Polymorphism of genes in the lipid metabolism pathway and the risk of biliary tract cancers: a population-based study in Shanghai, China

2557 Cancers of the biliary tract, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are rare, but often fatal. Their etiology remains poorly understood, with gallstones being one of the few known risk factors. Since cholesterol supersaturation of the bile is an essential component of gallstone formation, variants of genes encoding cholesterol transport and metabolism may affect the function of lipoproteins, thereby increasing the risk of gallstones and biliary tract cancers. In a population-based case-control study conducted in Shanghai, China, we examined the role of genetic susceptibility related to lipid metabolism in biliary tract stone and cancer etiology. The study included 406 incident biliary tract cancer cases (235 gallbladder, 125 extrahepatic bile duct, 46 ampulla of Vater), 880 biliary tract stone cases (663 gallbladder, 217 bile duct), and 779 healthy controls randomly selected from the general population and frequency matched to cancer cases on age and sex. Genomic DNA extracted from buffy coat was used to genotype the following 14 single nucleotide polymorphisms (SNPs) of five genes using Taqman assays: arachidonate 5-lipoxygenase ( ALOX5 IVS3+99), apolipoprotein B ( ApoB T98I, P2739L, IVS23-79, IVS6+360), apolipoprotein E ( ApoE IVS1+69), low-density lipoprotein receptor ( LDLR 3’UTR, IVS9-30, R471, R744, IVS17-53, IVS17-42, 441), and lipoprotein lipase ( LPL IVS5+948). The success rate of genotyping was > 98%, and the concordance of genotyping in duplicate samples was > 99%. All genotype frequencies were in Hardy-Weinberg equilibrium among population controls. Variants in two of the five genes were associated with biliary tract stones or cancers. Relative to individuals with the CC genotype of the ApoE IVS1+69 polymorphism those with the G allele (GC+GG genotypes) had a 2-fold (95% CI 1.3-3.1) and 2.5-fold (95% CI 1.2-5.1) risk of bile duct and ampulla of Vater cancers, respectively. These risks were more pronounced among men and among individuals without diabetes or with a lower body mass index (BMI ≤ 23 kg/m 2 ). Among men, but not women, the ApoE IVS1+69 G variant was also associated with a significant excess risk of gallstones and gallbladder cancer. There was a suggestive association between LDLR IVS9-30 and bile duct cancer. Men who carried both high-risk alleles for ApoE IVS1+69 and LDLR IVS9-30 had a 5-fold risk of bile duct cancer (OR=5.34, 95% CI 2.1-13.8). These results suggest that the etiology of biliary tract stones and cancers involves a complex interplay of the ApoE gene, which encodes the ApoE protein that is essential for lipoprotein binding and cholesterol homeostasis, with other risk factors. Further studies are needed to confirm these results and clarify the underlying mechanisms.