Paediatrics (RCH) - Research Publications
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ItemGenetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy(WILEY, 2017-08)BACKGROUND: Food allergies pose a considerable world-wide public health burden with incidence as high as one in ten in 12-month-old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE class switching in B cells. OBJECTIVE: Here, we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. METHOD: We genotyped nine IL13 "tag" single nucleotide polymorphisms (tag SNPs) in 367 challenge-proven food allergic cases, 199 food-sensitized tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month-old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located sample of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication sample phenotypes were defined by clinical history of reactivity, 95% PPV or challenge, and IL13 genotyping was performed. RESULTS: IL13 rs1295686 was associated with challenge-proven food allergy in the discovery sample (P=.003; OR=1.75; CI=1.20-2.53). This association was also detected in the replication sample (P=.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis (P=.0006, OR=1.50). However, we cannot rule out an association with food sensitization. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. CONCLUSIONS AND CLINICAL RELAVANCE: We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy.
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ItemThe skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants(WILEY, 2017-09)BACKGROUND: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. OBJECTIVE: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. METHOD: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. RESULTS: SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. CONCLUSIONS: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.
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ItemFormula and breast feeding in infant food allergy: A population-based study(WILEY, 2016-04)AIM: To determine whether infant-feeding practices, including duration of exclusive breastfeeding and use of partially hydrolysed formula, modify the risk of developing infant food allergy. METHODS: In an observational population-based study, 1 year olds were recruited from community immunisation clinics in Melbourne, Australia. Parent-reported data on infant-feeding practices and potential confounders were collected prior to infant skin prick testing for four food allergens. Sensitised infants attended hospital-based oral food challenges to establish food allergy status. Multiple logistic regression was used to investigate associations between breastfeeding and formula-feeding and infant food allergy adjusting for possible confounding variables. RESULTS: A total of 5276 (74% response) infants participated. Of the 4537 for whom food allergy status was determined, 515 (11.3%) were food allergic (challenge-proven in the context of skin prick testing positive (≥2 mm)). After adjusting for confounding variables, there was no association between duration of exclusive breastfeeding and food allergy. Use of partially hydrolysed formula did not reduce the risk of food allergy compared with cow's milk formula in the general population (adjusted odds ratios 1.03 (confidence interval 0.67-1.50)). CONCLUSION: Duration of exclusive breastfeeding and use of partially hydrolysed formula were not associated with food allergy at 1 year of age in this large population-based study. These findings have implications for population-based infant-feeding guidelines and do not support the use of partially hydrolysed formula for food allergy prevention.
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ItemNOx in exhaled breath condensate is related to allergic sensitization in young and middle-aged adults(WILEY, 2019-02)BACKGROUND: Asthma and allergic diseases are heterogeneous. Measurement of biomarkers in exhaled breath condensate (EBC) may help to discriminate between different phenotypes and may assist with clinical prognostication. OBJECTIVES: We aimed to assess associations between total nitric oxide products (NOx ) in EBC and different allergic phenotypes and lung function in young and middle-aged adults. METHODS: Cross-sectional analyses were nested within two Australian longitudinal studies, the Melbourne Atopy Cohort Study (MACS, mean age 17.8 years) and the Tasmanian Longitudinal Health Study (TAHS, mean age 49.4 years). Levels of EBC NOx were determined by Griess-reaction fluorescent method. Associations were assessed between EBC NOx and different allergic phenotypes, lung function and airway reactivity. RESULTS: Atopy, with or without asthma or rhinitis, was associated with increased EBC NOx levels particularly in individuals with poly-aero-sensitization. These findings were generally consistent across the two age groups. In the older cohort, use of ICS in the previous 12 months masked the association between sensitization and EBC NOx (OR = 0.64, 95% CI = 0.21-1.96, p for interaction = 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: In these population-based samples, EBC NOx was most strongly associated with atopic sensitization, rather than either current asthma or rhinitis, possibly indicating underlying increased airway inflammation associated with atopy. Therefore, EBC NOx could be a key predictor of atopy in both young and middle-aged adults, regardless of the presence of concomitant asthma or rhinitis.
