Genetic Variants in HSP70 Family Genes and Their Co-Chaperones Are Associated with Ischemic Stroke Susceptibility and Gene Expression During Acute and Early Recovery Phases

Heat shock protein 70 (HSP70) family members and co-chaperones participate in cellular stress responses, proteostasis, apoptosis, inflammation, and mitochondrial function implicated in ischemic stroke (IS). We investigated associations between genetic variants in HSP70 family genes and BAG co-chaperones and IS susceptibility, clinical characteristics, and gene expression. Twenty-three single-nucleotide polymorphisms were analyzed in 768 patients with IS and 794 controls. Functional annotation included eQTL resources, protein–protein interaction analyses, and targeted genotype–expression analysis of paired peripheral-blood transcriptomes from 19 patients during acute IS and on day 7. In the overall cohort, the variants rs2227956 in HSPA1L and rs7749960 variant in the BAG2 gene were associated with reduced IS risk. The variants rs2227956 and rs2075799 in HSPA1L, rs753856 in HSPA6, rs706121 in BAG1, rs7749960 in BAG2, and rs196329 in BAG3 were linked to IS risk, associations specific to certain subgroups. Additional variants were associated with age at IS onset, lipid levels, coagulation parameters, body mass index, and number of IS episodes. Functional analyses linked associated loci to pathways relevant to atherosclerosis, inflammation, apoptosis, oxidative stress, autophagy, mitochondrial dysfunction, and angiogenesis. Transcriptomic analysis identified associations of rs1043618 HSPA1A with C4B expression during acute IS and DDR1 expression on day 7, while rs1042665 HSPA9 was associated with genotype-dependent changes in HSPA9 expression. These findings support a role for HSP70-related genetic variation in IS susceptibility, clinical heterogeneity, and phase-specific gene-expression differences.