Genetically predicted small dense low-density lipoprotein cholesterol and ischemic stroke subtype: multivariable...

Area of Science:

• Cardiovascular Genetics
• Stroke Etiology
• Lipid Metabolism

Background:

• Small dense low-density lipoprotein cholesterol (S-LDL-C) is implicated in atherosclerosis.
• Causal links between S-LDL-C and specific ischemic stroke (IS) subtypes are not well-established.
• Understanding LDL subfractions' roles is crucial for IS prevention.

Purpose of the Study:

• To investigate the causal effects of S-LDL-C, medium (M-LDL-C), and large (L-LDL-C) subfractions on ischemic stroke (IS) risk.
• To analyze these effects across main IS etiological subtypes.
• To employ a two-sample Mendelian randomization (TSMR) design for robust causal inference.

Main Methods:

• Utilized genetic instruments for LDL subfractions from UK Biobank (n=115,082).
• Obtained summary-level data for ischemic stroke subtypes from the MEGASTROKE consortium.
• Conducted multivariable TSMR, adjusting for potential pleiotropic effects of triglycerides (TG) and HDL-C.

Main Results:

• A significant causal association was found between genetically predicted S-LDL-C and large artery stroke (LAS) (OR=1.481, P=0.006).
• No significant causal effects were observed for M-LDL-C or L-LDL-C on IS or its subtypes.
• The causal link between S-LDL-C and LAS remained significant in multivariable analysis (OR=1.329, P=0.002).

Conclusions:

• Findings provide genetic evidence supporting a causal role of S-LDL-C in large artery stroke (LAS).
• Further research is needed to clarify the underlying mechanisms.
• Clinical implications for targeting S-LDL-C in LAS prevention warrant investigation.