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ItemNo Preview AvailableEarly-life exposure to sibling modifies the relationship between CD14 polymorphisms and allergic sensitization(WILEY, 2019-03)BACKGROUND: Markers of microbial exposure are thought to be associated with risk of allergic sensitization; however, the associations are inconsistent and may be related to gene-environment interactions. OBJECTIVE: To examine the relationship between polymorphisms in the CD14 gene and allergic sensitization and whether sibling exposure, as a marker of microbial exposure, modified this relationship. METHODS: We used data from the Tasmanian Longitudinal Health Study and the Melbourne Atopy Cohort Study. Two CD14 polymorphisms were genotyped. Allergic sensitization was defined by a positive response to a skin prick test. Sibling exposure was measured as cumulative exposure to siblings before age 6 months, 2 and 4 years. Logistic regression and multi-level mixed-effects logistic regression were used to examine the associations. Effect estimates across the cohorts were pooled using random-effects meta-analysis. RESULTS: CD14 SNPs were not individually associated with allergic sensitization in either cohort. In TAHS, cumulative sibling exposure before age 6 months, 2 and 4 years was each associated with a reduced risk of allergic sensitization at age 45 years. A similar effect was observed in MACS. Meta-analysis across the two cohorts showed consistent evidence of an interaction between cumulative sibling exposure before 6 months and the rs5744455-SNP (P = 0.001) but not with the rs2569190-SNP (P = 0.60). The pooled meta-analysis showed that the odds of sensitization with increasing cumulative exposure to sibling before 6 months of age was 20.9% smaller in those with the rs5744455-C-allele than the T-allele (OR = 0.83 vs 1.05, respectively). CONCLUSION AND CLINICAL RELEVANCE: Cumulative sibling exposure reduced the risk of sensitization from childhood to middle age in genetically susceptible individuals.
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ItemEarly smoke exposure is associated with asthma and lung function deficits in adolescents(TAYLOR & FRANCIS LTD, 2017)OBJECTIVE: Early life tobacco smoke exposure may influence asthma, lung function and lung function growth into adolescence. We aimed to determine the associations between perinatal smoke exposure and asthma and lung function up to 18 years of age. METHODS: We prospectively recorded perinatal parental smoking and measured respiratory outcomes at 12 and 18 years in the Melbourne Atopy Cohort Study (MACS), a longitudinal birth cohort. Multiple logistic regression was used to analyse the associations between perinatal smoke exposure and asthma at 12 (n = 370) and 18 years (n = 411). Multiple linear regression was used to investigate the relationship between perinatal smoking and: lung function (12 and 18 years) and lung function growth (between 12 and 18 years). RESULTS: At 18 years, girls exposed to parental smoking during the perinatal period had increased odds of asthma (OR: 3.45, 95%CI: 1.36, 8.77), reduced pre-bronchodilator Forced expiratory volume in one-second (FEV1) (-272 ml/s; -438, -107); FEV1/ forced vital capacity (FVC) (-0.038; -0.065, -0.010); mid expiratory flow (MEF25-75) (-430 ml/s; -798, -61), and reduced post-bronchodilator FEV1/FVC (-0.028, -0.053, -0.004). No associations were found for boys (pre-bronchodilator FEV1 26ml/s; -202, 255; FEV1/FVC 0.018; -0.013, 0.049). CONCLUSIONS: Perinatal smoke may affect risk of asthma, reduce lung function and lung function growth in adolescence. Girls appear to be more susceptible than boys.
