Background: Ischemic stroke (IS) is the leading cause of death and disability worldwide. Chaperone proteins protect brain cells from the ischemic damage by restoring the structures of damaged proteins. Chaperone C9orf16 (also known as BBLN) belongs to the class of heat-resistant obscure (HERO) proteins, characterized by the ability to stabilize various proteins, suppress neurotoxicity and reduce proteotoxic stress. In this regard, it may play a potentially significant role in the risk of development and clinical manifestations of IS. The aim of the study: To investigate an association between a single nucleotide polymorphism rs2900262 in the gene encoding C9orf16 and predisposition to IS. Materials and methods: A total of 897 patients with IS and 1140 healthy controls were recruited for the study. Genotyping was done using a probe-based genotyping assay. Multiple logistic regression analysis was performed to evaluate the associations of the rs2900262 genotypes with the risk of IS and ischemic events. Dominant, recessive and additive models of associations of genotypes were analyzed. Adjustment for sex, age, and smoking was done throughout. Benjamini-Hogberg false-discovery rate was used to correct for multiple comparisons. Results: The rs2900262*T allele was found to be associated with the increased risk of IS exclusively in females (dominant model: OR=1.74, 95% CI=1.07-2.82, PFDR=0.042; additive model: OR=1.69, 95% CI=1.06-2.71, PFDR=0.042). Additional analysis showed that the rs2900262*T is associated with the increased risk of IS in smokers only (dominant model: OR=1.92, 95% CI=1.09-3.37, PFDR=0.042; additive model: OR=1.79, 95%CI=1.04-3.08, PFDR=0.042). Also, we demonstrated that C/T-T/T genotype carriers exhibit an earlier manifestation of IS (59.53±1.12 years) compared to the C/C genotype carriers (61.63±0.4 years); mean difference=-1.98; 95% CI=-3.61 – -0.36; PFDR=0.026. Conclusion: This study is the first in the world to demonstrate the possible contribution of the rs2900262 C9orf16 gene polymorphism to the risk of ischemic stroke.

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.