Abstract：
UNASSIGNED: The observational association between blood metabolites and asthma has been extensively studied. However, it is still unclear whether this association is causal. In this study, we aimed to investigate the causal relationship between blood metabolites and asthma using a bidirectional Mendelian randomization (MR) analysis. Additionally, we aimed to explore the potential mechanisms underlying this relationship.
UNASSIGNED: The study design involved the use of genetic instruments as instrumental variables (IVs) to fulfill the assumptions of MR analysis. The data on 1,091 metabolites and 309 metabolite ratios were obtained from the Canadian Longitudinal Study on Aging (CLSA), while the data on asthma were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project. Utilizing the inverse variance-weighted (IVW) method as the primary MR analysis approach, sensitivity tests were conducted to assess the reliability of the findings, which involved employing Cochran\'s Q and the MR-Egger intercept. Furthermore, Bayesian weighted MR was used to further test the robustness of the results. Additionally, pathway analysis was conducted to explore the metabolic explanations underlying asthma.
UNASSIGNED: In our study, a comprehensive MR Analysis identified 10 metabolites and 6 metabolite ratios significantly associated with the development of asthma (FDR < 0.05). The metabolites included glycerophosphocholines(GPCs), glycerophosphoethanolamines(GPEs), and an unknown metabolite. Of these, 1-arachidonoyl-GPC, 1-myristoyl-2-arachidonoyl-GPC, 1-palmitoyl-2-arachidonoyl-GPC, and 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC were associated with an increased risk of asthma, whereas 1,2-dilinoleoyl-GPC, 1-palmitoyl-2-linoleoyl-GPC, 1,2-dilinoleoyl-GPE, 1 - oleoyl - 2 - linoleoyl - GPE, 1-palmitoyl-2-linoleoyl-GPE, and X-21470 were found to have a protective effect. No heterogeneity and pleiotropy were observed in the significant metabolites (p > 0.05), and each metabolite exhibited a consistent effect direction across all five methods. BWMR analysis results confirmed the significance and direction of effects across exposures, except for Cholesterol to linoleoyl-arachidonoyl-glycerol ratio(p = 0.673). Pathway analysis suggests that glycerophospholipid metabolism may potentially be a mechanism underlying the development of asthma.
UNASSIGNED: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical asthma screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.
UNASSIGNED: The study design involved the use of genetic instruments as instrumental variables (IVs) to fulfill the assumptions of MR analysis. The data on 1,091 metabolites and 309 metabolite ratios were obtained from the Canadian Longitudinal Study on Aging (CLSA), while the data on asthma were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project. Utilizing the inverse variance-weighted (IVW) method as the primary MR analysis approach, sensitivity tests were conducted to assess the reliability of the findings, which involved employing Cochran\'s Q and the MR-Egger intercept. Furthermore, Bayesian weighted MR was used to further test the robustness of the results. Additionally, pathway analysis was conducted to explore the metabolic explanations underlying asthma.
UNASSIGNED: In our study, a comprehensive MR Analysis identified 10 metabolites and 6 metabolite ratios significantly associated with the development of asthma (FDR < 0.05). The metabolites included glycerophosphocholines(GPCs), glycerophosphoethanolamines(GPEs), and an unknown metabolite. Of these, 1-arachidonoyl-GPC, 1-myristoyl-2-arachidonoyl-GPC, 1-palmitoyl-2-arachidonoyl-GPC, and 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC were associated with an increased risk of asthma, whereas 1,2-dilinoleoyl-GPC, 1-palmitoyl-2-linoleoyl-GPC, 1,2-dilinoleoyl-GPE, 1 - oleoyl - 2 - linoleoyl - GPE, 1-palmitoyl-2-linoleoyl-GPE, and X-21470 were found to have a protective effect. No heterogeneity and pleiotropy were observed in the significant metabolites (p > 0.05), and each metabolite exhibited a consistent effect direction across all five methods. BWMR analysis results confirmed the significance and direction of effects across exposures, except for Cholesterol to linoleoyl-arachidonoyl-glycerol ratio(p = 0.673). Pathway analysis suggests that glycerophospholipid metabolism may potentially be a mechanism underlying the development of asthma.
UNASSIGNED: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical asthma screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.
摘要：
■血液代谢物与哮喘之间的观察性关联已得到广泛研究。然而,目前尚不清楚这种关联是否是因果关系.在这项研究中,我们旨在通过双向孟德尔随机(MR)分析,探讨血液代谢物与哮喘之间的因果关系.此外,我们旨在探讨这种关系的潜在机制.
■研究设计涉及使用遗传仪器作为工具变量（IV）来实现MR分析的假设。1,091种代谢物和309种代谢物比率的数据来自加拿大衰老纵向研究（CLSA），而哮喘的数据来自综合流行病学单位(IEU)OpenGWAS项目。利用逆方差加权(IVW)方法作为主要的MR分析方法，进行了敏感性测试，以评估结果的可靠性，其中涉及使用科克伦的Q和MR-Egger拦截。此外，采用贝叶斯加权MR进一步检验结果的稳健性。此外,我们进行了通路分析,以探讨哮喘的代谢解释.
■在我们的研究中，全面的MR分析确定了10种代谢物和6种代谢物的比例与哮喘的发展显著相关(FDR<0.05)。代谢物包括甘油磷胆碱（GPCs），甘油磷酸乙醇胺（GPE），还有一种未知的代谢产物.其中,1-花生四酰基-GPC,1-肉豆蔻酰基-2-花生四酰基-GPC,1-棕榈酰-2-花生酰-GPC,和1-(1-烯基-棕榈酰基)-2-花生四酰基-GPC与哮喘风险增加相关,而1,2-二亚油酰基-GPC，1-棕榈酰基-2-亚油酰基-GPC，1,2-二油酰基-GPE，1-油酰基-2-亚油酰基-GPE，1-棕榈酰基-2-亚油酰基-GPE，发现X-21470具有保护作用。在显著的代谢物中没有观察到异质性和多效性(p>0.05),每种代谢物在所有五种方法中表现出一致的作用方向。BWMR分析结果证实了跨暴露影响的重要性和方向，除了胆固醇与亚油酰基-花生四烯酸酰基-甘油的比例（p=0.673）。途径分析表明，甘油磷脂代谢可能是哮喘发展的潜在机制。
■我们的MR研究结果表明，所确定的代谢产物和途径可以作为临床哮喘筛查和预防的生物标志物。同时也为未来的机理探索和药物靶点选择提供了新的见解。
■研究设计涉及使用遗传仪器作为工具变量（IV）来实现MR分析的假设。1,091种代谢物和309种代谢物比率的数据来自加拿大衰老纵向研究（CLSA），而哮喘的数据来自综合流行病学单位(IEU)OpenGWAS项目。利用逆方差加权(IVW)方法作为主要的MR分析方法，进行了敏感性测试，以评估结果的可靠性，其中涉及使用科克伦的Q和MR-Egger拦截。此外，采用贝叶斯加权MR进一步检验结果的稳健性。此外,我们进行了通路分析,以探讨哮喘的代谢解释.
■在我们的研究中，全面的MR分析确定了10种代谢物和6种代谢物的比例与哮喘的发展显著相关(FDR<0.05)。代谢物包括甘油磷胆碱（GPCs），甘油磷酸乙醇胺（GPE），还有一种未知的代谢产物.其中,1-花生四酰基-GPC,1-肉豆蔻酰基-2-花生四酰基-GPC,1-棕榈酰-2-花生酰-GPC,和1-(1-烯基-棕榈酰基)-2-花生四酰基-GPC与哮喘风险增加相关,而1,2-二亚油酰基-GPC，1-棕榈酰基-2-亚油酰基-GPC，1,2-二油酰基-GPE，1-油酰基-2-亚油酰基-GPE，1-棕榈酰基-2-亚油酰基-GPE，发现X-21470具有保护作用。在显著的代谢物中没有观察到异质性和多效性(p>0.05),每种代谢物在所有五种方法中表现出一致的作用方向。BWMR分析结果证实了跨暴露影响的重要性和方向，除了胆固醇与亚油酰基-花生四烯酸酰基-甘油的比例（p=0.673）。途径分析表明，甘油磷脂代谢可能是哮喘发展的潜在机制。
■我们的MR研究结果表明，所确定的代谢产物和途径可以作为临床哮喘筛查和预防的生物标志物。同时也为未来的机理探索和药物靶点选择提供了新的见解。
