Systematic analysis of relationships between plasma branched-chain amino acid concentrations and cardiometabolic parameters: an association and Mendelian randomization study

Doestzada, Marwah; Zhernakova, Daria V.; Munckhof, Inge C.L. van den; Wang, Daoming; Kurilshikov, Alexander; Chen, Lianmin; Bloks, Vincent W.; Faassen, Martijn van; Rutten, Joost H.W.; Joosten, Leo A. B.; Netea, Mihai G.; Wijmenga, Cisca; Riksen, Niels P.; Zhernakova, Alexandra; Kuipers, Folkert; Fu, Jingyuan

doi:10.1186/s12916-022-02688-4

Cited by 9 publications

(7 citation statements)

References 68 publications

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“…Two of these genes are directly implicated in insulin signaling and resistance. Thus, these findings offer more support for the hypothesis that BCAA levels are modulated by physiological processes related to insulin signaling and glucose regulation [43]. We found that genetic instruments for BMI, fasting insulin levels, and T2D were associated with each BCAA, which is in line with well‐established observations from epidemiological studies.…”

Section: Discussionsupporting

confidence: 89%

“…Two of these genes are directly implicated in insulin signaling and resistance. Thus, these findings offer more support for the hypothesis that BCAA levels are modulated by physiological processes related to insulin signaling and glucose regulation [43]. We found that genetic Consistent with the finding of multiple SNPs related to insulin signaling in the genetic architecture of the BCAAs, a common feature of the phenotypes associated with the BCAAs in genetic studies is insulin resistance.…”

Section: Gwas Findings Highlight the Diverse Genetic Mechanismssupporting

confidence: 76%

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Branched‐chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis

Mosley,

Shi,

Agamasu

et al. 2024

Obesity

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ObjectiveGenetic studies have suggested that the branched‐chain amino acids (BCAAs) valine, leucine, and isoleucine have a causal association with type 2 diabetes (T2D). However, inferences are based on a limited number of genetic loci associated with BCAAs.MethodsInstrumental variables (IVs) for each BCAA were constructed and validated using large well‐powered data sets and their association with T2D was tested using a two‐sample inverse‐variance weighted Mendelian randomization approach. Sensitivity analyses were performed to ensure the accuracy of the findings. A reverse association was assessed using instrumental variables for T2D.ResultsEstimated effect sizes between BCAA IVs and T2D, excluding outliers, were as follows: valine (β = 0.14 change in log‐odds per SD change in valine, 95% CI: −0.06 to 0.33, p = 0.17), leucine (β = 0.15, 95% CI: −0.02 to 0.32, p = 0.09), and isoleucine (β = 0.13, 95% CI: −0.08 to 0.34, p = 0.24). In contrast, T2D IVs were positively associated with each BCAA, i.e., valine (β = 0.08 per SD change in levels per log‐odds change in T2D, 95% CI: 0.05 to 0.10, p = 1.8 × 10−9), leucine (β = 0.06, 95% CI: 0.04 to 0.09, p = 4.5 × 10−8), and isoleucine (β = 0.06, 95% CI: 0.04 to 0.08, p = 2.8 × 10−8).ConclusionsThese data suggest that the BCAAs are not mediators of T2D risk but are biomarkers of diabetes.

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Section: Discussionsupporting

confidence: 89%

“…Two of these genes are directly implicated in insulin signaling and resistance. Thus, these findings offer more support for the hypothesis that BCAA levels are modulated by physiological processes related to insulin signaling and glucose regulation [43]. We found that genetic Consistent with the finding of multiple SNPs related to insulin signaling in the genetic architecture of the BCAAs, a common feature of the phenotypes associated with the BCAAs in genetic studies is insulin resistance.…”

Section: Gwas Findings Highlight the Diverse Genetic Mechanismssupporting

confidence: 76%

Branched‐chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis

Mosley,

Shi,

Agamasu

et al. 2024

Obesity

View full text Add to dashboard Cite

show abstract

“…Collectively, the SNP associations support the hypothesis that BCAA levels are influenced not only by gene products directly involved in BCAA catabolism, but also physiological processes related to insulin signaling, glucose regulation and adiposity. 43 Consistently, we found that genetic instruments related to BMI, fasting insulin levels and type 2 diabetes associated with each BCAA. The associations were in a positive direction, consistent with well-established epidemiological observations.…”

Section: Discussionsupporting

confidence: 70%

Relationship between branched chain amino acids and type 2 diabetes: a bidirectional Mendelian Randomization study

