Branched chain amino acids harbor distinct and often opposing effects on health and disease.
Branched chain amino acids harbor distinct and often opposing effects on health and disease.
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DOI：
10.1038/s43856-023-00382-x
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发表时间：
2023-11-28
期刊：
影响因子：
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通讯作者：
Graff, Mariaelisa
中科院分区：
文献类型：
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作者：
Avery, Christy L;Howard, Annie Green;Lee, Harold H;Downie, Carolina G;Lee, Moa P;Koenigsberg, Sarah H;Ballou, Anna F;Preuss, Michael H;Raffield, Laura M;Yarosh, Rina A;North, Kari E;Gordon-Larsen, Penny;Graff, Mariaelisa
支链氨基酸 (BCAA) 亮氨酸、异亮氨酸和缬氨酸是与糖尿病、癌症和心血管疾病相关的必需营养素。观察性研究表明支链氨基酸具有同质的表型效应，但这些发现与人体和动物实验研究的结果不一致。假设观察性和实验性支链氨基酸研究之间的不一致反映了观察性研究中共同生活方式和遗传因素的偏差，我们使用英国生物银行的数据，并应用旨在解决这些偏差的多变量孟德尔随机化因果推理方法。在 n = 97,469 名欧洲血统的参与者中（平均年龄 = 56.7岁；54.1%为女性），我们估计了每种 BCAA 的不同且往往相反的总因果效应。例如，在 117 种表型中，有证据表明至少一种 BCAA 具有统计学上显着的总因果效应，几乎一半 (44%，n = 52) 仅与一种 BCAA 相关。这 52 种关联包括缬氨酸对糖尿病眼病的总因果效应 [比值比 = 1.51, 95% 置信区间 (CI) = 1.31, 1.76]、缬氨酸对蛋白尿的总因果效应 (比值比 = 1.14, 95% CI = 1.08, 1.20)，以及异亮氨酸治疗心绞痛（比值比 = 1.17，95% CI = 1.31，1.76）。我们的结果表明，观察性文献对 BCAA 表型效应的描述存在缺陷，与实验研究不一致，可能会误导新型疗法的开发工作。更广泛地说，这些发现推动了因果推理方法的开发和应用，使“在观察环境中进行的组学研究能够解释共同遗传和生活方式因素的偏差影响”。三种支链氨基酸 (BCAA) 亮氨酸、异亮氨酸和缬氨酸是从饮食中获得的肌肉蛋白的重要组成部分。许多针对人群的研究都检验了支链氨基酸是否影响健康和疾病。这些人类研究报告的结果与高度控制的动物研究的结果不一致。由于人们对支链氨基酸治疗靶向的兴趣与日俱增，我们希望更好地了解这些差异。简而言之，我们使用了来自大型数据库的数据，该数据库捕获了许多疾病（例如心血管疾病、癌症和呼吸系统疾病）和新的统计方法。我们的结果表明，人类研究和动物研究之间的差异可能反映了人类研究设计和进行方式的错误。因此，这些人体研究可能提供了 BCAA 效应的有缺陷的图片，这可能会误导开发新疗法的努力。艾弗里等人。利用英国生物银行的多变量孟德尔随机化研究数据来评估支链氨基酸 (BCAA) 对人类疾病的影响。他们的研究结果表明，BCAA 表型效应的观察性研究很容易出现重大错误，可能会误导开发新疗法的努力。
The branched chain amino acids (BCAA) leucine, isoleucine, and valine are essential nutrients that have been associated with diabetes, cancers, and cardiovascular diseases. Observational studies suggest that BCAAs exert homogeneous phenotypic effects, but these findings are inconsistent with results from experimental human and animal studies. Hypothesizing that inconsistencies between observational and experimental BCAA studies reflect bias from shared lifestyle and genetic factors in observational studies, we used data from the UK Biobank and applied multivariable Mendelian randomization causal inference methods designed to address these biases. In n = 97,469 participants of European ancestry (mean age = 56.7 years; 54.1% female), we estimate distinct and often opposing total causal effects for each BCAA. For example, of the 117 phenotypes with evidence of a statistically significant total causal effect for at least one BCAA, almost half (44%, n = 52) are associated with only one BCAA. These 52 associations include total causal effects of valine on diabetic eye disease [odds ratio = 1.51, 95% confidence interval (CI) = 1.31, 1.76], valine on albuminuria (odds ratio = 1.14, 95% CI = 1.08, 1.20), and isoleucine on angina (odds ratio = 1.17, 95% CI = 1.31, 1.76). Our results suggest that the observational literature provides a flawed picture of BCAA phenotypic effects that is inconsistent with experimental studies and could mislead efforts developing novel therapeutics. More broadly, these findings motivate the development and application of causal inference approaches that enable ‘omics studies conducted in observational settings to account for the biasing effects of shared genetic and lifestyle factors. The three branched chain amino acids (BCAAs) leucine, isoleucine, and valine are important building blocks of muscle proteins that are obtained from the diet. Many studies in human populations have examined whether BCAAs affect health and disease. These human studies report results that are inconsistent with results from highly controlled animal studies. Because interest in the therapeutic targeting of BCAAs is growing, we wanted to better understand these discrepancies. Briefly, we used data from a large database that captured many diseases (e.g., cardiovascular disease, cancers, and respiratory disease) and new statistical methods. Our results showed that discrepancies between human studies and animal studies may reflect errors in the ways human studies were designed and conducted. As a result, these human studies may provide a flawed picture of BCAA effects that could mislead efforts developing novel therapeutics. Avery et al. utilize data from the UK Biobank in a multivariable Mendelian randomization study to evaluate the effects of branched chain amino acids (BCAAs) on human disease. Their findings suggest observational studies of BCAA phenotypic effects are prone to substantial error, potentially misleading efforts to develop novel therapeutics.