Maternal vitamin D–related metabolome and offspring risk of asthma outcomes

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Min Kim
Nicklas Brustad
Mina Ali
Gözde Gürdeniz
Rasmussen, Morten Arendt
Augusto A. Litonjua
Craig E. Wheelock
Rachel S. Kelly
Yulu Chen
Nicole Prince
Feng Guo
Xiaobo Zhou
Stokholm, Jakob
Bønnelykke, Klaus
Scott T. Weiss
Hans Bisgaard
Jessica Lasky-Su
Chawes, Bo Lund Krogsgaard

Background: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. Objective: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. Methods: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood₂₀₁₀ (COPSAC₂₀₁₀) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC₂₀₁₀, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. Results: In COPSAC₂₀₁₀, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D–related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D₃ showed an increased cytoplasmic sphingolipid level (P < .01). Conclusions: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.

Originalsprog	Engelsk
Tidsskrift	Journal of Allergy and Clinical Immunology
Vol/bind	152
Udgave nummer	6
Sider (fra-til)	1646-1657.e11
Antal sider	23
ISSN	0091-6749
DOI	https://doi.org/10.1016/j.jaci.2023.06.030
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
All funding received by COPSAC is listed on www.copsac.com . The Lundbeck Foundation (Grant No. R16-A1694), the Danish Ministry of Health (Grant No. 903516), the Danish Council for Strategic Research (Grant No. 0603-00280B), and the Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 946228). VDAART ( ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from the National Heart, Lung, and Blood Institute (NHLBI) and grant U54TR001012 from the National Center for Advancing Translational Sciences . Metabolomics work by VDAART and COPSAC was supported by NHLBI grants R01HL123915 and R01HL141826. S.T. Weiss was supported by NHLBI grants R01HL091528 and P01HL132825 and grant UG3OD023268 from Office of the Director , National Institutes of Health . C.E. Wheelock acknowledges support from the Swedish Heart Lung Foundation (HLF 20210519 and HLF 20200693). The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. No pharmaceutical company was involved in the study.

Funding Information:
All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (Grant No. R16-A1694), the Danish Ministry of Health (Grant No. 903516), the Danish Council for Strategic Research (Grant No. 0603-00280B), and the Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (Grant Agreement No. 946228). VDAART (ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from the National Heart, Lung, and Blood Institute (NHLBI) and grant U54TR001012 from the National Center for Advancing Translational Sciences. Metabolomics work by VDAART and COPSAC was supported by NHLBI grants R01HL123915 and R01HL141826. S.T. Weiss was supported by NHLBI grants R01HL091528 and P01HL132825 and grant UG3OD023268 from Office of the Director, National Institutes of Health. C.E. Wheelock acknowledges support from the Swedish Heart Lung Foundation (HLF 20210519 and HLF 20200693). The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. No pharmaceutical company was involved in the study.

Publisher Copyright:
© 2023 The Authors

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