Mosley

Shi

Agamasu

et al. 2023

Preprint

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Background: Human genetic studies suggest that the branched chain amino acids (BCAA) valine, leucine and isoleucine have a causal association with type 2 diabetes. However, inferences are based on analyses of a limited number of genetic loci associated with BCAAs. Whether these conclusions are supported when using instrumental variables for BCAAs that capture a broad set of genetic mechanisms is not known. Methods: We constructed and validated instrumental variables for each BCAA using large well-powered datasets and tested their association with type 2 diabetes using the two-sample inverse variance weighted (IWV) Mendelian randomization (MR) approach. Sensitivity analyses were performed to ensure the accuracy of the findings. Instrumental variables for type 2 diabetes, fasting insulin and body mass index (BMI) were also tested for associations with BCAA levels. Results: There were no significant associations with diabetes for valine (beta=0.17 change in log-odds per standard deviation change in valine, [95% CI, -0.28 - 0.62], p=0.45), leucine (beta=0.19 [-0.30 - 0.68] p=0.45) or isoleucine (beta=0.02 [-0.54 - 0.59], p=0.94). In contrast, type 2 diabetes was associated with each BCAA (valine: beta=0.08 per standard deviation change in levels per log-odds change in type 2 diabetes, [0.05 - 0.10], p=1.8x10-9), (leucine: beta= 0.06 [0.04 - 0.09], p=4.5x10-8) and isoleucine (beta= 0.06 [0.04 - 0.08], p=2.8x10-8). The type 2 diabetes associations were replicated in an independent population, but not in a second population where type 2 diabetes cases were removed, highlighting the consistency and specificity of the association. Similar positive associations were seen for fasting insulin and BMI with the BCAAs. In multivariable MR analyses, type 2 diabetes and fasting insulin had consistent independent associations with each BCAA. Conclusions: These data suggest that the BCAAs are not mediators of type 2 diabetes risk but are biomarkers of diabetes and higher insulin.

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“…They have been implicated in the pathogenesis of various metabolic disorders. Previous studies have suggested roles for BCAAs in the onset of type 2 diabetes and cardiovascular diseases, and emerging evidence suggests their involvement in MASLD [3][4][5]. Increased levels of fasting plasma BCAAs partly mediate the association between MASLD and incident type 2 diabetes [6].…”

Section: Introductionmentioning

confidence: 96%

Novel genetic insights into the roles of amino acids in metabolic dysfunction-associated steatotic liver disease

Liu,

Chen,

Qian

et al. 2024

Preprint

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Background The liver metabolizes amino acids, but previous studies show that amino acids have significant effects also on cardiometabolic diseases like Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Our study investigates the genetic aspects of amino acids in MASLD, explores their causal links, accounting for obesity's influence, and investigates their potential in predicting MASLD complications Methods Using UK Biobank, we examined the observational associations of ten amino acids with MASLD in a cohort of 72,626 cases and 128,102 controls. We used Mendelian randomization (MR) to investigate the relationships between amino acids and MASLD, considering the impact of obesity. Survival analysis assessed the link between baseline amino acid levels and the incidence of major outcomes in 15 year follow-up. Results Nine amino acids showed significant association with MASLD. We observed that higher levels of genetically predicted leucine and valine were associated with an increased risk of MASLD. Among them, valine appeared to independently mediate the link between obesity and MASLD, suggesting a unique role in MASLD beyond its association with obesity. Moreover, an increased risk of genetically predicted MASLD was associated with higher phenylalanine levels. Elevated phenylalanine levels in MASLD patients were linked to increased risks of future metabolic dysfunction-associated steatohepatitis (MASH), hepatocellular carcinoma, cirrhosis, heart failure, stroke, and mortality. Conclusion Our results suggest that valine and leucine may cause incident MASLD, presenting as potential therapeutic targets for MASLD. Alterations in phenylalanine could serve as a novel biomarker for MASLD progression and predicting major outcomes in MASLD patients.

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Systematic analysis of relationships between plasma branched-chain amino acid concentrations and cardiometabolic parameters: an association and Mendelian randomization study

Cited by 9 publications

References 68 publications

Branched‐chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis

Branched‐chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis

Relationship between branched chain amino acids and type 2 diabetes: a bidirectional Mendelian Randomization study

Novel genetic insights into the roles of amino acids in metabolic dysfunction-associated steatotic liver disease

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