FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

Tarunveer S. Ahluwalia; Anders U. Eliasen; Astrid Sevelsted; Casper Emil T. Pedersen; Jakob Stokholm; Bo Chawes; Jette Bork-Jensen; Niels Grarup; Oluf Pedersen; Torben Hansen; Allan Linneberg; Amitabh Sharma; Scott T. Weiss; Michael D. Evans; Daniel J. Jackson; Andreanne Morin; Karen A. Krogfelt; Susanne Schjørring; Preben B. Mortensen; David M. Hougaard; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Ole Mors; Merete Nordentoft; Anders D. Børglum; Thomas Werge; Esben Agerbo; James E. Gern; Robert F. Lemanske; Carole Ober; Anders G. Pedersen; Hans Bisgaard; Klaus Bønnelykke

doi:10.1038/s41467-020-19814-6

FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

Tarunveer S. Ahluwalia, Anders U. Eliasen, Astrid Sevelsted, Casper Emil T. Pedersen, Jakob Stokholm, Bo Chawes, Jette Bork-Jensen, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Amitabh Sharma, Scott T. Weiss, Michael D. Evans, Daniel J. Jackson, Andreanne Morin, Karen A. Krogfelt, Susanne Schjørring, Preben B. Mortensen, David M. HougaardJonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Ole Mors, Merete Nordentoft, Anders D. Børglum, Thomas Werge, Esben Agerbo, James E. Gern, Robert F. Lemanske, Carole Ober, Anders G. Pedersen, Hans Bisgaard, Klaus Bønnelykke

CTSI Biostatistics

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19 Scopus citations

Abstract

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11–1.25), P_discovery = 2.6 × 10⁻⁹) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.

Original language	English (US)
Article number	6398
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19814-6
State	Published - Dec 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

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Ahluwalia, T. S., Eliasen, A. U., Sevelsted, A., Pedersen, C. E. T., Stokholm, J., Chawes, B., Bork-Jensen, J., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Sharma, A., Weiss, S. T., Evans, M. D., Jackson, D. J., Morin, A., Krogfelt, K. A., Schjørring, S., Mortensen, P. B., ... Bønnelykke, K. (2020). FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses. Nature communications, 11(1), Article 6398. https://doi.org/10.1038/s41467-020-19814-6

Ahluwalia, TS, Eliasen, AU, Sevelsted, A, Pedersen, CET, Stokholm, J, Chawes, B, Bork-Jensen, J, Grarup, N, Pedersen, O, Hansen, T, Linneberg, A, Sharma, A, Weiss, ST, Evans, MD, Jackson, DJ, Morin, A, Krogfelt, KA, Schjørring, S, Mortensen, PB, Hougaard, DM, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Mors, O, Nordentoft, M, Børglum, AD, Werge, T, Agerbo, E, Gern, JE, Lemanske, RF, Ober, C, Pedersen, AG, Bisgaard, H & Bønnelykke, K 2020, 'FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses', Nature communications, vol. 11, no. 1, 6398. https://doi.org/10.1038/s41467-020-19814-6

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abstract = "Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11–1.25), Pdiscovery = 2.6 × 10−9) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.",

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AU - Ahluwalia, Tarunveer S.

AU - Eliasen, Anders U.

AU - Sevelsted, Astrid

AU - Pedersen, Casper Emil T.

AU - Stokholm, Jakob

AU - Chawes, Bo

AU - Bork-Jensen, Jette

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - Sharma, Amitabh

AU - Weiss, Scott T.

AU - Evans, Michael D.

AU - Jackson, Daniel J.

AU - Morin, Andreanne

AU - Krogfelt, Karen A.

AU - Schjørring, Susanne

AU - Mortensen, Preben B.

AU - Hougaard, David M.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Børglum, Anders D.

AU - Werge, Thomas

AU - Agerbo, Esben

AU - Gern, James E.

AU - Lemanske, Robert F.

AU - Ober, Carole

AU - Pedersen, Anders G.

AU - Bisgaard, Hans

AU - Bønnelykke, Klaus

PY - 2020/12

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FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

Abstract

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