyses were performed by child sex. Among 632 metabolites, 19 (3.0%) and 62 (9.8%) from baseline and third trimester, respectively, were associated with the outcome (-value < 0.05). Coffee-related metabolites in the maternal metabolome appeared to be of particular importance. Caffeine, theophylline, trigonelline, quinate, and 3-hydroxypyridine sulfate were inversely associated with asthma risk at a minimum of one timepoint. Additional observations also highlight the roles of steroid and sphingolipid metabolites. Overall, there was a stronger relationship between the metabolome in later pregnancy and offspring asthma risk. Our results suggest that alterations in prenatal metabolites may act as drivers of the development of offspring asthma.
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http://dx.doi.org/10.3390/metabo11020065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910853PMC
January 2021

Low gestational vitamin D level and childhood asthma are related to impaired lung function in high-risk children.

J Allergy Clin Immunol 2021 07 22;148(1):110-119.e9. Epub 2021 Jan 22.

Division of Pediatric Pulmonary Medicine, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY.

Background: Lung function impairment in early life often persists into adulthood. Therefore, identifying risk factors for low childhood lung function is crucial.

Objective: We examined the effect of 25-hydroxyvitamin D (25[OH]D) level and childhood asthma phenotype on childhood lung function in the Vitamin D Antenatal Asthma Reduction Trial (VDAART).

Methods: The 25(OH)D level was measured at set time points in mothers during pregnancy and in children during early life. On the basis of parental reports, children were categorized into 3 clinical phenotypes: asymptomatic/infrequent wheeze, early transient wheeze, and asthma at age 6 years. Lung function was assessed with impulse oscillometry at ages 4, 5, and 6 years and with spirometry at ages 5 and 6 years.

Results: A total of 570 mother-child pairs were included in this post hoc analysis. Mean gestational 25(OH)D-level quartiles were negatively associated with child respiratory resistance at 5 Hz (R5) from age 4 to 6 years (β, -0.021 kPa/L/s; 95% CI, -0.035 to -0.007; P = .003) and positively associated with FEV (β, 0.018 L; 95% CI, 0.005-0.031; P = .008) and forced vital capacity (β, 0.022 L; 95% CI, 0.009-0.036; P = .002) from age 5 to 6 years. Children with asthma at age 6 years had lower lung function from age 4 to 6 years than the asymptomatic/infrequent wheeze group (β, 0.065 kPa/L/s; 95% CI, 0.028 to 0.102; P < .001 for R5 and β, -0.063 L; 95% CI, -0.099 to -0.028; P < .001 for FEV).

Conclusions: Low gestational 25(OH)D level and childhood asthma are important risk factors for decreased lung function in early childhood.
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http://dx.doi.org/10.1016/j.jaci.2020.12.647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315297PMC
July 2021

Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics.

J Pers Med 2021 Jan 19;11(1). Epub 2021 Jan 19.

Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA 02215, USA.

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10. Using a suggestive significance level of 5 × 10, three interactions, including one for a SNP within (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ) [-value = 0.009], rs10827492 () [-value = 0.02], and rs72646209 () [-value = 0.02]) had a marginally significant interaction with age on BDR ( < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.
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http://dx.doi.org/10.3390/jpm11010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833432PMC
January 2021

Metabolomic signatures of the long-term exposure to air pollution and temperature.

Environ Health 2021 01 7;20(1). Epub 2021 Jan 7.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Landmark Center, Room 414C, 401 Park Dr, Boston, MA, 02215, USA.

Background: Long-term exposures to air pollution has been reported to be associated with inflammation and oxidative stress. However, the underlying metabolic mechanisms remain poorly understood.

Objectives: We aimed to determine the changes in the blood metabolome and thus the metabolic pathways associated with long-term exposure to outdoor air pollution and ambient temperature.

Methods: We quantified metabolites using mass-spectrometry based global untargeted metabolomic profiling of plasma samples among men from the Normative Aging Study (NAS). We estimated the association between long-term exposure to PM, NO, O, and temperature (annual average of central site monitors) with metabolites and their associated metabolic pathways. We used multivariable linear mixed-effect regression models (LMEM) while simultaneously adjusting for the four exposures and potential confounding and correcting for multiple testing. As a reduction method for the intercorrelated metabolites (outcome), we further used an independent component analysis (ICA) and conducted LMEM with the same exposures.

