Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis
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. Genom...
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| Published in | PLoS medicine Vol. 13; no. 11; p. e1002179 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
29.11.2016
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1549-1676 1549-1277 1549-1676 |
| DOI | 10.1371/journal.pmed.1002179 |
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| Abstract | 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.
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.
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. |
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| AbstractList | 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.
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.
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. 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. Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 x 10.sup.-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 x 10.sup.-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 x 10.sup.-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 x 10.sup.-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 x 10.sup.-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. 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. 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 x 10.sup.-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 x 10.sup.-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 x 10.sup.-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 x 10.sup.-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 x 10.sup.-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. Claudia Langenberg and colleagues show that high circulating branched chain amino acids associate with future risk of type 2 diabetes. BackgroundHigher 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 findingsGenome-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.ConclusionsEvidence 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. 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. 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.BACKGROUNDHigher 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.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.METHODS AND FINDINGSGenome-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.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.CONCLUSIONSEvidence 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. 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. |
| Audience | Academic |
| Author | Luan, Jian’an Schmidt, Amand F. Imamura, Fumiaki Burgess, Stephen Forouhi, Nita G. Griffin, Julian L. Scott, Robert A. Koulman, Albert Barroso, Inês Marney, Luke Sjögren, Rasmus J. O. Lotta, Luca A. Langenberg, Claudia Tillin, Therese Zierath, Juleen R. Perry, John R. B. Khaw, Kay-Tee Chaturvedi, Nishi O’Rahilly, Stephen Stewart, Isobel D. Wareham, Nicholas J. Krook, Anna Savage, David B. McCarthy, Mark I. Karoly, Edward D. Näslund, Erik Hingorani, Aroon D. Sharp, Stephen J. |
| AuthorAffiliation | 2 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom 7 Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden 4 MRC Human Nutrition Research, Cambridge, United Kingdom 9 Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom 1 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom 6 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 11 Wellcome Trust Sanger Institute, Cambridge, United Kingdom 3 Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom 8 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 10 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom Imperial College London, UNITED KINGDOM 12 Oxford Centre for Diabetes, Endocrinology and Metabolism, and W |
| AuthorAffiliation_xml | – name: 5 Metabolon, Morrisville, North Carolina, United States of America – name: 1 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom – name: 7 Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden – name: 12 Oxford Centre for Diabetes, Endocrinology and Metabolism, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom – name: 8 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden – name: 9 Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom – name: 10 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom – name: 2 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom – name: 3 Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom – name: 4 MRC Human Nutrition Research, Cambridge, United Kingdom – name: 11 Wellcome Trust Sanger Institute, Cambridge, United Kingdom – name: Imperial College London, UNITED KINGDOM – name: 6 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden |
| Author_xml | – sequence: 1 givenname: Luca A. surname: Lotta fullname: Lotta, Luca A. – sequence: 2 givenname: Robert A. surname: Scott fullname: Scott, Robert A. – sequence: 3 givenname: Stephen J. orcidid: 0000-0003-2375-1440 surname: Sharp fullname: Sharp, Stephen J. – sequence: 4 givenname: Stephen orcidid: 0000-0001-5365-8760 surname: Burgess fullname: Burgess, Stephen – sequence: 5 givenname: Jian’an surname: Luan fullname: Luan, Jian’an – sequence: 6 givenname: Therese surname: Tillin fullname: Tillin, Therese – sequence: 7 givenname: Amand F. orcidid: 0000-0003-1327-0424 surname: Schmidt fullname: Schmidt, Amand F. – sequence: 8 givenname: Fumiaki orcidid: 0000-0002-6841-8396 surname: Imamura fullname: Imamura, Fumiaki – sequence: 9 givenname: Isobel D. surname: Stewart fullname: Stewart, Isobel D. – sequence: 10 givenname: John R. B. surname: Perry fullname: Perry, John R. B. – sequence: 11 givenname: Luke orcidid: 0000-0001-8117-8246 surname: Marney fullname: Marney, Luke – sequence: 12 givenname: Albert orcidid: 0000-0001-9998-051X surname: Koulman fullname: Koulman, Albert – sequence: 13 givenname: Edward D. surname: Karoly fullname: Karoly, Edward D. – sequence: 14 givenname: Nita G. surname: Forouhi fullname: Forouhi, Nita G. – sequence: 15 givenname: Rasmus J. O. orcidid: 