C9orf16 (BBLN) gene, encoding a member of Hero proteins, is a novel marker in ischemic stroke risk

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.