Results: Men (N = 456) provided 648 blood samples between 2000 and 2016 in which 1158 metabolites were quantified. On average, men were 75.0 years and had an average body mass index of 27.7 kg/m. Almost all men (97%) were not current smokers. The adjusted analysis showed statistically significant associations with several metabolites (58 metabolites with PM, 15 metabolites with NO, and 6 metabolites with temperature) while no metabolites were associated with O. One out of five ICA factors (factor 2) was significantly associated with PM. We identified eight perturbed metabolic pathways with long-term exposure to PM and temperature: glycerophospholipid, sphingolipid, glutathione, beta-alanine, propanoate, and purine metabolism, biosynthesis of unsaturated fatty acids, and taurine and hypotaurine metabolism. These pathways are related to inflammation, oxidative stress, immunity, and nucleic acid damage and repair.

Conclusions: Using a global untargeted metabolomic approach, we identified several significant metabolites and metabolic pathways associated with long-term exposure to PM, NO and temperature. This study is the largest metabolomics study of long-term air pollution, to date, the first study to report a metabolomic signature of long-term temperature exposure, and the first to use ICA in the analysis of both.
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http://dx.doi.org/10.1186/s12940-020-00683-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788989PMC
January 2021

Metabolomics, physical activity, exercise and health: A review of the current evidence.

Biochim Biophys Acta Mol Basis Dis 2020 12 19;1866(12):165936. Epub 2020 Aug 19.

Physical Activity for Health Research Center (PAHRC), University of Edinburgh, St Leonard's Land, Edinburgh EH8 8AQ, UK. Electronic address:

Physical activity (PA) and exercise are among the most important determinants of health. However, PA is a complex and heterogeneous behavior and the biological mechanisms through which it impacts individuals and populations in different ways are not well understood. Genetics and environment likely play pivotal roles but further work is needed to understand their relative contributions and how they may be mediated. Metabolomics offers a promising approach to explore these relationships. In this review, we provide a comprehensive appraisal of the PA-metabolomics literature to date. This overwhelmingly supports the hypothesis of a metabolomic response to PA, which can differ between groups and individuals. It also suggests a biological gradient in this response based on PA intensity, with some evidence for global longer-term changes in the metabolome of highly active individuals. However, many questions remain and we conclude by highlighting future critical research avenues to help elucidate the role of PA in the maintenance of health and the development of disease.
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http://dx.doi.org/10.1016/j.bbadis.2020.165936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680392PMC
December 2020

Delayed Motor Milestones Achievement in Infancy Associates with Perturbations of Amino Acids and Lipid Metabolic Pathways.

Metabolites 2020 Aug 19;10(9). Epub 2020 Aug 19.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, 1017 Copenhagen, Denmark.

The relationship between developmental milestone achievement in infancy and later cognitive function and mental health is well established, but underlying biochemical mechanisms are poorly described. Our study aims to discover pathways connected to motor milestone achievement during infancy by using untargeted plasma metabolomic profiles from 571 six-month-old children in connection with age of motor milestones achievement (Denver Developmental Index) in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother-child cohort. We used univariate regression models and multivariate modelling (Partial Least Squares Discriminant Analysis: PLS-DA) to examine the associations and the VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort for validation. The univariate analyses showed 62 metabolites associated with gross-motor milestone achievement ( < 0.05) as well as the PLS-DA significantly differentiated between slow and fast milestone achievers (AUC = 0.87, = 0.01). Higher levels of tyramine-O-sulfate in the tyrosine pathway were found in the late achievers in COPSAC ( = 0.0002) and in VDAART ( = 0.02). Furthermore, we observed that slow achievers were characterized by higher levels of fatty acids and products of fatty acids metabolism including acyl carnitines. Finally, we also observed changes in the lysine, histidine, glutamate, creatine and tryptophan pathways. Observing these metabolic changes in relation to gross-motor milestones in the first year of life, may be of importance for later cognitive function and mental health.
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http://dx.doi.org/10.3390/metabo10090337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570268PMC
August 2020

Metabolomic signatures of lead exposure in the VA Normative Aging Study.

