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Variants in Inflammation Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China

Ann W. Hsing¹, Lori C. Sakoda³, Asif Rashid⁴, Gabriella Andreotti¹, Jinbo Chen⁵, Bin-Shen Wang⁶, Ming-Chang Shen⁷, Bingshu E. Chen¹, Philip S. Rosenberg¹, Mingdong Zhang⁹, Shelley Niwa¹⁰, Lisa Chu^1,2, Robert Welch^11,, Meredith Yeager^1,11, Joseph F. Fraumeni, Jr.¹, Yu-Tang Gao⁸ and Stephen J. Chanock^1,11

¹ Division of Cancer Epidemiology and Genetics and ² Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland; ³ Department of Epidemiology, University of Washington, Seattle, Washington; ⁴ Department of Pathology, M. D. Anderson Cancer Center, Houston, Texas; ⁵ Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; ⁶ Department of Surgery, Zhong Shan Hospital, Fudan University, ⁷ Shanghai Tumor Hospital, and ⁸ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China; ⁹ Food and Drug Administration, Silver Spring, Maryland; ¹⁰ Westat, Rockville, Maryland; and ¹¹ Core Genotyping Facility, Advanced Technology Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland

Requests for reprints: Ann Hsing, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 5024, MSC 7234, Bethesda, MD 20892-7234. Phone: 301-496-1691; Fax: 301-402-0916; E-mail: hsinga{at}mail.nih.gov.

Key Words: gallstones • biliary tract cancer • inflammation • genetic susceptibility

To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), in 22 inflammation-related genes, in a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of individual SNPs and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer (P = 0.003) and biliary stones (P = 0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer. [Cancer Res 2008;68(15):6442–52]