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Carcinogenesis Advance Access originally published online on March 28, 2008
Carcinogenesis 2008 29(5):944-948; doi:10.1093/carcin/bgn025
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Published by Oxford University Press 2008.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

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

Shih-Chen Chang1, Asif Rashid2, Yu-Tang Gao3, Gabriella Andreotti1, Ming-Chang Shen4, Bin-Sheng Wang5, Tian-Quan Han6, Bai-He Zhang7, Lori C. Sakoda1, Michael F. Leitzmann1, Bingshu E. Chen1, Philip S. Rosenberg1, Jinbo Chen8, Stephen J. Chanock1,9,10 and Ann W. Hsing1,*

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
2 Department of Pathology MD Anderson Cancer Center, Houston, TX 77030, USA
3 Department of Epidemiology 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 19104, USA
9 Core Genotyping Facility, National Cancer Institute, Gaithersburg, MD 20877, USA
10 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

* To whom correspondence should be addressed. Tel: +1 301 496 1691; Fax: +1 301 401 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 in the PPAR-{gamma}, PPAR-{delta}, RXR-{alpha}, 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 [odds ratio (OR) = 1.67; 95% confidence interval (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) (≥23 kg/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.

Abbreviations: BMI, body mass index; CI, confidence interval; INS, insulin; LD, linkage disequilibrium; OR, odds ratio; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SNP, single-nucleotide polymorphism

Received September 28, 2007; revised January 14, 2008; accepted January 17, 2008.


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