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ItemChildhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life(ELSEVIER SCI LTD, 2018-07)BACKGROUND: Lifetime lung function is related to quality of life and longevity. Over the lifespan, individuals follow different lung function trajectories. Identification of these trajectories, their determinants, and outcomes is important, but no study has done this beyond the fourth decade. METHODS: We used six waves of the Tasmanian Longitudinal Health Study (TAHS) to model lung function trajectories measured at 7, 13, 18, 45, 50, and 53 years. We analysed pre-bronchodilator FEV1 z-scores at the six timepoints using group-based trajectory modelling to identify distinct subgroups of individuals whose measurements followed a similar pattern over time. We related the trajectories identified to childhood factors and risk of chronic obstructive pulmonary disease (COPD) using logistic regression, and estimated population-attributable fractions of COPD. FINDINGS: Of the 8583 participants in the original cohort, 2438 had at least two waves of lung function data at age 7 years and 53 years and comprised the study population. We identified six trajectories: early below average, accelerated decline (97 [4%] participants); persistently low (136 [6%] participants); early low, accelerated growth, normal decline (196 [8%] participants); persistently high (293 [12%] participants); below average (772 [32%] participants); and average (944 [39%] participants). The three trajectories early below average, accelerated decline; persistently low; and below average had increased risk of COPD at age 53 years compared with the average group (early below average, accelerated decline: odds ratio 35·0, 95% CI 19·5-64·0; persistently low: 9·5, 4·5-20·6; and below average: 3·7, 1·9-6·9). Early-life predictors of the three trajectories included childhood asthma, bronchitis, pneumonia, allergic rhinitis, eczema, parental asthma, and maternal smoking. Personal smoking and active adult asthma increased the impact of maternal smoking and childhood asthma, respectively, on the early below average, accelerated decline trajectory. INTERPRETATION: We identified six potential FEV1 trajectories, two of which were novel. Three trajectories contributed 75% of COPD burden and were associated with modifiable early-life exposures whose impact was aggravated by adult factors. We postulate that reducing maternal smoking, encouraging immunisation, and avoiding personal smoking, especially in those with smoking parents or low childhood lung function, might minimise COPD risk. Clinicians and patients with asthma should be made aware of the potential long-term implications of non-optimal asthma control for lung function trajectory throughout life, and the role and benefit of optimal asthma control on improving lung function should be investigated in future intervention trials. FUNDING: National Health and Medical Research Council of Australia; European Union's Horizon 2020; The University of Melbourne; Clifford Craig Medical Research Trust of Tasmania; The Victorian, Queensland & Tasmanian Asthma Foundations; The Royal Hobart Hospital; Helen MacPherson Smith Trust; and GlaxoSmithKline.
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ItemNo Preview AvailableHouse dust mite sensitization in toddlers predicts current wheeze at age 12 years(MOSBY-ELSEVIER, 2011-10)BACKGROUND: Identification of children at risk of developing asthma provides a window of opportunity for risk-reducing interventions. Allergen sensitization might identify high-risk children. OBJECTIVE: We sought to determine whether skin prick tests (SPTs) to individual allergens up to age 2 years predict wheeze at age 12 years. METHODS: In a birth cohort of 620 children oversampled for familial allergy, sensitization was assessed by using SPTs (monosensitized, polysensitized, or either) to 6 allergens at ages 6, 12, and 24 months. Wheeze and eczema were recorded 18 times during the first 2 years. Current wheeze was recorded at age 12 years. Adjusted associations were evaluated by multiple logistic regression. RESULTS: A positive SPT to house dust mite (HDM) at age 1 or 2 years predicted wheeze at age 12 years (adjusted odds ratio: 1 year, 3.31 [95% CI 1.59-6.91]; 2 years, 6.37 [95% CI, 3.48-11.66]). Among wheezy 1-year-olds, those who were HDM sensitized had a 75% (95% CI, 51% to 91%) probability of wheeze at age 12 years compared with a 36% (95% CI, 23% to 50%) probability among those not sensitized. Among eczematous 1-year-olds, those who were HDM sensitized had a 67% (95% CI, 45% to 84%) probability of wheeze at age 12 years compared with a 35% (95% CI, 25% to 45%) probability among those not sensitized. Among 1-year-old children with both eczema and wheeze, the probability of wheeze at age 12 years was 64% (95% CI, 35% to 87%) if HDM sensitized and 50% (95% CI, 26% to 74%) if not. CONCLUSION: HDM sensitization at age 1 or 2 years in wheezing and eczematous children at increased familial allergy risk predicts asthma and may inform management of these high-risk groups.
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ItemNo Preview AvailableCohort Profile: The Tasmanian Longitudinal Health STUDY (TAHS)(OXFORD UNIV PRESS, 2017-04)
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ItemNo Preview AvailableCohort Profile: Melbourne Atopy Cohort study (MACS)(OXFORD UNIV PRESS, 2017-02)