鞘脂类相关儿童哮喘内型的特点和机制
2021/05/26
摘要
理论基础:鞘脂类、17q21基因变异与儿童哮喘之间存在联系，但这种哮喘内型的潜在机制和特征仍有待阐明。
目的:利用多组学数据研究鞘脂类相关的儿童哮喘内型。
方法：在COPSAC2010(哥本哈根儿童哮喘前瞻性研究)出生队列研究中，我们使用了500多名6个月和6岁儿童的非靶向液相色谱-质谱血浆代谢组谱，重点关注鞘脂类，我们整合了SPT(丝氨酸棕榈酰辅酶a转移酶)的17q21基因型和鼻部基因表达(即从头鞘脂合成的限速酶)与婴儿至6岁哮喘发展和肺功能性状的关系。在独立的VDAART(维生素D产前减少哮喘试验)队列中寻求复制。
结果：6个月大时神经酰胺和鞘磷脂浓度较低与3岁前发生哮喘的风险增加相关，VDAART中也发现了这一点。在6岁时，较低浓度的关键鞘磷脂(例如，鞘氨醇-1-磷酸)与增加的气道阻力相关。这种关系依赖于17q21基因型和鼻腔SPT基因表达，基因型和鞘磷脂浓度之间以及基因型和SPT表达之间存在显著的相互作用。其中较低的鞘磷脂浓度和减少的SPT表达与风险等位基因数量的增加相关。然而，结果没有通过错误发现率阈值＜0.05。
结论：这项探索性研究表明，存在一种儿童哮喘内型，其发病较早且气道阻力增加，其特征是鞘磷脂浓度降低，这与17q21基因变异和SPT酶的表达有关。
Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype
Daniela Rago , Casper-Emil T Pedersen , Mengna Huang, Rachel S Kelly, Gözde Gürdeniz, Nicklas Brustad, Hanna Knihtilä, Kathleen A Lee-Sarwar, Andréanne Morin, Morten A Rasmussen, Jakob Stokholm, Klaus Bønnelykke , Augusto A Litonjua , Craig E Wheelock, Scott T Weiss, Jessica Lasky-Su, Hans Bisgaard, Bo L Chawes
Abstract
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.
理论基础:鞘脂类、17q21基因变异与儿童哮喘之间存在联系，但这种哮喘内型的潜在机制和特征仍有待阐明。
目的:利用多组学数据研究鞘脂类相关的儿童哮喘内型。
方法：在COPSAC2010(哥本哈根儿童哮喘前瞻性研究)出生队列研究中，我们使用了500多名6个月和6岁儿童的非靶向液相色谱-质谱血浆代谢组谱，重点关注鞘脂类，我们整合了SPT(丝氨酸棕榈酰辅酶a转移酶)的17q21基因型和鼻部基因表达(即从头鞘脂合成的限速酶)与婴儿至6岁哮喘发展和肺功能性状的关系。在独立的VDAART(维生素D产前减少哮喘试验)队列中寻求复制。
结果：6个月大时神经酰胺和鞘磷脂浓度较低与3岁前发生哮喘的风险增加相关，VDAART中也发现了这一点。在6岁时，较低浓度的关键鞘磷脂(例如，鞘氨醇-1-磷酸)与增加的气道阻力相关。这种关系依赖于17q21基因型和鼻腔SPT基因表达，基因型和鞘磷脂浓度之间以及基因型和SPT表达之间存在显著的相互作用。其中较低的鞘磷脂浓度和减少的SPT表达与风险等位基因数量的增加相关。然而，结果没有通过错误发现率阈值＜0.05。
结论：这项探索性研究表明，存在一种儿童哮喘内型，其发病较早且气道阻力增加，其特征是鞘磷脂浓度降低，这与17q21基因变异和SPT酶的表达有关。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Am J Respir Crit Care Med . 2021 Apr 1;203(7):853-863. doi: 10.1164/rccm.202008-3206OC .)
(Am J Respir Crit Care Med . 2021 Apr 1;203(7):853-863. doi: 10.1164/rccm.202008-3206OC .)
Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype
Daniela Rago , Casper-Emil T Pedersen , Mengna Huang, Rachel S Kelly, Gözde Gürdeniz, Nicklas Brustad, Hanna Knihtilä, Kathleen A Lee-Sarwar, Andréanne Morin, Morten A Rasmussen, Jakob Stokholm, Klaus Bønnelykke , Augusto A Litonjua , Craig E Wheelock, Scott T Weiss, Jessica Lasky-Su, Hans Bisgaard, Bo L Chawes
Abstract
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.
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雾化环索奈德增强肺泡沉积减轻气道炎症:克服计量吸入器缺点的策略
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