Biochemistry and Pharmacology - Research Publications

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Type: Journal Article × Author: Holt, Kathryn × Author: Inouye, Michael × Author: Teo, Shu Mei × Start date: 2020 × End date: 2022 ×

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    Developmental patterns in the nasopharyngeal microbiome during infancy are associated with asthma risk
    Tang, HHF ; Lang, A ; Teo, SM ; Judd, LM ; Gangnon, R ; Evans, MD ; Lee, KE ; Vrtis, R ; Holt, PG ; Lemanske, RF ; Jackson, DJ ; Holt, KE ; Inouye, M ; Gern, JE (MOSBY-ELSEVIER, 2021-05-05)
    BACKGROUND: Studies indicate that the nasal microbiome may correlate strongly with the presence or future risk of childhood asthma. OBJECTIVES: In this study, we tested whether developmental trajectories of the nasopharyngeal microbiome in early life and the composition of the microbiome during illnesses were related to risk of childhood asthma. METHODS: Children participating in the Childhood Origins of Asthma study (N = 285) provided nasopharyngeal mucus samples in the first 2 years of life, during routine healthy study visits (at 2, 4, 6, 9, 12, 18, and 24 months of age), and during episodes of respiratory illnesses, all of which were analyzed for respiratory viruses and bacteria. We identified developmental trajectories of early-life microbiome composition, as well as predominant bacteria during respiratory illnesses, and we correlated these with presence of asthma at 6, 8, 11, 13, and 18 years of age. RESULTS: Of the 4 microbiome trajectories identified, a Staphylococcus-dominant microbiome in the first 6 months of life was associated with increased risk of recurrent wheezing by age 3 years and asthma that persisted throughout childhood. In addition, this trajectory was associated with the early onset of allergic sensitization. During wheezing illnesses, detection of rhinoviruses and predominance of Moraxella were associated with asthma that persisted throughout later childhood. CONCLUSION: In infancy, the developmental composition of the microbiome during healthy periods and the predominant microbes during acute wheezing illnesses are both associated with the subsequent risk of developing persistent childhood asthma.
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    Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk
    Huang, QQ ; Tang, HHF ; Teo, SM ; Mok, D ; Ritchie, SC ; Nath, AP ; Brozynska, M ; Salim, A ; Bakshi, A ; Holt, BJ ; Khor, CC ; Sly, PD ; Holt, PG ; Holt, KE ; Inouye, M (NATURE PORTFOLIO, 2020-07-28)
    Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.