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Carcinogenesis Advance Access published online on August 2, 2006
Carcinogenesis, doi:10.1093/carcin/bgl130
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Published by Oxford University Press 2006
Received March 1, 2006
Revised June 16, 2006
Accepted July 11, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer

L. Hou 1 *, E. M. El-Omar 2, J. Chen 1, P. Grillo 3, C. Rabkin 1, A. Baccarelli 4, M. Yeager 5, S. J. Chanock 6, W. Zatonski 7, L. H. Sobin 8, J. Lissowska 7, J. F. Fraumeni Jr 1, and W. H. Chow 1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA
2 Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
3 Epidemiology Unit, Department of Occupational, Clinical and Preventive Medicine, IRCCS "Ospedale Maggiore Policlinico, Mangiagallie Regina Elena" I-20122 Milan, Italy
4 Epidemiology Unit, Department of Occupational, Clinical and Preventive Medicine, IRCCS "Ospedale Maggiore Policlinico, Mangiagallie Regina Elena" I-20122 Milan, Italy; EPOCA Research Center for Clinical, Occupational and Environmental Epidemiology, Department of Occupational Medicine, University of Milan, I-20122 Milan, Italy
5 Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20892, USA
6 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA; Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20892, USA
7 Division of Cancer Epidemiology and Prevention, Cancer Center and M.Sklodowska-Curie Institute of Oncology, 02-781 Warsaw, Poland
8 Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC, 20306

* To whom correspondence should be addressed.
L. Hou, E-mail: lifangh2{at}mail.nih.gov


  Abstract

H. pylori infection, the dominant risk factor for gastric cancers, has been demonstrated to elicit Th1-polarized immunologic responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqManTM assays to determine TNFA (-308 G>A, -417 G>A, -555G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL2 (-330 T>G), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G, and Ex2-16 A>G), and IL12A (IVS2-798 T>A, IVS2-701 C>A, and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate ORs and 95% CIs, adjusting for sex, age, education, and smoking status. Out of six SNPs tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95%CI: 1.0-2.0) for the G/A and 2.5 (95%CI: 1.3-4.9) for the A/A genotype carriers, when compared to the more frequent genotype (G/G) (p-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95%CI: 1.0-2.3) for T/C and 1.7 (95%CI: 1.1-2.7) for C/C carriers when compared to T/T carriers (p-trend=0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR=5.5, 95% CI 1.5-19.4), although the interaction was not statistically significant. IL2 (-330 T>G), IL1A (-889 C>T), and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

Keywords: Polymorphisms; Th1 response; H. pylori; gastric cancer.
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