Cargando…
Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis
BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this que...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127513/ https://www.ncbi.nlm.nih.gov/pubmed/27898682 http://dx.doi.org/10.1371/journal.pmed.1002179 |
_version_ | 1782470252695650304 |
---|---|
author | Lotta, Luca A. Scott, Robert A. Sharp, Stephen J. Burgess, Stephen Luan, Jian’an Tillin, Therese Schmidt, Amand F. Imamura, Fumiaki Stewart, Isobel D. Perry, John R. B. Marney, Luke Koulman, Albert Karoly, Edward D. Forouhi, Nita G. Sjögren, Rasmus J. O. Näslund, Erik Zierath, Juleen R. Krook, Anna Savage, David B. Griffin, Julian L. Chaturvedi, Nishi Hingorani, Aroon D. Khaw, Kay-Tee Barroso, Inês McCarthy, Mark I. O’Rahilly, Stephen Wareham, Nicholas J. Langenberg, Claudia |
author_facet | Lotta, Luca A. Scott, Robert A. Sharp, Stephen J. Burgess, Stephen Luan, Jian’an Tillin, Therese Schmidt, Amand F. Imamura, Fumiaki Stewart, Isobel D. Perry, John R. B. Marney, Luke Koulman, Albert Karoly, Edward D. Forouhi, Nita G. Sjögren, Rasmus J. O. Näslund, Erik Zierath, Juleen R. Krook, Anna Savage, David B. Griffin, Julian L. Chaturvedi, Nishi Hingorani, Aroon D. Khaw, Kay-Tee Barroso, Inês McCarthy, Mark I. O’Rahilly, Stephen Wareham, Nicholas J. Langenberg, Claudia |
author_sort | Lotta, Luca A. |
collection | PubMed |
description | BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. METHODS AND FINDINGS: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10(−8)). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10(−25)), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26–1.65, p = 9.5 × 10(−8)) for isoleucine, 1.85 (95% CI 1.41–2.42, p = 7.3 × 10(−6)) for leucine, and 1.54 (95% CI 1.28–1.84, p = 4.2 × 10(−6)) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. CONCLUSIONS: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes. |
format | Online Article Text |
id | pubmed-5127513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-51275132016-12-15 Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis Lotta, Luca A. Scott, Robert A. Sharp, Stephen J. Burgess, Stephen Luan, Jian’an Tillin, Therese Schmidt, Amand F. Imamura, Fumiaki Stewart, Isobel D. Perry, John R. B. Marney, Luke Koulman, Albert Karoly, Edward D. Forouhi, Nita G. Sjögren, Rasmus J. O. Näslund, Erik Zierath, Juleen R. Krook, Anna Savage, David B. Griffin, Julian L. Chaturvedi, Nishi Hingorani, Aroon D. Khaw, Kay-Tee Barroso, Inês McCarthy, Mark I. O’Rahilly, Stephen Wareham, Nicholas J. Langenberg, Claudia PLoS Med Research Article BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. METHODS AND FINDINGS: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10(−8)). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10(−25)), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26–1.65, p = 9.5 × 10(−8)) for isoleucine, 1.85 (95% CI 1.41–2.42, p = 7.3 × 10(−6)) for leucine, and 1.54 (95% CI 1.28–1.84, p = 4.2 × 10(−6)) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. CONCLUSIONS: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes. Public Library of Science 2016-11-29 /pmc/articles/PMC5127513/ /pubmed/27898682 http://dx.doi.org/10.1371/journal.pmed.1002179 Text en © 2016 Lotta et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Lotta, Luca A. Scott, Robert A. Sharp, Stephen J. Burgess, Stephen Luan, Jian’an Tillin, Therese Schmidt, Amand F. Imamura, Fumiaki Stewart, Isobel D. Perry, John R. B. Marney, Luke Koulman, Albert Karoly, Edward D. Forouhi, Nita G. Sjögren, Rasmus J. O. Näslund, Erik Zierath, Juleen R. Krook, Anna Savage, David B. Griffin, Julian L. Chaturvedi, Nishi Hingorani, Aroon D. Khaw, Kay-Tee Barroso, Inês McCarthy, Mark I. O’Rahilly, Stephen Wareham, Nicholas J. Langenberg, Claudia Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
title | Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
title_full | Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
title_fullStr | Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
title_full_unstemmed | Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
title_short | Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
title_sort | genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a mendelian randomisation analysis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127513/ https://www.ncbi.nlm.nih.gov/pubmed/27898682 http://dx.doi.org/10.1371/journal.pmed.1002179 |
work_keys_str_mv | AT lottalucaa geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT scottroberta geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT sharpstephenj geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT burgessstephen geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT luanjianan geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT tillintherese geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT schmidtamandf geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT imamurafumiaki geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT stewartisobeld geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT perryjohnrb geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT marneyluke geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT koulmanalbert geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT karolyedwardd geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT forouhinitag geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT sjogrenrasmusjo geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT naslunderik geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT zierathjuleenr geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT krookanna geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT savagedavidb geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT griffinjulianl geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT chaturvedinishi geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT hingoraniaroond geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT khawkaytee geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT barrosoines geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT mccarthymarki geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT orahillystephen geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT warehamnicholasj geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis AT langenbergclaudia geneticpredispositiontoanimpairedmetabolismofthebranchedchainaminoacidsandriskoftype2diabetesamendelianrandomisationanalysis |