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 (β 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.
Abstract
Genetic variation in the 17q21 locus and vitamin D play a role in asthma risk and, as demonstrated for the first time in a human population, sphingolipid biosynthesis may partially underlie these relationships http://bit.ly/2ZbIpsp
Footnotes
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This is a combined secondary analysis of two trials with clinicaltrials.gov identifiers NCT00920621 (VDAART) and NCT00856947 (COPSAC2010). Because both COPSAC2010 and VDAART are ongoing, full phenotype and genetic data will not be available until after the studies have been completed.
Author contributions: R.S. Kelly and B.L. Chawes performed the statistical analysis and wrote the first draft of the manuscript. Functional work was performed by F. Guo, L. Zhang and X. Zhou, with support from B.A. Raby and B.D. Levy. A.A. Litonjua and S.T. Weiss are the principal investigators of VDAART and H. Bisgaard is the principal investigator of COPSAC2010, and as such contributed to the overall concept and study design together with J.A. Lasky-Su; all four provided funding support. K. Blighe, D. Rago, J. Stokholm and K. Bønnelykke provided analytical support. All authors assisted with the editing of the final draft of the manuscript and provide their approval for its submission. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication and takes full responsibility for the integrity of the data and the accuracy of the data analysis. No honorarium, grant or other form of payment was given to anyone to produce the manuscript.
Conflict of interest: R.S. Kelly has nothing to disclose.
Conflict of interest: B.L. Chawes has nothing to disclose.
Conflict of interest: F. Guo has nothing to disclose.
Conflict of interest: L. Zhang has nothing to disclose.
Conflict of interest: K. Blighe has nothing to disclose.
Conflict of interest: A.A. Litonjua reports author royalties from UpToDate, Inc.
Conflict of interest: B.A. Raby has nothing to disclose.
Conflict of interest: B.D. Levy reports grants from National Institutes of Health and personal fees for consultancy from GossamerBio, Novartis, Pieris Pharmaceuticals, Sanofi and Teva, during the conduct of the study.
Conflict of interest: D. Rago has nothing to disclose.
Conflict of interest: J. Stokholm has nothing to disclose.
Conflict of interest: K. Bønnelykke has nothing to disclose.
Conflict of interest: H. Bisgaard has been a consultant for Chiesi and Boehringer Ingelheim.
Conflict of interest: X. Zhou has nothing to disclose.
Conflict of interest: J.A. Lasky-Su has nothing to disclose.
Conflict of interest: S.T. Weiss reports that he is an author for UpToDate, principal investigator of several National Institutes of Health grants and an unpaid advisor to Novartis Pharmaceuticals.
Support statement: VDAART was supported by U01HL091528, 1R01HL123915-01 and 1R01HL123546-01A1 from the National Heart, Lung, and Blood Institute (NHLBI); and U54TR001012 from the National Centers for Advancing Translational Sciences. Metabolomic analyses and R.S. Kelly were supported by 5R01HL123915-05, 1R01HL141826-0 and W81XWH-17-1-0533. COPSAC2010 was supported by The Lundbeck Foundation (R16-A1694); The Danish Ministry of Health (903516); Danish Council for Strategic Research (grant number 0603-00280B) and The Capital Region Research Foundation (full list www.copsac.com). B.L. Chawes was supported by a European Respiratory Society fellowship. The funding bodies played no role in the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; nor decision to submit the manuscript for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 15, 2019.
- Accepted July 18, 2019.
- Copyright ©ERS 2019