0000-0002-0640-8504 surname: Sjögren fullname: Sjögren, Rasmus J. O. – sequence: 16 givenname: Erik orcidid: 0000-0002-0166-6344 surname: Näslund fullname: Näslund, Erik – sequence: 17 givenname: Juleen R. surname: Zierath fullname: Zierath, Juleen R. – sequence: 18 givenname: Anna orcidid: 0000-0002-0891-0258 surname: Krook fullname: Krook, Anna – sequence: 19 givenname: David B. surname: Savage fullname: Savage, David B. – sequence: 20 givenname: Julian L. surname: Griffin fullname: Griffin, Julian L. – sequence: 21 givenname: Nishi orcidid: 0000-0002-6211-2775 surname: Chaturvedi fullname: Chaturvedi, Nishi – sequence: 22 givenname: Aroon D. surname: Hingorani fullname: Hingorani, Aroon D. – sequence: 23 givenname: Kay-Tee surname: Khaw fullname: Khaw, Kay-Tee – sequence: 24 givenname: Inês orcidid: 0000-0001-5800-4520 surname: Barroso fullname: Barroso, Inês – sequence: 25 givenname: Mark I. orcidid: 0000-0002-4393-0510 surname: McCarthy fullname: McCarthy, Mark I. – sequence: 26 givenname: Stephen surname: O’Rahilly fullname: O’Rahilly, Stephen – sequence: 27 givenname: Nicholas J. orcidid: 0000-0003-1422-2993 surname: Wareham fullname: Wareham, Nicholas J. – sequence: 28 givenname: Claudia surname: Langenberg fullname: Langenberg, Claudia |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27898682$$D View this record in MEDLINE/PubMed http://kipublications.ki.se/Default.aspx?queryparsed=id:134963592$$DView record from Swedish Publication Index |
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| Copyright | COPYRIGHT 2016 Public Library of Science 2016 Public Library of Science. 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 credited: Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, et al. (2016) Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLoS Med 13(11): e1002179. doi:10.1371/journal.pmed.1002179 2016 Lotta et al 2016 Lotta et al 2016 Public Library of Science. 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 credited: Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, et al. (2016) Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLoS Med 13(11): e1002179. doi:10.1371/journal.pmed.1002179 |
| Copyright_xml | – notice: COPYRIGHT 2016 Public Library of Science – notice: 2016 Public Library of Science. 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 credited: Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, et al. (2016) Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLoS Med 13(11): e1002179. doi:10.1371/journal.pmed.1002179 – notice: 2016 Lotta et al 2016 Lotta et al – notice: 2016 Public Library of Science. 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 credited: Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, et al. (2016) Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLoS Med 13(11): e1002179. doi:10.1371/journal.pmed.1002179 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 CL receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal's editorial board. MIM is a member of the Editorial Board of PLOS Medicine. MIM is a member of advisory boards for NovoNordisk and Pfizer. MIM received honoraria for speaking engagements: NovoNordisk, Pfizer, Eli Lilly. MIM receives research funding from: NovoNordisk, Pfizer, Eli Lilly, Takeda, Servier, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Merck, Roche, Astra-Zeneca. EDK is an employee of Metabolon Inc., a fee-for-service metabolomics provider and received salary and stock options as compensation. IB and her spouse own stock in GlaxoSmithKline and Incyte Corporation. SB acts as an occasional paid statistical referee for PLOS Medicine, however had no reviewer role in this paper. The other authors report no conflict of interest relative to this study. Conceptualization: LAL RAS NJW CL. Formal analysis: LAL RAS SJS SB JAL TT AFS IDS JRBP. Funding acquisition: RAS NJW CL. Investigation: LAL RAS SJS SB JL TT AFS FI IDS JRBP LM AK EDK NGF RJOS EN JRZ AK DBS JLG NC ADH KK IB MIM SOR NJW CL. Methodology: LAL RAS SJS SB JL TT AFS FI IDS JRBP LM AK EDK NGF RJOS EN JRZ AK DBS JLG NC ADH KK IB MIM SOR NJW CL. Project administration: LAL CL. Resources: LAL RAS SJS SB JL TT AFS FI IDS JRBP LM AK EDK NGF RJOS EN JRZ AK DBS JLG NC ADH KK IB MIM SOR NJW CL. Supervision: NJW CL. Visualization: LAL RAS CL. Writing – original draft: LAL CL. Writing – review & editing: LAL RAS SJS SB JL TT AFS FI IDS JRBP LM AK EDK NGF RJOS EN JRZ AK DBS JLG NC ADH KK IB MIM SOR NJW CL. |
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| Snippet | Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes... Background Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type... Claudia Langenberg and colleagues show that high circulating branched chain amino acids associate with future risk of type 2 diabetes. BackgroundHigher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2... Background Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher... |
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| SubjectTerms | Adult Aged Amino Acids, Branched-Chain - metabolism Analysis Biology and Life Sciences Branched chain amino acids Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Diabetes Mellitus, Type 2 - physiopathology Genes Genetic aspects Genetic Predisposition to Disease Genome-Wide Association Study Humans Insulin resistance Laboratories Male Medicine and Health Sciences Mendelian Randomization Analysis Metabolism Metabolites Middle Aged Physical Sciences Physiological aspects Prospective Studies Research and Analysis Methods Risk Factors Science Studies Sweden Type 2 diabetes Young Adult |
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| Title | Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/27898682 https://www.proquest.com/docview/1849658124 https://www.proquest.com/docview/1845251425 https://pubmed.ncbi.nlm.nih.gov/PMC5127513 http://kipublications.ki.se/Default.aspx?queryparsed=id:134963592 https://doaj.org/article/83944e1595d0460791be9b9ab3a376df http://dx.doi.org/10.1371/journal.pmed.1002179 |
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