HSP90 Family Members, Their Regulators and Ischemic Stroke Risk: A Comprehensive Molecular-Genetics and Bioinformatics Analysis.

Background: Disruptions in proteostasis are recognized as key drivers in cerebro- and cardiovascular disease progression. Heat shock proteins (HSPs), essential for maintaining protein stability and cellular homeostasis, are pivotal in neuroperotection. Consequently, deepening the understanding the role of HSPs in ischemic stroke (IS) risk is crucial for identifying novel therapeutic targets and advancing neuroprotective strategies.

Aim: Our objective was to examine the potential correlation between single nucleotide polymorphisms (SNPs) in genes that encode members of the Heat shock protein 90 (HSP90), small heat shock proteins (HSPB), and heat shock factors (HSF) families, and the risk and clinical characteristics of IS.

Methods: 953 IS patients and 1265 controls from Central Russia were genotyped for nine SNPs in genes encoding HSP90AA1, HSFs, and HSPBs using the MassArray-4 system and probe-based polymerase chain reaction (PCR).

Results: In smokers, SNP rs1133026 HSPB8 increased the risk of IS (risk allele A, odds ratio (OR) = 1.43, 95% Confidence Interval (CI) 1.02-2.02, p = 0.035), and rs556439 HSF2 increased the brain infarct size (risk allele A, p = 0.02). In non-smokers, SNPs rs4279640 HSF1 (protective allele T, OR = 0.58, 95% CI 0.37-0.92, p = 0.02) and rs4264324 HSP90AA1 (protective allele C, OR = 0.11, 95% CI 0.01-0.78, p = 0.001) lowered the risk of recurrent stroke; SNP rs7303637 HSPB8 increased the age of onset of IS (protective allele T, p = 0.04). In patients with body mass index (BMI) ≥25, SNPs rs556439 HSF2 (risk allele A, OR = 1.33, 95% CI 1.04-1.69, p = 0.02) and rs549302 HSF2 (risk allele G, OR = 1.34, 95% CI 1.02-1.75, p = 0.03) were linked to a higher risk of IS.

Conclusions: The primary molecular mechanisms through which the studied SNPs contribute to IS pathogenesis were found to be the regulation of cell death, inflammatory and oxidative stress responses.