Abstract
BackgroundCarcinoma 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 MethodsThe 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.ResultsOn 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 rs2234693G rs9340799C 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].ConclusionUsing 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.
Highlights
Carcinoma of the gallbladder is a highly fatal disease with late diagnosis, limited treatment options and deprived prognosis [1]
The variant-containing genotypes (DI+II) of progesterone receptor (PGR) showed low risk in both GBC [OR = 0.4] and gallstone patients [OR = 0.4].On performing the multifactor dimensionality reduction (MDR) analysis, estrogen receptor 1 (ESR1) IVS1-397C.T, ESR1 IVS1-351A.G, and estrogen receptor 2 (ESR2)-789 A.C yielded the highest testing accuracy of 0.634. These results were further supported by the classification and regression tree (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]
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
Summary
Carcinoma of the gallbladder is a highly fatal disease with late diagnosis, limited treatment options and deprived prognosis [1]. Hormone replacement therapy significantly increases the risk of gallbladder diseases [10,11] suggesting a noteworthy role of sex hormones in the etiology of GBC [12,13,14,15,16]. women are two to six times more affected than men. These evidences have raised the possibility that sex steroids (estrogen and progesterone) could play a key pathophysiological role in the development of gallbladder carcinoma. 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
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