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Background  Carcinoma of gallbladder (GBC) is an aggressive malignancy. The higher incidence of gallbladder cancer in women has been partly attributed to hormonal factors. Therefore the present study was designed to explore the role of genetic variants in estrogen ( ESR1, ESR2 ) and progesterone ( PGR ) receptors in conferring risk of gallbladder cancer.    Materials and Methods  The present case-control study recruited total of 860 subjects, including 410 GBC patients, 230 gallstone patients and 220 controls. We examined the associations of 6 selected polymorphisms in three genes:  ESR1  (rs2234693, rs9340799, rs1801132),  ESR2  (rs1271572, rs1256049) and  PGR  (rs1042838) with GBC risk. Genotyping for all the polymorphisms was done using PCR-RFLP. Multifactor dimensionality reduction and classification and regression tree approaches were combined with logistic regression to discover high-order gene-gene interactions in hormonal pathway.    Results  On comparing the genotype frequency distribution in gallstone and GBC patients with that of healthy subjects, the homozygous variant genotypes of  ESR1 -397TT (rs2234693) polymorphism showed significant risk for developing gallstone [odds ratio: OR = 2.9] and GBC [OR = 1.8] respectively. Detailed haplotypes analysis suggested that  ESR1  T  rs2234693 G  rs9340799 C  rs1801132  have significant association in conferring risk for both gallstones [OR = 2.2] and GBC [OR = 3.0]. However, the variant-containing genotypes (DI+II) of  PGR  (rs1042838) showed low risk in both GBC [OR = 0.4] and gallstone patients [OR = 0.4].On performing the MDR analysis,  ESR1  IVS1-397C>T,  ESR1  IVS1-351A>G, and  ESR2 -789 A>C yielded the highest testing accuracy of 0.634. These results were further supported by the CART analysis which revealed that individuals with the combined genotypes of  ESR1 -397 CT or TT,  ESR1 -351 AG or GG and  ESR2  -789 AA had the highest risk for GBC [OR  = 3.9].    Conclusion  Using multi-analytical approaches, our study showed important role of  ESR1  IVS1-397C>T,  ESR1  IVS1-351A>G, and  ESR2 -789 A>C variants in GBC susceptibility and the risk appears to be mediated through gallstone dependent pathway.

Significant Role of Estrogen and Progesterone Receptor Sequence Variants in Gallbladder Cancer Predisposition: A Multi-Analytical Strategy