RT Journal Article
SR Electronic
T1 The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1900761
DO 10.1183/13993003.00761-2019
A1 Rachel S. Kelly
A1 Bo L. Chawes
A1 Feng Guo
A1 Li Zhang
A1 Kevin Blighe
A1 Augusto A. Litonjua
A1 Benjamin A. Raby
A1 Bruce D. Levy
A1 Daniela Rago
A1 Jakob Stokholm
A1 Klaus Bønnelykke
A1 Hans Bisgaard
A1 Xiaobo Zhou
A1 Jessica A. Lasky-Su
A1 Scott T. Weiss
YR 2019
UL http://erj.ersjournals.com/content/early/2019/07/17/13993003.00761-2019.abstract
AB Background Evidence suggests vitamin D has preventive potential for asthma, however, not all children benefit from this intervention. This study aims to investigate whether variation in the functional 17q21 SNP; rs12936231 affects the preventive potential of vitamin D against asthma.Methods 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.Results The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG-genotype (HR (95%CI) 0.49 (0.26, 0.94), p=0.032), but not the high-risk CC-genotype (HR(95%CI) 1.08 (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: (sphingosine-1-phosphate (β (95% CI) 0.022 (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*age1: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).Conclusion Results suggest prenatal vitamin D supplementation may reduce risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on 17q21 genotype.Trial Registration clinicaltrials.gov Identifiers: VDAART NCT00920621, COPSAC2010 NCT00856947FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. kelly has nothing to disclose.Conflict of interest: Dr. Chawes has nothing to disclose.Conflict of interest: Dr. Guo has nothing to disclose.Conflict of interest: Dr. Zhang has nothing to disclose.Conflict of interest: Dr. Blighe has nothing to disclose.Conflict of interest: Dr. Litonjua reports Author royalties from UpToDate, Inc.Conflict of interest: Dr. Raby has nothing to disclose.Conflict of interest: Dr. Levy reports grants from NIH, personal fees from GossamerBio, personal fees from Novartis, personal fees from Pieris Pharmaceuticals, personal fees from Sanofi, personal fees from Teva, during the conduct of the study.Conflict of interest: Dr. Rago has nothing to disclose.Conflict of interest: Dr. Stokholm has nothing to disclose.Conflict of interest: Dr. Bonnelykke has nothing to disclose.Conflict of interest: Dr. Bisgaard has been a consultant for Chiesi and Boehringer Ingelheim.Conflict of interest: Dr. Zhou has nothing to disclose.Conflict of interest: Dr. Lasky-Su has nothing to disclose.Conflict of interest: Dr. Weiss reports that he is an author for UpToDate, PI of several NIH grants and an unpaid advisor to Novartis Pharmaceuticals.