A Nonsynonymous Polymorphism in IL23R Gene Is Associated With Risk of Gastric Cancer in a Chinese Population Jianjian Chen, 1 Yan Lu, 1 Hanze Zhang, 1 Yanbing Ding, 2 Chuanli Ren, 3 Zhaolai Hua, 4 Yan Zhou, 5 Bin Deng, 2 Guangfu Jin, 1 Zhibin Hu, 1 Yaochu Xu, 1 and Hongbing Shen 1 * 1 Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China 2 Department of Gastroenterology, Yangzhou First People’s Hospital, Yangzhou, China 3 Medical Lab, Northern Jiangsu People’s Hospital, Yangzhou, China 4 Department of Epidemiology, Yangzhong Cancer Institute, Yangzhong, China 5 Department of Oncology, Yixing People’s Hospital, Yixing, China Interleukin-23 receptor (IL-23R) is a key element in T helper (Th)17 cell-mediated inflammatory process, which plays an important role in pathogenesis of gastric cancer. Genetic variants of IL-23R have been identified as the predisposing factors for immunopathologic process. In this study, we hypothesized that the functional genetic variants of IL-23R gene may modify the risk of gastric cancer. To test this hypothesis, we conducted a case–control study including 1043 gastric cancer patients and 1089 controls in a Chinese population to assess the association between two potentially functional single nucleotide polymorphisms (SNPs) rs6682925 T>C and rs1884444 T>G of IL-23R and risk of gastric cancer. We found that the variant allele (G) of rs1884444 T>G, with amino acid His substituted by Gln at codon 3, was significantly associated with a decreased risk of gastric cancer [adjusted allelic odds ratio (OR) ¼ 0.78, 95% confidence interval (CI) ¼ 0.68–0.88]. In the stratified analysis, we found that this protective effect of rs1884444 G allele was mainly evident in intestinal-type gastric cancer (adjusted allelic OR ¼ 0.75, 95% CI ¼ 0.65–0.87) other than in diffuse-type gastric cancer (adjusted allelic OR ¼ 0.96, 95% CI ¼ 0.76–1.22). However, we did not find any significant association of rs6682925 T>C with gastric cancer risk. These findings indicate, for the first time, that the nonsynonymous variant rs1884444 T>G of IL-23R may contribute to gastric cancer susceptibility, especially in intestinal-type gastric cancer, in Chinese population. Mol. Carcinog. ß 2010 Wiley-Liss, Inc. Key words: IL-23R; polymorphism; gastric cancer; molecular epidemiology INTRODUCTION Despite the incidence of gastric cancer keeps declining over past decades, it still remains one of the most common malignancies around the world. It was estimated that almost 40% of gastric cancer cases occurred in China [1]. The mechanism of gastric cancer development is unclear and is believed to be the results of interactions between genetic components and various environmental factors. Since Helicobacter pylori was identified by Marshall and Warren [2], epidemiological studies and animal models have shown that gastric cancer attributes largely to H. pylori infection [3,4], which was defined as a Group I human carcinogen by the International Agency for Research on Cancer (IARC) [5]. The infection rate of H. pylori is about 50% in adult world population [6], but only <1% develop gastric cancer [7], indicating that other factors such as host factors and genetic alterations may also be important in gastric carcinogenesis. Since the first promising markers of IL1B-511 and -31 polymorphisms in gastric cancer was identified [8], more and more evidence suggested that the polymorphisms of host cytokine genes may influence the outcome of H. pylori infection [9–11]. IL-23 is a heterodimeric cytokine comprised of a unique p19 subunit linked to a p40 subunit in common with IL-12. Likewise, IL-23 receptor is composed of interleukin-23 receptor (IL-23R) sub- unit and IL-12Rb1 subunit shared with IL-12R [12]. Although the structures and biological activities of IL-23 and IL-12 as well as their receptors are similar, IL-12/IL-12R is mainly involved in T helper (Th) 1-cell immune regulation while IL-23/IL-23R is MOLECULAR CARCINOGENESIS 49:862–868 (2010) ß 2010 WILEY-LISS, INC. Additional Supporting Information may be found in the online version of this article. Abbreviations: IL-23R, interleukin-23 receptor; Th, T helper; OR, odds ratio; CI, 95% confidence interval. Jianjian Chen and Yan Lu contributed equally to this work. *Correspondence to: Department of Epidemiology and Bio- statistics, Cancer Center, Nanjing Medical University, 140 Hanzhong Rd, Nanjing 210029, China. Received 27 October 2009; Revised 30 April 2010; Accepted 25 May 2010 DOI 10.1002/mc.20661 Published online 6 July 2010 in Wiley Online Library (wileyonlinelibrary.com)