BackgroundDiabetes and Hyperlipidemia are major risk factors for stroke across the world population.TCF7L2, a key player of the WNT signaling pathway shows genetic association with both metabolic disturbances. However, its role in stroke pathogenesis (if any) is not well characterized.ObjectivesThus, here we aim to (a) examine and correlate dysregulation ofTCF7L2expression with diabetes or hyperlipidemia-associated Ischemic Stroke, (b) identify genetic risk variants in theTCF7L2gene and (c) establish a correlation betweenTCF7L2mRNA expressions with biochemical parameters.MethodsBased on radiological findings for Ischemic Stroke, a total of 50 unrelated subjects were recruited with diverse biochemical parameters for TCF7L2 mRNA expression study in PBMC, followed by correlation with fasting blood sugar and lipid profile. Furthermore, mutation screening and genetic association studies (rs7901695 & rs7903146) were performed among 326 cases and 258 controls from India.ResultsHere, we observed a significant downregulation ofTCF7L2gene expression among hyperlipidemic stroke patients than cases and control without dyslipidemia but no change between the cases with different diabetic statuses. Moreover, a strong negative correlation betweenTCF7L2mRNA level and total blood cholesterol but not for FBS was identified. The rs7901695T/C appeared as a promising genetic risk factor for stroke among eastern Indians.ConclusionTherefore, we can suggest that alteration inTCF7L2leading to stroke pathogenesis is more associated with hyperlipidemia than diabetes among Indians. Its expression level in PBMC is influenced by rs7901695T/C and holds a good promise to be used as a diagnostic marker.