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Differential ischemic stroke risk linked to novel subtypes of type 2 diabetes: insights from a Mendelian randomization analysis

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Abstract

Purpose

This study employs a two-sample Mendelian randomization (MR) approach to investigate the variation in ischemic stroke risk across novel subtypes of adult-onset type 2 diabetes.

Methods

Leveraging pooled genome-wide association study (GWAS) data from the Swedish ANDIS cohort, we explored the association of four newly identified type 2 diabetes subtypes—severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD)—with ischemic stroke risk. The outcome data for ischemic stroke and its three subtypes (large artery, cardioembolic, and small vessel stroke) were sourced from the MEGASTROKE Consortium. Our analysis applied multiple MR methods, focusing on the inverse-variance weighted (IVW) technique, complemented by thorough sensitivity analyses to examine heterogeneity and potential horizontal pleiotropy.

Results

Our findings reveal a significant causal relationship between the SIDD subtype and small vessel stroke (OR = 1.06, 95% CI: 1.01–1.11, p = 0.025), while no causal associations were observed for SIRD with any stroke subtype. MOD was causally linked to small vessel stroke (OR = 1.07, 95% CI: 1.02–1.12, p = 0.004) and large artery stroke (OR = 1.07, 95% CI: 1.01–1.13, p = 0.015). Similarly, MARD showed a causal relationship with small vessel stroke (OR = 1.09, 95% CI: 1.03–1.16, p = 0.006) and overall ischemic stroke risk (OR = 1.04, 95% CI: 1.01–1.08, p = 0.010).

Conclusions

Our study highlights distinct causal links between specific type 2 diabetes subtypes and ischemic stroke risks, emphasizing the importance of subtype-specific prevention and treatment strategies.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

CES :

Cardiogenic stroke

GWAS :

Genome-wide association studies

IS :

Ischemic stroke

IVW :

Inverse variance weighted

LD :

Linkage disequilibrium

LAS :

Large artery stroke

MR :

Mendelian randomization

OR :

Odds ratios

SVS :

Small vessel stroke

SNPs :

Single nucleotide polymorphisms

SIDD :

Severe insulin-deficiencyent diabetes

SIRD :

Severe insulin-resistant diabetes

MOD :

Mild obesity-related diabetes

MARD :

Mild age-related diabetes

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Acknowledgements

We thank all the genetics consortiums for making the GWAS summary data publicly available.

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  1. Department of Endocrinology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China

    Zhichao Ruan & Jinxi Zhao

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zhichao Ruan and Jinxi Zhao. The first draft of the manuscript was written by Zhichao Ruan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Ruan, Z., Zhao, J. Differential ischemic stroke risk linked to novel subtypes of type 2 diabetes: insights from a Mendelian randomization analysis. Endocrine (2024). https://doi.org/10.1007/s12020-024-03842-z

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