The rs6647 variant G allele inSERPINA1gene was reported to be associated with the risk of large artery atherosclerotic stroke (LAS), however, the mechanism remains unclear. Here, we performed a functional annotation of the rs6647 variant by using the software HaploReg version 4.1 (HaploReg v4.1). Next, the expression quantitative trait loci (eQTLs) analysis of multiple datasets was conducted for determining the association between the rs6647 andSERPINA1expression in various tissues. Then, a case-control gene expression analysis was done using two independent ischemic stroke (IS) gene expression datasets. Finally,SERPINA1expression in whole blood samples from 8 LAS patients and 14 healthy persons were compared. The functional annotation suggested that the rs6647 regulates gene expression in multiple human tissues especially in brain and blood. The eQTLs analysis revealed a significant association of the rs6647 G allele with increased expression ofSERPINA1gene only in whole blood. Compared with the controls, there was an increased expression ofSERPINA1gene in whole blood in both IS patients and LAS patients.SERPINA1gene expression in whole blood bridges the rs6647 variant G allele with increased LAS risk, providing new insights into the mechanisms underlying role of the rs6647 in determining LAS risk.