Carcinogenesis Advance Access published online on March 28, 2008
Carcinogenesis, doi:10.1093/carcin/bgn025
Published by Oxford University Press 2008.
Polymorphism of genes related to insulin sensitivity and the risk of biliary tract cancer and biliary stone: a population-based case-control study in Shanghai, China
1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD, USA
2 MD Anderson Cancer Center, Houston, Texas, USA
3 Shanghai Cancer Institute, Shanghai, China
4 Shanghai Tumor Hospital, Shanghai, China
5 Zhongshan Hospital, Shanghai, China
6 Rui-jian Hospital, Shanghai, China
7 Oriental Hepato-biliary Surgery Hospital, Shanghai, China
8 Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
9 Core Genotyping Facility, National Cancer Institute, Gaithersburg, MD, USA
10 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
* To whom correspondence should be address. Tel: 301 496 1691; FAX: 301 401 0916; Email: hsinga{at}mail.nih.gov
Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single nucleotide polymorphisms (SNPs) in the PPAR-
, PPAR-
, RXR-
, RXR-β and INS genes with biliary cancer and stones in a population-based case-control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater cancer cases, 895 stone cases, and 786 population controls. Relative to individuals with the RXR-β C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer (OR = 1.67; 95% CI = 0.99-2.84), with a more pronounced association among men (OR = 2.30; 95% CI = 1.14-4.65; P interaction = 0.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (
23kg/m2) (OR = 1.80; 95% CI = 1.09-2.94), although the interaction with BMI was not statistically significant (P interaction = 0.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones
Key Words: Biliary tract cancer • gallstone • peroxisome proliferator-activated receptors • and retinoid X receptors
Received September 28, 2007; revised January 14, 2008; accepted January 17, 2008.