鞘脂分类及其与儿童哮喘和哮喘危险因素间相互关系
2024/02/23
摘要
背景：虽然鞘脂代谢失调与儿童哮喘风险相关，但具体鞘脂类别和/或驱动上述关系的机制尚不清楚。
目的：本研究旨在了解鞘脂和其他已确定哮喘风险因素之间的多重作用，上述因素使这种关系复杂化。
方法：本研究对来自两个独立队列（VDAART和COPSAC2010）的997名6岁儿童的血浆中77种鞘脂进行基于LC-MS/MS的靶向定量。本文对循环鞘脂与儿童哮喘、肺功能和3个哮喘风险因素（ORMDL3中的功能性SNPs、低维生素D水平和肠道微生物成熟度降低）的关系进行研究。考虑到队列间种族差异，本研究分别对其进行关联分析，之后行荟萃分析。
结果：本研究观察到循环鞘脂升高与哮喘表型和危险因素相关；然而，鞘脂类与临床结果和/或危险因素之间存在差异性关联。虽然参与神经酰胺循环和分解代谢途径的代谢产物升高与哮喘和肺功能恶化相关[荟萃p值范围：1.863E-04至2.24E-3]，但神经酰胺水平升高与哮喘危险因素相关[荟萃p值范围：7.75E-5至.013]，但与哮喘无关。进一步研究发现，部分神经酰胺充当中介，部分神经酰胺与哮喘预后相关风险因素相互作用。
结论：本研究证实，不同类型鞘脂在哮喘及其危险因素中可能发挥不同作用。而鞘脂整体升高总的来说似乎有害；神经酰胺升高仅与哮喘危险因素增加相关；而哮喘表型升高与鞘脂再循环相关。调整哮喘危险因素可能在哮喘相关神经酰胺介导的鞘脂稳态调节中发挥重要作用。未来可通过功能学研究验证本研究所观察到的相关性。
Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors
Li M, Zhong X, Xu W.
Chen Y, Checa A, Zhang P, Huang M, Kelly RS, Kim M, Chen YS, Lee-Sarwar KA, Prince N, Mendez KM, Begum S, Kachroo P, Chu SH, Stokholm J, Bønnelykke K, Litonjua AA, Bisgaard H, Weiss ST, Chawes BL, Wheelock CE, Lasky-Su JA.
Abstract
BACKGROUND:While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear.
OBJECTIVE:We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship.
METHODS:We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together.
RESULTS:We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes.
CONCLUSION:This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.
背景：虽然鞘脂代谢失调与儿童哮喘风险相关，但具体鞘脂类别和/或驱动上述关系的机制尚不清楚。
目的：本研究旨在了解鞘脂和其他已确定哮喘风险因素之间的多重作用，上述因素使这种关系复杂化。
方法：本研究对来自两个独立队列（VDAART和COPSAC2010）的997名6岁儿童的血浆中77种鞘脂进行基于LC-MS/MS的靶向定量。本文对循环鞘脂与儿童哮喘、肺功能和3个哮喘风险因素（ORMDL3中的功能性SNPs、低维生素D水平和肠道微生物成熟度降低）的关系进行研究。考虑到队列间种族差异，本研究分别对其进行关联分析，之后行荟萃分析。
结果：本研究观察到循环鞘脂升高与哮喘表型和危险因素相关；然而，鞘脂类与临床结果和/或危险因素之间存在差异性关联。虽然参与神经酰胺循环和分解代谢途径的代谢产物升高与哮喘和肺功能恶化相关[荟萃p值范围：1.863E-04至2.24E-3]，但神经酰胺水平升高与哮喘危险因素相关[荟萃p值范围：7.75E-5至.013]，但与哮喘无关。进一步研究发现，部分神经酰胺充当中介，部分神经酰胺与哮喘预后相关风险因素相互作用。
结论：本研究证实，不同类型鞘脂在哮喘及其危险因素中可能发挥不同作用。而鞘脂整体升高总的来说似乎有害；神经酰胺升高仅与哮喘危险因素增加相关；而哮喘表型升高与鞘脂再循环相关。调整哮喘危险因素可能在哮喘相关神经酰胺介导的鞘脂稳态调节中发挥重要作用。未来可通过功能学研究验证本研究所观察到的相关性。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Allergy. 2024 Feb;79(2):404-418. doi: 10.1111/all.15942. Epub 2023 Nov 28.)
(Allergy. 2024 Feb;79(2):404-418. doi: 10.1111/all.15942. Epub 2023 Nov 28.)
Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors
Li M, Zhong X, Xu W.
Chen Y, Checa A, Zhang P, Huang M, Kelly RS, Kim M, Chen YS, Lee-Sarwar KA, Prince N, Mendez KM, Begum S, Kachroo P, Chu SH, Stokholm J, Bønnelykke K, Litonjua AA, Bisgaard H, Weiss ST, Chawes BL, Wheelock CE, Lasky-Su JA.
Abstract
BACKGROUND:While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear.
OBJECTIVE:We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship.
METHODS:We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together.
RESULTS:We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes.
CONCLUSION:This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.
上一篇：
血嗜酸性粒细胞和部分呼出气一氧化氮可作为儿童哮喘预后和疗效预测的生物标志物
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衰弱与慢性阻塞性肺病或哮喘之间的因果关系：双向孟德尔随机抽样研究
