Association between HSPA8 Gene Variants and Ischemic Stroke: A Pilot Study Providing Additional Evidence for the Role of Heat Shock Proteins in Disease Pathogenesis.

HSPA8 is involved in many stroke-associated cellular processes, playing a pivotal role in the protein quality control system. Here we report the results of the pilot study aimed at determining whether HSPA8 SNPs are linked to the risk of ischemic stroke (IS). DNA samples from 2139 Russians (888 IS patients and 1251 healthy controls) were genotyped for tagSNPs (rs1461496, rs10892958, and rs1136141) in the HSPA8 gene using probe-based PCR. SNP rs10892958 of HSPA8 was associated with an increased risk (risk allele G) of IS in smokers (OR = 1.37; 95% CI = 1.07-1.77; p = 0.01) and patients with low fruit and vegetable consumption (OR = 1.36; 95% CI = 1.14-1.63; p = 0.002). SNP rs1136141 of HSPA8 was also associated with an increased risk of IS (risk allele A) exclusively in smokers (OR = 1.68; 95% CI = 1.23-2.28; p = 0.0007) and in patients with a low fruit and vegetable intake (OR = 1.29; 95% CI = 1.05-1.60; p = 0.04). Sex-stratified analysis revealed an association of rs10892958 HSPA8 with an increased risk of IS in males (risk allele G; OR = 1.30; 95% CI = 1.05-1.61; p = 0.01). Thus, SNPs rs10892958 and rs1136141 in the HSPA8 gene represent novel genetic markers of IS.

SERPINE1 mRNA Binding Protein 1 Is Associated with Ischemic Stroke Risk: A Comprehensive Molecular-Genetic and Bioinformatics Analysis of SERBP1 SNPs.

The SERBP1 gene is a well-known regulator of SERPINE1 mRNA stability and progesterone signaling. However, the chaperone-like properties of SERBP1 have recently been discovered. The present pilot study investigated whether SERBP1 SNPs are associated with the risk and clinical manifestations of ischemic stroke (IS). DNA samples from 2060 unrelated Russian subjects (869 IS patients and 1191 healthy controls) were genotyped for 5 common SNPs-rs4655707, rs1058074, rs12561767, rs12566098, and rs6702742 SERBP1-using probe-based PCR. The association of SNP rs12566098 with an increased risk of IS (risk allele C; p = 0.001) was observed regardless of gender or physical activity level and was modified by smoking, fruit and vegetable intake, and body mass index. SNP rs1058074 (risk allele C) was associated with an increased risk of IS exclusively in women (p = 0.02), non-smokers (p = 0.003), patients with low physical activity (p = 0.04), patients with low fruit and vegetable consumption (p = 0.04), and BMI ≥25 (p = 0.007). SNPs rs1058074 (p = 0.04), rs12561767 (p = 0.01), rs12566098 (p = 0.02), rs6702742 (p = 0.036), and rs4655707 (p = 0.04) were associated with shortening of activated partial thromboplastin time. Thus, SERBP1 SNPs represent novel genetic markers of IS. Further studies are required to confirm the relationship between SERBP1 polymorphism and IS risk.

Polymorphism of SERF2, the gene encoding a heat-resistant obscure (Hero) protein with chaperone activity, is a novel link in ischemic stroke.

Background: Ischemic stroke (IS) is one of the most serious cardiovascular events associated with high risk of death or disability. The growing body of evidence highlights molecular chaperones as especially important players in the pathogenesis of the disease. Since six small proteins called "Hero" have been recently identified as a novel class of chaperones we aimed to evaluate whether SNP rs4644832 in SERF2 gene encoding the member of Hero-proteins, is associated with the risk of IS. Methods: A total of 1929 unrelated Russians (861 patients with IS and 1068 healthy individuals) from Central Russia were recruited into the study. Genotyping was done using a probe-based PCR approach. Statistical analysis was carried out in the whole group and stratified by age, gender and smoking status. Results: Analysis of the link between rs4644832 SERF2 and IS showed that G allele is the risk factor of IS only in females (OR=1.29, 95%CI 1.02-1.64, Padj=0.035). In addition, the analysis of associations of rs4644832 SERF2 and IS depending on the smoking status revealed that this genetic variant is associated with an increased risk of IS exclusively in non-smoking individuals (OR=1.26, 95%CI 1.01-1.56, P = 0.041). Discussion: Sex- and smoking interactions between rs4644832 polymorphism and IS may be related to the impact of tobacco components metabolism and sex hormones on SERF2 expression. Conclusion: The present study reveals the novel genetic association between rs4644832 polymorphism and the risk of IS suggesting that SERF2, the part of the protein quality control system, contributes to the pathogenesis of the disease.