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Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes.

ABSTRACT: Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine/methionine ratio with type 2 diabetes (OR = 0.87 (0.81-0.93)). Multivariable Mendelian randomization revealed inverse association for higher log₁₀-transformed tyrosine levels with type 2 diabetes (OR = 0.19 (0.04-0.88)), independent of other amino acids. Tyrosine might be a causal trait for type 2 diabetes independent of other diabetes-associated amino acids.

SUBMITTER: Jager S

PROVIDER: S-EPMC7766372 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes.

Jäger Susanne S Cuadrat Rafael R Wittenbecher Clemens C Floegel Anna A Hoffmann Per P Prehn Cornelia C Adamski Jerzy J Pischon Tobias T Schulze Matthias B MB

Nutrients 20201219 12

Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization s ...[more]

PMID: 33352682

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Project description:BackgroundThe presence of type 1 diabetes mellitus (T1DM) has been demonstrated to pose an increased risk for developing cardiovascular diseases (CVDs). However, the causal relationships between T1DM and CVDs remain unclear due to the uncontrolled confounding factors and reverse causation bias of the observational studies.MethodsSummary statistics of T1DM and seven CVDs from the largest available genome-wide association studies (GWAS) of European ancestry and FinnGen biobank were extracted for the primary MR analysis, and the analysis was replicated using UK biobank (UKBB) for validation. Three complementary methods: inverse variance weighted (IVW), weighted median, and MR-Egger were used for the MR estimates. The potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to examine whether T1DM has independent effects on CVDs with adjustment of potential confounding factors. Moreover, a two-step MR approach was used to assess the potential mediating effects of these factors on the causal effects between T1DM and CVDs.ResultsCausal effects of T1DM on peripheral atherosclerosis (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.02-1.10; p = 0.002)] and coronary atherosclerosis (OR = 1.03, 95% CI: 1.01-1.05; p = 0.001) were found. The results were less likely to be biased by the horizontal pleiotropic effects (both p values of MR-Egger intercept and MR-PRESSO Global test > 0.05). In the following MVMR analysis, we found the causal effects of T1DM on peripheral atherosclerosis and coronary atherosclerosis remain significant after adjusting for a series of potential confounding factors. Moreover, we found that hypertension partly mediated the causal effects of T1DM on peripheral atherosclerosis (proportion of mediation effect in total effect: 11.47%, 95% CI: 3.23-19.71%) and coronary atherosclerosis (16.84%, 95% CI: 5.35-28.33%). We didn't find significant causal relationships between T1DM and other CVDs, including heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), myocardial infarction (MI) and stroke. For the reverse MR from CVD to T1DM, no significant causal relationships were identified.ConclusionThis MR study provided evidence supporting the causal effect of T1DM on peripheral atherosclerosis and coronary atherosclerosis, with hypertension partly mediating this effect.

Project description:Background and purposeThe relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization.MethodsFive CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank.ResultsT2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P=0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P=0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P=0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P=0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P=0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P=0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P=0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P=0.008) after adjusting for potential confounders.ConclusionsOur Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA.

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Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes.

Publications

Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes.

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