Environ Res 2020 11 11;190:110022. Epub 2020 Aug 11.

Channing Division of Network Medicine; Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02129, USA.

Background: Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood.

Objectives: To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails.

Methods: In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure.

Results: In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (β(95%CI): 1.52 (0.93,2.12), p = 7.18x10), N-acetylglycine (β(95%CI): 1.44 (0.85,2.02), p = 1.12x10), tartarate (β(95%CI): 0.68 (0.35,1.00), p = 4.84x10), vanillylmandelate (β(95%CI): 1.05 (0.47,1.63), p = 4.44x10), and lysine (β(95%CI): 1.88 (-2.8,-0.95), p = 9.10x10). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails.

Discussion: Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden.
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http://dx.doi.org/10.1016/j.envres.2020.110022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983049PMC
November 2020

Circulating Plasma Metabolites and Cognitive Function in a Puerto Rican Cohort.

J Alzheimers Dis 2020 ;76(4):1267-1280

Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA, USA.

Background: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer's disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity.

Objective: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline.

Methods: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet.

Results: Of 621 metabolites, FDR corrected (p < 0.05) multivariable linear regression identified 3 metabolites positively, and 10 negatively, associated with cognitive function in the BPRHS. In a combination of FDR-corrected linear regression, logistic regression regularized via LASSO, and sensitivity analyses restricted to participants without diabetes, and with good adherence to the Mediterranean diet, β-cryptoxanthin plasma concentration was consistently associated with better cognitive function and N-acetylisoleucine and tyramine O-sulfate concentrations were consistently associated with worse cognitive function.

Conclusion: This untargeted metabolomics study identified potential biomarkers for cognitive function in a cohort of Puerto Rican older adults.
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http://dx.doi.org/10.3233/JAD-200040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061579PMC
June 2021

Stability of developmental status and risk of impairment at 24 and 36 months in late preterm infants.

Infant Behav Dev 2020 08 26;60:101462. Epub 2020 Jun 26.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Partners Center for Personalized Medicine, Partners Health Care, Boston, MA, USA.

Background: Few studies investigated whether late preterm infants might have developmental delays in several domains in early life and how stable the lag in developmental status might be.

Aim: We aimed to examine the stability of potential delays across developmental domains at 24 and 36 months of age in late preterm (34°-36 weeks) and term (≥37 weeks) children and whether the risk of delays remained high at 36 months.

Study Design, Subjects, And Outcome Measure: We conducted a prospective cohort analysis of the children of pregnant women participating in the Vitamin Antenatal Asthma Reduction Trial (VDAART). 652 children who were prospectively followed up and had parent-completed Ages Stages Questionnaires (ASQ-3) questionnaires at both 24 and 36 months were analyzed to assess their domain-specific developmental status.

Results: 6.61 % (42/635) of children had a late preterm birth. Developmental delays were stable between 24 and 36 months on all 5 domains for the children born preterm and on 4/5 domains for those born at term. The developmental domains with the status stability at 24 and 36 months in both late preterm and term children were the gross motor, communication, personal-social skills, and problem-solving. Late preterm children compared with term children remained at higher risk of delays at 36 months for gross motor, communication, and problem-solving skills (aOR = 4.54, 95 %CI: 1.81-10.79; aOR = 8.60, 95 %CI: 3.10-23.28 and aOR = 3.80, 95 %CI: 1.58-8.73, respectively).

Conclusion: Late preterm birth is associated with suboptimal development and stability in several domains at both 24 and 36 months and compared with term birth, requiring early monitoring and assessment of the developmental lag to avoid potential long-term implications.
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http://dx.doi.org/10.1016/j.infbeh.2020.101462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704576PMC
August 2020

Metabolome-Microbiome Crosstalk and Human Disease.

