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The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

ABSTRACT: Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed, stratifying by genotype and integrating metabolite data to explore underlying mechanisms.The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG genotype (hazard ratio (HR) 0.49, 95% CI 0.26-0.94, p=0.032) but not the high-risk CC genotype (HR 1.08, 95% CI 0.69-1.69, p=0.751). In VDAART, in the GG genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate (? 0.022, 95% CI 0.001-0.044, p=0.038), but this was not evident with the CC genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control human bronchial epithelial cell line and a cell line overexpressing ORMDL3 (p=0.002).Results suggest prenatal vitamin D supplementation may reduce the risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on the 17q21 genotype.

SUBMITTER: Kelly RS

PROVIDER: S-EPMC7181456 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

Kelly Rachel S RS Chawes Bo L BL Guo Feng F Zhang Li L Blighe Kevin K Litonjua Augusto A AA Raby Benjamin A BA Levy Bruce D BD Rago Daniela D Stokholm Jakob J Bønnelykke Klaus K Bisgaard Hans H Zhou Xiaobo X Lasky-Su Jessica A JA Weiss Scott T ST

The European respiratory journal 20191024 4

Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) an ...[more]

PMID: 31439681

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Project description:BackgroundWe recently published two independent randomized controlled trials of vitamin D supplementation during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 years of age. However, neither reached statistical significance.ObjectiveTo perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D (25(OH)D) level at trial entry modified the intervention effect.MethodsVDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry.ResultsThe analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ≥30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level <30ng/ml at study entry: aOR = 0.84 (0.62-1.15), p = 0.25. The IPD meta-analyses showed similar results. There was no effect on the secondary end-points.ConclusionsThis combined analysis shows that vitamin D supplementation during pregnancy results in a significant reduced risk of asthma/recurrent wheeze in the offspring, especially among women with 25(OH)D level ≥ 30 ng/ml at randomization, where the risk was almost halved. Future studies should examine the possibility of raising 25(OH)D levels to at least 30 ng/ml early in pregnancy or using higher doses than used in our studies.Trial registrationCOPSAC2010: ClinicalTrials.gov NCT00856947; VDAART: ClinicalTrials.gov NCT00920621.

Project description:BackgroundLower respiratory tract infection (LRTI) caused by respiratory syncytial virus (RSV) has been associated with greater risk of recurrent wheezing and subsequent asthma. However, it is still unclear whether this association is causal or not. RSV-specific monoclonal antibodies have been shown to reduce RSV-related hospitalisations in high-risk infants, i.e. those born pre-term, but the longer term follow-up has given conflicting evidence for the prevention of recurrent wheeze or asthma.ObjectiveWe aim to perform a systematic review and meta-analysis to determine whether or not prophylaxis with a monoclonal antibody for prevention of RSV-bronchiolitis reduces the risk of subsequent recurrent wheeze or asthma. If so, this would support the hypothesis that the association between RSV and recurrent wheeze and/or asthma is causative.MethodsTo identify relevant studies, we will search a number of databases including Medline, Embase, PubMed and Web of Science and will also manually look for unpublished data by contacting the manufacturers of monoclonal antibodies. The intervention being investigated is RSV-specific monoclonal antibody prophylaxis, and the outcome being measured is recurrent wheeze and/or asthma. Studies will be screened according to inclusion/exclusion criteria, to include primary studies of any study design type. Eligible studies will then be evaluated for quality and assessed for bias independently by three reviewers using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) approach. The results of the studies will be extracted into 2 × 2 outcome tables, and a meta-analysis will be carried out to produce forest plots based on relative risk. Heterogeneity will be assessed using the I2 statistic. The statistical software we will use is StatsDirect.DiscussionThis review will aid in determining if the relationship between RSV and asthma development is a causal one, by showing the effect (if any) of RSV prophylaxis on subsequent recurrent wheeze/asthma. If this study shows RSV prophylaxis to have no effect on the outcome of recurrent wheeze/asthma, the question of causality remains.

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The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

Publications

The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

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