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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Cardiovascular Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1404234

Genetically predicted small dense low-density lipoprotein cholesterol and ischemic stroke subtype: multivariable Mendelian randomization study

Provisionally accepted
Xiao Yu Xiao Yu 1*Guangxun Shen Guangxun Shen 1Yan Zhang Yan Zhang 1*Cancan Cui Cancan Cui 1Yining Zha Yining Zha 2*Pingan Li Pingan Li 3Lihong Li Lihong Li 1*Xu Wang Xu Wang 1*Guangxian Nan Guangxian Nan 1*
  • 1 China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
  • 2 School of Public Health, Harvard University, Boston, Massachusetts, United States
  • 3 Capital Medical University, Beijing, Beijing Municipality, China

The final, formatted version of the article will be published soon.

    Purpose Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design.We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis.In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI):1.117-1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106-1.597, P = 0.002).Conclusions Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.

    Keywords: Low-density lipoprotein cholesterol (LDL-C) subfractions, small low-density lipoprotein cholesterol (S-LDL-C), ischemic stroke, large artery stroke (LAS), Mendelian randomization LDL-C: Low-density lipoprotein cholesterol, IS: ischemic stroke, S-LDL-C: small low-density lipoprotein cholesterol, M-LDL-C: medium low-density lipoprotein cholesterol

    Received: 20 Mar 2024; Accepted: 12 Jul 2024.

    Copyright: © 2024 Yu, Shen, Zhang, Cui, Zha, Li, Li, Wang and Nan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Xiao Yu, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin Province, China
    Yan Zhang, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin Province, China
    Yining Zha, School of Public Health, Harvard University, Boston, MA 02115, Massachusetts, United States
    Lihong Li, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin Province, China
    Xu Wang, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin Province, China
    Guangxian Nan, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin Province, China

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