Metabolites 2020 May 1;10(5). Epub 2020 May 1.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

In this review, we discuss the growing literature demonstrating robust and pervasive associations between the microbiome and metabolome. We focus on the gut microbiome, which harbors the taxonomically most diverse and the largest collection of microorganisms in the human body. Methods for integrative analysis of these "omics" are under active investigation and we discuss the advances and challenges in the combined use of metabolomics and microbiome data. Findings from large consortia, including the Human Microbiome Project and Metagenomics of the Human Intestinal Tract (MetaHIT) and others demonstrate the impact of microbiome-metabolome interactions on human health. Mechanisms whereby the microbes residing in the human body interact with metabolites to impact disease risk are beginning to be elucidated, and discoveries in this area will likely be harnessed to develop preventive and treatment strategies for complex diseases.
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http://dx.doi.org/10.3390/metabo10050181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281736PMC
May 2020

Plasma 25-Hydroxyvitamin D Concentrations are Associated with Polyunsaturated Fatty Acid Metabolites in Young Children: Results from the Vitamin D Antenatal Asthma Reduction Trial.

Metabolites 2020 Apr 14;10(4). Epub 2020 Apr 14.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Vitamin D deficiency contributes to a multitude of health conditions, but its biological mechanisms are not adequately understood. Untargeted metabolomics offers the opportunity to comprehensively examine the metabolic profile associated with variations in vitamin D concentrations. The objective of the current analysis was to identify metabolites and metabolic pathways associated with plasma 25-hydroxyvitamin D [25(OH)D] concentrations. The current study included children of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial, who had 25(OH)D and global metabolomics data at age 1 and 3 years. We assessed the cross-sectional associations between individual metabolites and 25(OH)D using linear regression adjusting for confounding factors. Twelve metabolites were significantly associated with plasma 25(OH)D concentrations at both age 1 and 3 after correction for multiple comparisons, including three members of the n-6 polyunsaturated fatty acid (PUFA) metabolism pathway (linoleate, arachidonate, and docosapentaenoate) inversely associated with 25(OH)D. These PUFAs along with four other significant metabolites were replicated in the independent Childhood Asthma Management Program (CAMP) cohort. Both vitamin D and n-6 PUFAs are involved in inflammatory processes, and evidence from cell and animal studies demonstrate a plausible biological mechanism where the active form of 25(OH)D may influence n-6 PUFA metabolism. These relationships warrant further investigation in other populations.
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http://dx.doi.org/10.3390/metabo10040151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240965PMC
April 2020

Gut Microbial-Derived Metabolomics of Asthma.

Metabolites 2020 Mar 6;10(3). Epub 2020 Mar 6.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

In this review, we discuss gut microbial-derived metabolites involved with the origins and pathophysiology of asthma, a chronic respiratory disease that is influenced by the microbiome. Although both gut and airway microbiomes may be important in asthma development, we focus here on the gut microbiome and metabolomic pathways involved in immune system ontogeny. Metabolite classes with existing evidence that microbial-derived products influence asthma risk include short chain fatty acids, polyunsaturated fatty acids and bile acids. While tryptophan metabolites and sphingolipids have known associations with asthma, additional research is needed to clarify the extent to which the microbiome contributes to the effects of these metabolites on asthma. These metabolite classes can influence immune function in one of two ways: (i) promoting growth or maturity of certain immune cell populations or (ii) influencing antigenic load by enhancing the number or species of specific bacteria. A more comprehensive understanding of how gut microbes and metabolites interact to modify asthma risk and morbidity will pave the way for targeted diagnostics and treatments.
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http://dx.doi.org/10.3390/metabo10030097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142494PMC
March 2020

Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma.

PLoS One 2020 2;15(3):e0229241. Epub 2020 Mar 2.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10-05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10-08) (rs34631960 [OR 2.3±1.6-3.3] in thrombospondin type 1 domain-containing protein 4 (THSD4) and rs2328386 [OR 0.5±0.3-0.7] in human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229241PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051058PMC
June 2020

Plasmalogens Mediate the Effect of Age on Bronchodilator Response in Individuals With Asthma.

Front Med (Lausanne) 2020 14;7:38. Epub 2020 Feb 14.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States.

