Dataset Information

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.

ABSTRACT:

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.

SUBMITTER: Lotta LA

PROVIDER: S-EPMC5127513 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

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 LA Scott Robert A RA Sharp Stephen J SJ Burgess Stephen S Luan Jian'an J Tillin Therese T Schmidt Amand F AF Imamura Fumiaki F Stewart Isobel D ID Perry John R B JR Marney Luke L Koulman Albert A Karoly Edward D ED Forouhi Nita G NG Sjögren Rasmus J O RJ Näslund Erik E Zierath Juleen R JR Krook Anna A Savage David B DB Griffin Julian L JL Chaturvedi Nishi N Hingorani Aroon D AD Khaw Kay-Tee KT Barroso Inês I McCarthy Mark I MI O'Rahilly Stephen S Wareham Nicholas J NJ Langenberg Claudia C

PLoS medicine 20161129 11

<h4>Background</h4>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.<h4>Methods and findings</h4>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 st ...[more]

PMID: 27898682

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Project description:Branched chained amino acids (BCAA) are essential components of the human diet and important nutrient signals, which regain particular interest in recent years with the avenue of metabolomics studies suggesting their potential role as biomarkers. There is now compelling evidence for predictive role of BCAA in progression of diabetes, but causality relationship is still debated concerning insulin resistance and genetic versus non-genetic pathogenesis. Mendelian randomization studies in large cohorts of diabetes indicated pathogenic role of PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) on Chr 4q22.1 gene, encoding for a phosphatase that activates BCKDH (branched chain keto acid dehydrogenase) complex. Recent studies indicated that insulin rapidly and dose-dependently regulates gene expression of the same complex, but the relationship with systemic insulin resistance and glucose levels is complex. Rare genetic syndromes due to Mendelian mutations in key genes in BCAA catabolism may be good models to understand potential role of gene of BCAA catabolism. However, in studying complex disorders geneticists are faced to complete new aspects of metabolic regulation complicating understanding genetics of obesity, diabetes or metabolic syndrome. A review of genetic syndromes of BCAA metabolism suggests that insulin resistance is not present, except rare cases of methylmalonic aciduria due to MUT (methylmalonyl-coA mutase) gene on Chr 6p12.3. Another aspect that complicates understanding is the new role of central nervous system (CNS) in insulin resistance. For a long time the hypothalamic hunger/satiety neuronal system was considered a key site of nutrient regulation. Genes may also affect the brain rewarding system (BRS) that would regulate food intake by modulating the motivation to obtain food and considering hedonic properties. Nutrigenomic and nutrigenetic investigations taking into account concurrently BCAA intake, metabolic regulation and gene variation have large perspectives to merge genetic and nutritional understanding in complex disorders.

Project description:BackgroundThere have been reports linking branched-chain amino acids (BCAAs) to the hazard of various cardiovascular diseases (CVDs); however, the causal role of this relationship is still unclear. We conducted a study using bi-directional two-sample Mendelian randomization (MR) with the aim of investigating the possible causal correlation between BCAAs and 13 types of cardiovascular diseases.MethodsThe study analyzed data of the largest genome-wide association studies (GWAS) published for the total BCAAs, encompassing isoleucine, leucine, and valine, which were obtained from the UK Biobank, as well as data for 13 cardiovascular endpoints from the MRC-IEU, the FinnGen consortium, and the EBI database. The approach of the primary dissection used became the inverse-variance-weighted (IVW) approach, with additional analyses using the MR-PRESSO global test as well as MR-Egger regression with a view to determining horizontal pleiotropy. Heterogeneity was evaluated by means of Cochran's Q test. The study also conducted logistic regression dissection for the sake of investigating the correlation between cardiovascular events and serum BCAAs in the UK biobank cohort study.ResultsIn this study, it was found that individuals with a genetic predisposition to more elevated levels for circulating total BCAAs had a higher hazard of peripheral arterial disease (OR 1.400, 95% CI 1.063, 1.844; p = 0.017) in addition to stroke (OR 1.266, 95% CI 1.012, 1.585; p = 0.039); circulating valine casually increased the risk of intracerebral hemorrhage (OR 1.760, 95% CI 1.116, 2.776; p = 0.015), along with stroke (OR 1.269, 95% CI 1.079, 1.492; p = 0.004); genetically predicted isoleucine showed a positive association with peripheral arterial disease (OR 1.466, 95% CI 1.044, 2.058; p = 0.027), along with cardioembolic stroke (OR 1.547, 95% CI 1.126, 2.124; p = 0.007); furthermore, leucine causally associated with stroke (OR 1.310, 95% CI 1.031, 1.663, p = 0.027). In the UK Biobank cohort study, we detected that total BCAAs (OR: 1.285; 95% CI: 1.009, 1.636), valine (OR: 1.287; 95% CI: 1.009, 1.642), and isoleucine (OR: 1.352; 95% CI: 1.064, 1.718) were independently linked to stroke, but not leucine (OR: 1.146; 95% CI: 0.901, 1.458). No such association was found for BCAAs with peripheral arterial disease and intracerebral hemorrhage in the cohort study.ConclusionsIn summary, circulating total BCAAs and valine may be causally associated with stroke. The association of BCAAs with other CVD events needs further study.

Dataset Information

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.

Background

Methods and findings

Conclusions

Publications

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.

Similar Datasets

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