Lipid Traits and Risk of Subarachnoid Haemorrhage: A Systematic Review and Mendelian Randomization Study in UK Biobank.
4 affiliations
- 1Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, Hampshire, UK. [email protected].
- 2Department of Neurosurgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD, UK. [email protected].
- 3Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, Hampshire, UK.
- 4Department of Neurosurgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.
Abstract
Lipid traits are established risk factors for atherosclerotic disease; however, their relationship with intracranial aneurysms and subarachnoid haemorrhage (SAH) remains unclear. Recent Mendelian randomisation (MR) studies have reported inconsistent findings. This study aimed to review the literature and assess the association between lipid traits and SAH using a one-sample MR analysis accounting for statin use and nonlinearity. We performed a systematic review of MR studies investigating lipid traits and intracranial aneurysms/SAH. A meta-analysis was not undertaken because studies used overlapping datasets. In parallel, we conducted a one-sample MR analysis of 486,603 UK Biobank participants. Genetic instruments for low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglycerides (TG) were derived from published genome-wide association studies. Associations with SAH were adjusted for lipid-lowering therapy. Nonlinear relationships were explored using cubic splines and piecewise MR. While eight MR studies met the inclusion criteria, seven relied on the same outcome cohort. Despite this, these studies showed no consistent direction of effect across lipid traits, suggesting that the estimates were unstable. In the UK Biobank, there was no evidence of an association between genetically predicted lipid traits and SAH for LDL (HR 1.06 [0.64-1.73]), HDL (HR 2.57 [0.42-15.74]), TC (HR 1.06 [0.71-1.60]), or TG (HR 1.05 [0.69-1.59). Results were consistent across different MR methods and sensitivity analyses, including adjustment for lipid-lowering therapy. Current evidence does not support a major association between lipid traits and SAH, with the heterogeneity observed across previous MR studies likely reflecting methodological limitations rather than a consistent biological effect. However, small effects and lipid-independent effects of lipid-lowering therapies cannot be excluded.
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BibTeX
@article{ewbank2026lipid,
title = {{Lipid Traits and Risk of Subarachnoid Haemorrhage: A Systematic Review and Mendelian Randomization Study in UK Biobank.}},
author = {Frederick Ewbank and Cameron Pinn and Benjamin Gaastra and William Tapper and Ian Galea and Diederik Bulters},
journal = {Translational stroke research},
year = {2026},
month = oct,
doi = {10.1007/s12975-026-01499-6},
url = {https://europepmc.org/article/MED/42848158},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lipid Traits and Risk of Subarachnoid Haemorrhage: A Systematic Review and Mendelian Randomization Study in UK Biobank.
AU - Frederick Ewbank
AU - Cameron Pinn
AU - Benjamin Gaastra
AU - William Tapper
AU - Ian Galea
AU - Diederik Bulters
PY - 2026
DA - 2026/10/08
JO - Translational stroke research
DO - 10.1007/s12975-026-01499-6
UR - https://europepmc.org/article/MED/42848158
AB - Lipid traits are established risk factors for atherosclerotic disease; however, their relationship with intracranial aneurysms and subarachnoid haemorrhage (SAH) remains unclear. Recent Mendelian randomisation (MR) studies have reported inconsistent findings. This study aimed to review the literature and assess the association between lipid traits and SAH using a one-sample MR analysis accounting for statin use and nonlinearity. We performed a systematic review of MR studies investigating lipid traits and intracranial aneurysms/SAH. A meta-analysis was not undertaken because studies used overlapping datasets. In parallel, we conducted a one-sample MR analysis of 486,603 UK Biobank participants. Genetic instruments for low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglycerides (TG) were derived from published genome-wide association studies. Associations with SAH were adjusted for lipid-lowering therapy. Nonlinear relationships were explored using cubic splines and piecewise MR. While eight MR studies met the inclusion criteria, seven relied on the same outcome cohort. Despite this, these studies showed no consistent direction of effect across lipid traits, suggesting that the estimates were unstable. In the UK Biobank, there was no evidence of an association between genetically predicted lipid traits and SAH for LDL (HR 1.06 [0.64-1.73]), HDL (HR 2.57 [0.42-15.74]), TC (HR 1.06 [0.71-1.60]), or TG (HR 1.05 [0.69-1.59). Results were consistent across different MR methods and sensitivity analyses, including adjustment for lipid-lowering therapy. Current evidence does not support a major association between lipid traits and SAH, with the heterogeneity observed across previous MR studies likely reflecting methodological limitations rather than a consistent biological effect. However, small effects and lipid-independent effects of lipid-lowering therapies cannot be excluded.
SN - 1868-4483
SN - 1868-601X
ER -