Immunology

Biography

Biography: Kiran L Sharma

Abstract

Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants associated inflammation and tumorigenesis. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were (matrix etallopeptidase-2, MMP-7, MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha and LXR-beta. Genotypes were determined by PCR-RFLP andTaqMan probes. Statistical analysis was done by SPSS version 16.Multilocus analysis was performed by Classification and RegressionTree (CART) analysis and multifactor dimensionality reduction(MDR) to gene–gene interactions in modifying GBC risk. In silicoanalysis was done using various bioinformatics tools (F-SNP,FAST-SNP). Single locus analysis showed association of MMP-2(−735 C > T, −1306 C > T), MP-7 − 181 A > G, MMP-9 (P574R,R668Q), TIMP-2 − 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val,PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C(rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associatedwith GBC risk. Multidimensional reduction analysis revealed LXR-β(rs3546355 G > A, rs2695121 T > C), MMP-2 (−1306 C > T), MMP-9(R668Q), and PLCE1 rs2274223 A > G to be key players in GBCcausation (p < 0.001, CVC = 7/10). The results were further supportedby independent CART analysis (p < 0.001). In-silico analysis ofassociated variants suggested change in splicing or transcriptionalregulation. Interactome and STRING analysis showed network ofassociated genes. The study found PLCE1 and LXR-β networkinteractions as important contributory factors for geneticpredisposition in gallbladder cancer.