Asthma is known to display different phenotypes across the life-course, suggesting that age related changes are particularly relevant to understanding asthma pathogenesis and remission. We have previously demonstrated that a lung function phenotype associated with asthma, bronchodilator response, is reduced with age, at rate of 0.24 percent per year. In this study, we interrogated the serum metabolome, to determine whether circulating metabolites mediate age-related changes in bronchodilator response (BDR) for individuals with asthma. We used data on 295 participants from the follow-up phase of the CAMP clinical trial (age 12.2-25.9 years; mean BDR of 8%, standard deviation 7%). Using a counterfactual framework, we analyzed over 500 pareto-scaled metabolites using mediation analysis to identify indirect effects of age through potential metabolite mediators. There was a significant indirect effect of age on BDR through 4 plasmalogens (C36:1 PC and related metabolites) (Indirect Effect Beta = -0.001, = 0.006). Our findings suggest that plasmalogens may contribute to age-related asthma phenotypes, and may also serve as potential pharmacologic targets for enhancement of lung function in individuals with asthma. This work uses data from the previous clinical trial of asthma, the Childhood Asthma Management Program (CAMP), registered at ClinicalTrials.gov, # NCT00000575.
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http://dx.doi.org/10.3389/fmed.2020.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034309PMC
February 2020

Allergic disease and low ASQ communication score in children.

Brain Behav Immun 2020 01 10;83:293-297. Epub 2019 Oct 10.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.

Autism Spectrum Disorders (ASD) are complex and multifactorial. Previous investigations have revealed associations between allergic disease and ASD, which are characterized by impaired communication skills. In this study we observed an association between allergic disease and communication skills development as assessed by the Ages and Stages Questionnaire (ASQ) communication score, as a proxy for ASD, among children who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In particular, we observed significant associations between both a diagnosis of eczema at age 3 years (OR = 1.87; confidence interval [CI]: 0.97-3.47; p = 0.054) and a diagnosis of food allergy at age 6 years (OR = 3.61; 95% CI: 1.18-9.85; p = 0.015) with ASQ communication score. Plasma metabolomics analyses suggest that dysregulated tryptophan metabolism may contribute to the pathogenesis of these co-morbidities.
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http://dx.doi.org/10.1016/j.bbi.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906237PMC
January 2020

The nuts and bolts of omics for the clinical allergist.

Ann Allergy Asthma Immunol 2019 12 25;123(6):558-563. Epub 2019 Sep 25.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Objective: Omics, aka multi-omics, is an emerging area of research that is advancing the use of personalized medicine in clinical practice and is therefore relevant for the practicing allergist.

Data Sources: We performed a literature search of a selection of scientific findings in omics and allergy, including variants that may be important to allergy outcomes in the genome, transcriptome, metabolome, microbiome, epigenome, and exposome, among others.

Study Selections: Basic science papers and review articles.

Results: The use of multi-omic data in clinical practice is changing how clinicians treat their patients whereby more personalized approaches are becoming standard in medical practice and has the potential to transform the treatment of allergies.

Conclusion: Multi-omic data are relevant and will become increasingly important for the clinical allergist.
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http://dx.doi.org/10.1016/j.anai.2019.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099443PMC
December 2019

Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma.

Chest 2019 12 23;156(6):1068-1079. Epub 2019 Sep 23.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.

Background: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma.

Methods: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes.

Results: A genome-wide significant association was identified between baseline FEV/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV (P = 3.3 × 10), postbronchodilator (PB) FEV (7.3 × 10), and PB FEV/FVC ratio (P = 2.7 × 10). The identified baseline FEV/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR.

Conclusions: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
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http://dx.doi.org/10.1016/j.chest.2019.08.2202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904857PMC
December 2019

Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions.

Metabolites 2019 Sep 7;9(9). Epub 2019 Sep 7.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA.

The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = -0.004, ; GACRS: β = -0.015, ), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005, GACRS: β = 0.023, ) Five additional metabolites had a -value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response.
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http://dx.doi.org/10.3390/metabo9090179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780678PMC
September 2019
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