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. 2024 May 9;10(10):e30909.
doi: 10.1016/j.heliyon.2024.e30909. eCollection 2024 May 30.

Effects of antidiabetic agents on platelet characteristics with implications in Alzheimer's disease: Mendelian randomization and colocalization study

Zhipeng Xie  1   2 , Yijie Liu  3   2 , Min Huang  4 , Shilong Zhong  1   2   5   6 , Weihua Lai  1   2
Affiliations

Effects of antidiabetic agents on platelet characteristics with implications in Alzheimer's disease: Mendelian randomization and colocalization study

Zhipeng Xie et al. Heliyon. .

Abstract

Background: Observational studies have found a potential link between the use of thiazolidinediones (TZDs) and a lower risk of Alzheimer's disease (AD) development. Platelets were the great source of amyloid-β (Aβ) and involved in the development of AD. This study aimed to assess the correlation between antidiabetic agents and platelet characteristics, hoping to provide a potential mechanism of TZDs neuroprotection in AD.

Method: Drug-targeted Mendelian randomization (MR) was performed to systematically illustrate the long-term effects of antidiabetic agents on platelet characteristics. Four antidiabetic agent targets were considered. Positive control analysis for type 2 diabetes (T2D) was conducted to validate the selection of instrumental variables (IVs). Colocalization analysis was used to further strengthen the robustness of the results.

Result: Positive control analysis showed an association of four antidiabetic agents with lower risk of T2D, which was consistent with their mechanisms of action and previous evidence from clinical trials. Genetically proxied TZDs were associated with lower platelet count (β[IRNT] = -0.410 [95 % CI -0.533 to -0.288], P = 5.32E-11) and a lower plateletcrit (β[IRNT] = -0.344 [95 % CI -0.481 to -0.206], P = 1.04E-6). Colocalization suggested the posterior probability of hypothesis 4 (PPH4) > 0.8, which further strengthened the MR results.

Conclusion: Genetically proxied TZDs were causally associated with lower platelet characteristics, particularly platelet count and plateletcrit, providing insight into the involvement of platelet-related pathways in the neuroprotection of TZDs against AD. Future studies are warranted to reveal the underlying molecular mechanism of TZDs' neuroprotective effects through platelet pathways.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
The effect estimates of four antidiabetic agents on T2D were assessed by the IVW method in positive control analysis. IVW: inverse variance weighted, nSNP: number of single nucleotide polymorphism, OR: odds ratio, CI: confidence interval.
Fig. 2
Fig. 2
The effect estimates of four antidiabetic agents on platelet characteristics were assessed by the IVW method. IVW: inverse variance weighted, nSNP: number of single nucleotide polymorphism, β: beta coefficient, CI: confidence interval.
Fig. 3
Fig. 3
Colocalization analysis of genetically proxied TZDs and platecrit. PPARG: Peroxisome Proliferator Activated Receptor Gamma as a target of thiazolidinediones; Points were color-coded according to the LD (r2) of each variant relative to the variant with the highest posterior probability of colocalization within the gene region. In the left panel, －log10 P values for associations with platecrit are on the x-axes, and －log10 P values for associations with the PPARG on the y-axes. In the right panels, genomic positions are on the x-axes, and the y-axes show －log10 P values for platecrit on the upper panel and －log10 P values with the PPARG on the lower panel for the corresponding region. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
Fig. 4
Colocalization analysis of genetically proxied TZDs and platelet count. PPARG: Peroxisome Proliferator Activated Receptor Gamma as a target of thiazolidinediones; Points were color-coded according to the LD (r2) of each variant relative to the variant with the highest posterior probability of colocalization within the gene region. In the left panel, －log10 P values for associations with platelet count are on the x-axes, and －log10 P values for associations with the PPARG on the y-axes. In the right panels, genomic positions are on the x-axes, and the y-axes show －log10 P values for platelet count on the upper panel and －log10 P values with the PPARG on the lower panel for the corresponding region. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
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