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Circulating proteins and risk of small vessel stroke: A two-sample Mendelian randomization study

Ziwei Gao1,2, Yawen Xu1,2, Yue Chen1,2

  • 1Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.

Medicine
|May 23, 2026
PubMed

Insights

This study identified GRAMD1C as a circulating protein causally linked to increased small vessel stroke (SVS) risk. This finding suggests GRAMD1C as a potential biomarker for SVS diagnosis and therapy.

Area of Science:

  • Genetics
  • Neurology
  • Biomarker Discovery

Background:

  • Small vessel stroke (SVS) poses a significant health burden.
  • Identifying reliable circulating biomarkers for SVS remains a challenge.
  • Mendelian randomization (MR) offers a robust approach to investigate causal relationships.

Purpose of the Study:

  • To systematically screen circulating proteins for potential causal associations with SVS risk.
  • To identify novel protein biomarkers for SVS diagnosis and therapeutic targeting.

Main Methods:

  • A two-sample Mendelian randomization (MR) design was employed.
  • Utilized summary statistics from the MEGASTROKE Consortium (446,696 participants) and data on 4782 circulating proteins.
  • Applied inverse variance weighting and sensitivity analyses for robust association estimates.

Main Results:

  • GRAMD1C was identified as a circulating protein causally increasing SVS risk (OR=2.86, P=5.61e-05).
  • PTGR1 showed a suggestive association with SVS risk (OR=1.15, P=6.65e-03).
  • The cholesterol transporter GRAMD1C emerged as a significant risk factor for SVS.

Conclusions:

  • GRAMD1C is a promising circulating biomarker for small vessel stroke.
  • Targeting GRAMD1C may offer new avenues for SVS diagnosis and treatment.
  • This MR study highlights the utility of proteomic data in understanding stroke etiology.
Keywords:
GRAMD1CMendelian randomizationPTGR1causal effectcirculating proteinssmall vessel stroke

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