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Branched chain amino acids harbor distinct and often opposing effects on health and disease

BACKGROUND: 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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684599/
https://www.ncbi.nlm.nih.gov/pubmed/38017291
http://dx.doi.org/10.1038/s43856-023-00382-x
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author 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
author_facet 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
author_sort Avery, Christy L.
collection PubMed
description BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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spelling pubmed-106845992023-11-30 Branched chain amino acids harbor distinct and often opposing effects on health and disease 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 Commun Med (Lond) Article BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. Nature Publishing Group UK 2023-11-28 /pmc/articles/PMC10684599/ /pubmed/38017291 http://dx.doi.org/10.1038/s43856-023-00382-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Branched chain amino acids harbor distinct and often opposing effects on health and disease
title Branched chain amino acids harbor distinct and often opposing effects on health and disease
title_full Branched chain amino acids harbor distinct and often opposing effects on health and disease
title_fullStr Branched chain amino acids harbor distinct and often opposing effects on health and disease
title_full_unstemmed Branched chain amino acids harbor distinct and often opposing effects on health and disease
title_short Branched chain amino acids harbor distinct and often opposing effects on health and disease
title_sort branched chain amino acids harbor distinct and often opposing effects on health and disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684599/
https://www.ncbi.nlm.nih.gov/pubmed/38017291
http://dx.doi.org/10.1038/s43856-023-00382-x
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