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Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were  XRCC1 ,  OGG1 ,  ERCC2 ,  MSH2 ,  CASP8 ,  TLR2 ,  TLR4  and  PTGS2 . Single locus analysis by logistic regression showed association of  MSH2  IVS1+9G>C (rs2303426),  ERCC2  Asp312Asn (rs1799793),  OGG1  Ser326Cys (rs1052133),  OGG1  IVS4-15C>G (rs2072668),  CASP8  -652 6N ins/del (rs3834129),  PTGS 2 -1195G>A (rs689466),  PTGS2  -765G>C (rs20417),  TLR4  Ex4+936C>T (rs4986791) and  TLR2  –196 to –174del polymorphisms with GBC risk. The CART analysis revealed  OGG1  Ser326Cys, and  OGG1  IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of  PTGS2 - 1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population.

Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes