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. 2023 Oct 30:10:1234271.
doi: 10.3389/fcvm.2023.1234271. eCollection 2023.

Unraveling the role of VLDL in the relationship between type 2 diabetes and coronary atherosclerosis: a Mendelian randomization analysis

Wenshuai Feng  1 , Liuli Guo  1 , Yiman Liu  1 , Ming Ren  2
Affiliations

Unraveling the role of VLDL in the relationship between type 2 diabetes and coronary atherosclerosis: a Mendelian randomization analysis

Wenshuai Feng et al. Front Cardiovasc Med. .

Abstract

Background: The causal link between Type 2 diabetes (T2D) and coronary atherosclerosis has been established through wet lab experiments; however, its analysis with Genome-wide association studies (GWAS) data remains unexplored. This study aims to validate this relationship using Mendelian randomization analysis and explore the potential mediation of VLDL in this mechanism.

Methods: Employing Mendelian randomization analysis, we investigated the causal connection between T2D and coronary atherosclerosis. We utilized GWAS summary statistics from European ancestry cohorts, comprising 23,363 coronary atherosclerosis patients and 195,429 controls, along with 32,469 T2D patients and 183,185 controls. VLDL levels, linked to SNPs, were considered as a potential mediating causal factor that might contribute to coronary atherosclerosis in the presence of T2D. We employed the inverse variance weighted (IVW), Egger regression (MR-Egger), weighted median, and weighted model methods for causal effect estimation. A leave-one-out sensitivity analysis was conducted to ensure robustness.

Results: Our Mendelian randomization analysis demonstrated a genetic association between T2D and an increased coronary atherosclerosis risk, with the IVW estimate at 1.13 [95% confidence interval (CI): 1.07-1.20]. Additionally, we observed a suggestive causal link between T2D and VLDL levels, as evidenced by the IVW estimate of 1.02 (95% CI: 0.98-1.07). Further supporting lipid involvement in coronary atherosclerosis pathogenesis, the IVW-Egger estimate was 1.30 (95% CI: 1.06-1.58).

Conclusion: In conclusion, this study highlights the autonomous contributions of T2D and VLDL levels to coronary atherosclerosis development. T2D is linked to a 13.35% elevated risk of coronary atherosclerosis, and within T2D patients, VLDL concentration rises by 2.49%. Notably, each standard deviation increase in VLDL raises the likelihood of heart disease by 29.6%. This underscores the significant role of lipid regulation, particularly VLDL, as a mediating pathway in coronary atherosclerosis progression.

Keywords: Mendelian randomization; coronary atherosclerosis; mediation pathway; type 2 diabetes; very low-density lipoprotein.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Three assumptions about instrumental variables (IV).
Figure 2
Figure 2
Research flow chart. Adapted from Smart Medical Art (Available at: https://smart.servier.com/).
Figure 3
Figure 3
MR analysis.
Figure 4
Figure 4
Forest plots of MR analysis.
Figure 5
Figure 5
The result of 5 methods and 2 tests.
Figure 6
Figure 6
“leave one out” sensitivity analysis.
See this image and copyright information in PMC

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