中国成年人BMI与血浆氨基酸和酰基肉碱水平关联的观察性和孟德尔随机化研究

程思; 巫婷; 余灿清; 孙点剑一; 裴培; 杜怀东; 陈君石; 陈铮鸣; 庞元捷; 吕筠; 李立明; 代表中国慢性病前瞻性研究项目协作组

Abstract

程思,巫婷,余灿清,孙点剑一,裴培,杜怀东,陈君石,陈铮鸣,庞元捷,吕筠,李立明,代表中国慢性病前瞻性研究项目协作组.中国成年人BMI与血浆氨基酸和酰基肉碱水平关联的观察性和孟德尔随机化研究[J].Chinese journal of Epidemiology,2024,45(6):770-778

中国成年人BMI与血浆氨基酸和酰基肉碱水平关联的观察性和孟德尔随机化研究

An observational and Mendelian randomization study of the associations of body mass index with plasma amino acids and acylcarnitines in Chinese adults

Received:January 30, 2024

DOI：10.3760/cma.j.cn112338-20240130-00052

KeyWord: 体质指数氨基酸酰基肉碱孟德尔随机化

English Key Word: Body mass index Amino acids Acylcarnitines Mendelian randomization

FundProject:国家自然科学基金（82304223，82192901，82192904，82192900，81973125）；国家重点研发计划（2023YFC3606302）；中国香港Kadoorie Charitable基金

Author Name	Affiliation	E-mail
Cheng Si	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
Wu Ting	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
Yu Canqing	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
Sun Dianjianyi	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
Pei Pei	Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China
Du Huaidong	Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, United Kingdom
Chen Junshi	China National Center for Food Safety Risk Assessment, Beijing 100022, China
Chen Zhengming	Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, United Kingdom
Pang Yuanjie	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
Lyu Jun	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
Li Liming	Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China	lmleeph@vip.163.com
for the China Kadoorie Biobank Collaborative Group	1 Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China 2 Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing 100191, China 3 Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China 4 Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, United Kingdom 5 China National Center for Food Safety Risk Assessment, Beijing 100022, China

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Abstract:

目的探讨中国成年人BMI与血浆氨基酸和酰基肉碱水平的关联。方法基于中国慢性病前瞻性研究（CKB）第一次重复调查中2 182名具有靶向质谱代谢组检测的研究对象，采用多元线性回归模型和限制性立方样条模型分析BMI与血浆20种氨基酸和40种酰基肉碱的线性和非线性关联，并识别BMI相关的代谢通路。以BMI的遗传风险评分作为工具变量，采用单样本孟德尔随机化（MR）分析进一步探索BMI与20种氨基酸和40种酰基肉碱的潜在因果关联，并使用MR-Egger法检验水平多效性。结果观察性分析结果显示，BMI与3种支链氨基酸（异亮氨酸、亮氨酸和缬氨酸）、2种芳香族氨基酸（苯丙氨酸和酪氨酸）、3种其他氨基酸（半胱氨酸、谷氨酸、赖氨酸）以及7种酰基肉碱（C3、C4、C5、C10、C10：1、C14和C16）的血浆水平升高相关，与天冬酰胺、丝氨酸和甘氨酸水平降低相关。通路分析发现7个与BMI相关的氨基酸代谢通路（错误发现率校正后均P<0.05），包括支链氨基酸和芳香族氨基酸的生物合成、谷胱甘肽代谢等。BMI与亮氨酸、缬氨酸和苏氨酸呈非线性关联，BMI与其他氨基酸和酰基肉碱均呈线性关联。单样本MR分析发现BMI与酪氨酸和4种酰基肉碱［C5-DC（C6-OH）、C5-M-DC、C12-DC和C14］水平升高相关，其中酪氨酸和酰基肉碱C14在观察性分析［β值（95%CI）分别为0.057（0.044~0.070）和0.018（0.005~0.032）］和单样本MR分析［β值（95%CI）分别为0.102（0.035~0.169）和0.104（0.036~0.173）］中均与BMI呈显著正相关。经检验，本研究的MR分析满足工具变量的3个核心假设。结论中国成年人BMI与血浆11种氨基酸和7种酰基肉碱水平相关，涉及支链氨基酸和芳香族氨基酸代谢、脂肪酸代谢和氧化应激等多种途径，BMI与酪氨酸和酰基肉碱C14可能存在因果关联。

English Abstract:

Objective　To explore the relationship between BMI and levels of plasma amino acids and acylcarnitines in Chinese adults. Methods　Based on 2 182 individuals with targeted mass spectrometry metabolomic measurements from the first resurvey of the China Kadoorie Biobank, we assessed the linear and nonlinear associations between BMI and plasma levels of 20 amino acids and 40 acylcarnitines using linear regression models and restricted cubic spline models, and identified BMI-related metabolic pathways. We conducted one-sample Mendelian randomization (MR) with BMI genetic risk scores as the instrumental variable further to explore the potential causal relationships between BMI and 20 amino acids and 40 acylcarnitines, and tested for horizontal pleiotropy using the MR-Egger method. Results　Observational analyses found that BMI was associated with increased plasma levels of 3 branched-chain amino acids (isoleucine, leucine, and valine), 2 aromatic amino acids (phenylalanine and tyrosine), 3 other amino acids (cysteine, glutamate, lysine), and 7 acylcarnitines (C3, C4, C5, C10, C10:1, C14, and C16), and with decreased circulating levels of asparagine, serine, and glycine. Pathway analysis identified 7 BMI-related amino acids metabolic pathways (false discovery rate corrected all P<0.05), including branched-chain amino acids and aromatic amino acids biosynthesis, glutathione metabolism, etc. BMI showed a nonlinear relationship with leucine, valine, and threonine, and a linear relationship with other amino acids and acylcarnitines. One-sample MR analyses revealed that BMI was associated with elevated levels of tyrosine and 4 acylcarnitines [C5-DC(C6-OH), C5-M-DC, C12-DC, and C14], with tyrosine and acylcarnitine C14 positively correlated with BMI in both observational [the β values (95%CIs) were 0.057 (0.044-0.070) and 0.018 (0.005-0.032), respectively] and One-sample MR analyses [the β values (95%CIs) were 0.102 (0.035-0.169) and 0.104 (0.036-0.173), respectively]. The MR analyses of the current study satisfied the 3 core assumptions of instrumental variable. Conclusions　BMI was associated with circulating 11 amino acids and 7 acylcarnitines in Chinese adults, involving several pathways such as branched-chain amino acid and aromatic amino acid metabolism, fatty acid metabolism, and oxidative stress. There may be a causal relationship between BMI and tyrosine and acylcarnitine C14.

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