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.
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.
Authors: A J Ammit; A T Hastie; L C Edsall; R K Hoffman; Y Amrani; V P Krymskaya; S A Kane; S P Peters; R B Penn; S Spiegel; R A Panettieri Journal: FASEB J Date: 2001-05 Impact factor: 5.191
Authors: Sita D Gupta; Kenneth Gable; Aikaterini Alexaki; Panagiotis Chandris; Richard L Proia; Teresa M Dunn; Jeffrey M Harmon Journal: J Biol Chem Date: 2014-11-13 Impact factor: 5.157
Authors: Tilla S Worgall; Arul Veerappan; Biin Sung; Benjamin I Kim; Evan Weiner; Reshma Bholah; Randi B Silver; Xian-Cheng Jiang; Stefan Worgall Journal: Sci Transl Med Date: 2013-05-22 Impact factor: 17.956
Authors: Clement Oyeniran; Jamie L Sturgill; Nitai C Hait; Wei-Ching Huang; Dorit Avni; Michael Maceyka; Jason Newton; Jeremy C Allegood; Alison Montpetit; Daniel H Conrad; Sheldon Milstien; Sarah Spiegel Journal: J Allergy Clin Immunol Date: 2015-04-02 Impact factor: 10.793
Authors: Rachel S Kelly; Bo L Chawes; Feng Guo; Li Zhang; Kevin Blighe; Augusto A Litonjua; Benjamin A Raby; Bruce D Levy; Daniela Rago; Jakob Stokholm; Klaus Bønnelykke; Hans Bisgaard; Xiaobo Zhou; Jessica A Lasky-Su; Scott T Weiss Journal: Eur Respir J Date: 2019-10-24 Impact factor: 16.671
Authors: Michelle M Stein; Emma E Thompson; Nathan Schoettler; Britney A Helling; Kevin M Magnaye; Catherine Stanhope; Catherine Igartua; Andréanne Morin; Charles Washington; Dan Nicolae; Klaus Bønnelykke; Carole Ober Journal: J Allergy Clin Immunol Date: 2018-01-04 Impact factor: 10.793
Authors: Ariangela J Kozik; Fernando Holguin; Leopoldo N Segal; Talal A Chatila; Anne E Dixon; James E Gern; Catherine Lozupone; Nicholas Lukacs; Carey Lumeng; Philip L Molyneaux; Nichole Reisdorph; Ivan Vujkovic-Cvijin; Alkis Togias; Yvonne J Huang Journal: Am J Respir Cell Mol Biol Date: 2022-08 Impact factor: 7.748