Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts

Min Kim, Nicklas Brustad, Anders U. Eliasen, Mina Ali, Tingting Wang, Morten A. Rasmussen, Madeleine Ernst, David Hougaard, Augusto A. Litonjua, Craig E. Wheelock, Rachel S. Kelly, Yulu Chen, Nicole Prince, Paul A. Townsend, Jakob Stokholm, Scott T. Weiss, Klaus Bønnelykke, Jessica Lasky-Su, Bo Chawes*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

Background: Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts. Methods: Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms. Findings: Increasing bilirubin (Z,Z) at ages 1.5–3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20–2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR = 1.31 [0.97–1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5–3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81–0.91, p < 0.049) but without a significant interaction with the UGT1A genotype (p interactions > 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections. Conclusions: Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes. Funding: The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), 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 (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was supported by R01HL091528 from the NHLBI, UG3OD023268 from Office of The Director, National Institute of Health, and P01HL132825 from the NHLBI.

OriginalsprogEngelsk
TidsskriftMed
ISSN2666-6359
DOI
StatusAccepteret/In press - 2024

Bibliografisk note

Funding Information:
We express our deepest gratitude to the children and families of the COPSAC and VDAART cohorts\u2019 studies for all their support and commitment. We acknowledge and appreciate the unique efforts of the research teams. All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (grant no. R16-A1694), The Ministry of Health of Denmark (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 (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 946228). VDDART (ClinicalTrials.gov: NCT00920621) was supported by grant U01HL091528 from NHLBI and U54TR001012 from the National Center for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123915 and R01HL141826. S.T.W. was supported by R01HL091528 from the NHLBI; UG3OD023268 from the Office of The Director, National Institutes of Health; and P01HL132825 from the NHLBI. The guarantor of the study, from conception and design to the conduct of the study, is B.C. M.K. conducted analyses. B.C. and M.K. had unrestricted access to all data. M.E. D.H. A.A.L. R.S.K, J.S. S.T.W. K.B. Y.C. N.P. A.U.E. J.L.-S. and B.C. participated in data acquisition. M.K. prepared the first draft of the manuscript. All co-authors have provided important intellectual input and contributed considerably to the analyses and interpretation of the data. All authors guarantee that the accuracy and integrity of any part of the work have been appropriately investigated and resolved, and all have approved the final version of the manuscript. The corresponding author had full access to the data and final responsibility for the decision to submit for publication. No honorarium, grant, or other form of payment was given to any of the authors to produce this manuscript. The authors declare no competing interests.

Funding Information:
All funding received by COPSAC is listed on www.copsac.com . The Lundbeck Foundation (grant no. R16-A1694 ), The 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 (ERC) under the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement no. 946228 ). VDDART (ClinicalTrials.gov: NCT00920621) was supported by grant U01HL091528 from NHLBI and U54TR001012 from the National Center for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123915 and R01HL141826 . S.T.W. was supported by R01HL091528 from the NHLBI ; UG3OD023268 from the Office of The Director, National Institutes of Health ; and P01HL132825 from the NHLBI .

Publisher Copyright:
© 2024 Elsevier Inc.

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