Genes Encoding Heat Shock Proteins Are Associated with Risk and Clinical Course of Severe COVID-19: A Pilot Study

In viral infections human heat shock proteins (HSPs) play a dual role by either protecting host cells or acting on viruses’ needs. The roles of HSPs have been extensively studied in various human pathologies, but their involvement in the progression of COVID-19 remains unexplored. It makes HSPs genetic variants particularly interesting in the context of severe COVID-19 risk. In this study, 1228 subjects (199 hospitalized COVID-19 patients and 962 controls) were genotyped for 20 SNPs in genes encoding HSPs and their regulators. SNP rs7189628 DNAJA2 (effect allele [EA] T) increased the risk of severe COVID-19 in the entire group (p = 0.002), males (p = 0.00008), and smokers (p = 0.0003). SNP rs910652 HSPA12B (EA C) decreased the risk of severe COVID-19 in the entire group (p = 0.01), females (p = 0.04), and patients with normal physical activity levels (p = 0.01). SNP rs1136141 HSPA8 (EA A) increased the risk of severe COVID-19 in patients with low fruit/vegetable intake (p = 0.004). Moreover, we observed significant changes in ground-glass opacity and alterations in blood coagulation and inflammation parameters, influenced by the SNPs of BAG3, HSF2, HSPA6, HSPA8, HSPA9, and DNAJA2. The molecular mechanisms underlying these associations are discussed. Together, our study provides preliminary evidence that SNPs of HSPs can significantly modulate the risk of severe COVID-19. © 2025 Elsevier B.V., All rights reserved.