Genetic Variants and Alteration in Transcription Factor 7-Like 2 (TCF7L2) mRNA Level in Ischemic Stroke Patients...

Diabetes and Hyperlipidemia are major risk factors for stroke across the world population. TCF7L2, a key regulator of the WNT signaling pathway shows genetic association with these metabolic disorders in ethnicity dependant manner. However, its role in stroke pathogenesis (if any) is not well characterized. Here, we aim to (a) investigate and correlate dysregulation of TCF7L2 expression with diabetes or hyperlipidemia-associated Ischemic Stroke (b) identify genetic risk variants in the TCF7L2 gene, and (c) establish correlations between TCF7L2 mRNA levels and biochemical parameters. Based 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 (31 Cases and 30 Controls) and genetic association studies (rs7901695 & rs7903146) were performed among 326 cases and 258 controls from two different ethnic population of India. In our study, a significant downregulation of TCF7L2 transcript was observed between stroke cases and controls as major finding. Furthermore, stratification of stroke cases, according to their blood lipid and glucose level revealed a lower quantity of TCF7L2 transcript in hyperlipidemia stroke cases than non-hyperlipidemia subjects. However, no such association against diabetic status was observed. A simultaneous finding showing negative correlation of gene expression with total blood cholesterol level (P = 0.0187; r = - 0.4012) but not for diabetes, thus suggests TCF7L2 mediated altered lipid metabolism as a risk for stroke pathogenesis. On the other hand, allelic (P = 0.0207) and genotypic (P = 0.0002) association of functional variants like rs7901695 variants [P = 0.0207] among the majorly Bengali population of Kolkata and rs7903146 [P = 0.0164] among the Gujarati cohort was observed, respectively. Thus, on basis of our findings, genotyping of TCF7L2 variants or quantification of transcript, consumption of low-fat diet may be recommended to hyperlipidemia individuals for risk prediction and preventive treatment regimen, respectively.