Dataset Information

Genetic predisposition to impaired metabolism of the branched chain amino acids, dietary intakes, and risk of type 2 diabetes

ABSTRACT:

Background and objectives

Circulating branched chain amino acids (BCAAs) increase the risk of type 2 diabetes (T2D). The genetic variants in the BCAA metabolic pathway influence the individual metabolic ability of BCAAs and may affect circulating BCAA levels together with dietary intakes. So, we investigated whether genetic predisposition to impaired BCAA metabolism interacts with dietary BCAA intakes on the risk of type 2 diabetes and related parameters.

Methods

We estimated dietary BCAA intakes among 434 incident T2D cases and 434 age-matched controls from The Harbin Cohort Study on Diet, Nutrition and Chronic Non-Communicable Diseases. The genetic risk score (GRS) was calculated on the basis of 5 variants having been identified in the BCAA metabolic pathway. Multivariate logistic regression models and general linear regression models were used to assess the interaction between dietary BCAAs and GRS on T2D risk and HbA1c.

Results

Dietary BCAAs significantly interact with metabolism related GRS on T2D risk and HbA1c (p for interaction = 0.038 and 0.015, respectively). A high intake of dietary BCAAs was positively associated with diabetes incidence only among high GRS (OR 2.40, 95% CI 1.39, 4.12, P for trend = 0.002). Dietary BCAAs were associated with 0.14% elevated HbA1c (p = 0.003) and this effect increased to 0.21% in high GRS (p = 0.003). Furthermore, GRS were associated with 9.19 μmol/L higher plasma BCAA levels (p = 0.006, P for interaction = 0.015) only among the highest BCAA intake individuals.

Conclusions

Our study suggests that genetic predisposition to BCAA metabolism disorder modifies the effect of dietary BCAA intakes on T2D risk as well as HbA1c and that higher BCAA intakes exert an unfavorable effect on type 2 diabetes risk and HbA1c only among those with high genetic susceptibility.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12263-021-00695-3.

SUBMITTER: Wang W

PROVIDER: S-EPMC8561969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.