Dataset Information

Causal Association of Type 2 Diabetes Mellitus and Glycemic Traits With Cardiovascular Diseases and Lipid Traits: A Mendelian Randomization Study.

ABSTRACT:

Objective

We aimed to evaluate the causal effect of type 2 diabetes mellitus (T2DM) and glycemic traits on the risk of a wide range of cardiovascular diseases (CVDs) and lipid traits using Mendelian randomization (MR).

Methods

Genetic variants associated with T2DM, fasting glucose, fasting insulin, and hemoglobin A1c were selected as instrumental variables to perform both univariable and multivariable MR analyses.

Results

In univariable MR, genetically predicted T2DM was associated with higher odds of peripheral artery disease (pooled odds ratio (OR) =1.207, 95% CI: 1.162-1.254), myocardial infarction (OR =1.132, 95% CI: 1.104-1.160), ischemic heart disease (OR =1.129, 95% CI: 1.105-1.154), heart failure (OR =1.050, 95% CI: 1.029-1.072), stroke (OR =1.087, 95% CI: 1.068-1.107), ischemic stroke (OR =1.080, 95% CI: 1.059-1.102), essential hypertension (OR =1.013, 95% CI: 1.010-1.015), coronary atherosclerosis (OR =1.005, 95% CI: 1.004-1.007), and major coronary heart disease event (OR =1.003, 95% CI: 1.002-1.004). Additionally, T2DM was causally related to lower levels of high-density lipoprotein cholesterol (OR =0.965, 95% CI: 0.958-0.973) and apolipoprotein A (OR =0.982, 95% CI: 0.977-0.987) but a higher level of triglycerides (OR =1.060, 95% CI: 1.036-1.084). Moreover, causal effect of glycemic traits on CVDs and lipid traits were also observed. Finally, most results of univariable MR were supported by multivariable MR.

Conclusion

We provided evidence for the causal effects of T2DM and glycemic traits on the risk of CVDs and dyslipidemia. Further investigations to elucidate the underlying mechanisms are warranted.

SUBMITTER: Huang M

PROVIDER: S-EPMC9072667 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Causal Association of Type 2 Diabetes Mellitus and Glycemic Traits With Cardiovascular Diseases and Lipid Traits: A Mendelian Randomization Study.

Huang Mingkai M Laina-Nicaise Loum-Davadi LD Zha Lingfeng L Tang Tingting T Cheng Xiang X

Frontiers in endocrinology 20220422

<h4>Objective</h4>We aimed to evaluate the causal effect of type 2 diabetes mellitus (T2DM) and glycemic traits on the risk of a wide range of cardiovascular diseases (CVDs) and lipid traits using Mendelian randomization (MR).<h4>Methods</h4>Genetic variants associated with T2DM, fasting glucose, fasting insulin, and hemoglobin A1c were selected as instrumental variables to perform both univariable and multivariable MR analyses.<h4>Results</h4>In univariable MR, genetically predicted T2DM was as ...[more]

PMID: 35528012

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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:ObjectiveWe employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.MethodsWe selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and β-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).ResultsGenetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume.ConclusionsThis study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms.Classification of evidenceThis study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.

Project description:ObjectivePrevious research has established a connection between Type 2 Diabetes Mellitus (T2DM), glycemic traits, dietary habits, and the risk of Pressure Ulcers (PUs). The aim of our study is to disentangle any potential causal relationship between T2DM, glycemic traits, and dietary factors, and the risk of PUs.MethodsThe exposure and outcome datasets were sourced from the IEU Open GWAS project, the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and the FinnGen biobank, respectively. The primary MR analysis method employed was the inverse variance-weighted method. Furthermore, we employed multivariable MR (MVMR) adjusting for BMI. Then, we investigated the possibility of a reverse association between glycemic traits and PUs through bidirectional MR. Finally, Heterogeneity and pleiotropic analysis were conducted to ensure the accuracy and robustness of the results.ResultsThe findings revealed that T2DM (OR = 1.282, 95% CI: 1.138-1.445, p < 0.001) and Fasting Glucose (FG; OR = 2.111, 95% CI: 1.080-4.129, p = 0.029) were associated with an increased risk of PUs, while salad/raw vegetable intake (OR: 0.014; 95% CI: 0.001-0.278; p = 0.005) was identified as a protective element. However, no other dietary elements demonstrated a statistically significant causality with PUs. In addition, in the reverse direction, there were positive correlation between genetic susceptibility to PUs and an increase in FG (OR: 1.007, 95% CI: 1.000-1.013, p = 0.048) and Fasting Insulin (FI; OR: 1.012, 95% CI: 1.003-1.022, p = 0.011). MVMR results indicated that the causal effect of T2DM on PUs was independent of BMI (OR: 1.260, 95% CI: 1.112-1.427, p < 0.001). These results remained robust when considering weak instrument bias, pleiotropy, and heterogeneity.ConclusionThis study establishes a causal link between genetically predicted T2DM, FG and an increased risk of PUs. Conversely, Salad/raw vegetable intake is significantly inversely associated with PUs. Simultaneously, we identified two downstream effector factor (FG and FI) that were associated with PUs. These findings may have clinical implications for both prevention and treatment.

Dataset Information

Causal Association of Type 2 Diabetes Mellitus and Glycemic Traits With Cardiovascular Diseases and Lipid Traits: A Mendelian Randomization Study.

Objective

Methods

Results

Conclusion

Publications

Causal Association of Type 2 Diabetes Mellitus and Glycemic Traits With Cardiovascular Diseases and Lipid Traits: A Mendelian Randomization Study.

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