Genetic Variations and Altered Blood mRNA Level of Circadian Genes and BDNF as Risk Factors of Post-Stroke Cognitive Impairment among Eastern Indians

Abstract

ABSTRACTBackgroundPost-stroke cognitive impairment (PSCI) is a clinical outcome in around 30% of post-stroke survivors. BDNF is a major gene in this regard. It regulates and being regulated by circadian rhythm. The circadian genes are correlated with stroke timings at molecular level. However, studies suggesting the role of these on susceptibility to PSCI is limited.AimWe aim here to determine a) genetic risk variants in circadian clock genes,BDNFand b) dysregulation in expression level ofCLOCK, BMAL1 andBDNF, that may be associated with PSCI.MethodsBDNF (rs6265G/A, rs56164415C/T), CLOCK (rs1801260T/C, rs4580704G/C) and CRY2 (rs2292912C/G) genes variants were genotyped among 119 post-stroke survivors and 292 controls from Eastern part of India. In addition, we analysed their gene expression in PBMC from 15 PSCI cases and 12 controls. The mRNA data for BDNF was further validated by its plasma level through ELISA.ResultsAmong the studied variants, only rs4580704/CLOCKshowed an overall association with PSCI (P = 0.001) and lower BMSE score. Its ‘C’ allele showed a correlation with attention deficiency. The language and memory impairments showed association with rs6265/BDNFwhile the ‘CC’ genotype of rs2292912/CRY2negatively influenced language and executive function. A significant decrease in gene expression forCLOCKandBDNFin PBMC (influenced by specific genotypes) of PSCI patients was observed than controls. Unlike, Pro-BDNF, plasma level mBDNF was also lower in them.ConclusionsOur results suggest that the circadian genes andBDNFplay a role in PSCI on both genetic and transcript level.