Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype. / Rago, Daniela; Pedersen, Casper-Emil T; Huang, Mengna; Kelly, Rachel S; Gürdeniz, Gözde; Brustad, Nicklas; Knihtilä, Hanna; Lee-Sarwar, Kathleen A; Morin, Andréanne; Rasmussen, Morten A.; Stokholm, Jakob; Bønnelykke, Klaus; Litonjua, Augusto A; Wheelock, Craig E; Weiss, Scott T; Lasky-Su, Jessica; Bisgaard, Hans; Chawes, Bo L.
I: American Journal of Respiratory and Critical Care Medicine, Bind 203, Nr. 7, 2021, s. 853-863.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype
AU - Rago, Daniela
AU - Pedersen, Casper-Emil T
AU - Huang, Mengna
AU - Kelly, Rachel S
AU - Gürdeniz, Gözde
AU - Brustad, Nicklas
AU - Knihtilä, Hanna
AU - Lee-Sarwar, Kathleen A
AU - Morin, Andréanne
AU - Rasmussen, Morten A.
AU - Stokholm, Jakob
AU - Bønnelykke, Klaus
AU - Litonjua, Augusto A
AU - Wheelock, Craig E
AU - Weiss, Scott T
AU - Lasky-Su, Jessica
AU - Bisgaard, Hans
AU - Chawes, Bo L
PY - 2021
Y1 - 2021
N2 - Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data.Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.
AB - Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data.Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.
U2 - 10.1164/rccm.202008-3206OC
DO - 10.1164/rccm.202008-3206OC
M3 - Journal article
C2 - 33535020
VL - 203
SP - 853
EP - 863
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 7
ER -
ID: 259830700