World J Gastroenterol. 2010 April 14; 16(14): 1788-1794.
Published online 2010 April 14. doi: 10.3748/wjg.v16.i14.1788.
Inflammatory cytokine gene polymorphisms increase the risk of atrophic gastritis and intestinal metaplasia
Zhong-Wu Li, Ying Wu, Yu Sun, Lu-Ying Liu, Meng-Meng Tian, Guo-Shuang Feng, Wei-Cheng You and Ji-You Li.
Zhong-Wu Li, Ying Wu, Yu Sun, Lu-Ying Liu, Meng-Meng Tian, Ji-You Li, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, China
Guo-Shuang Feng, Wei-Cheng You, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Epidemiology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, China
Author contributions: Li ZW performed the majority of experiments and participated in the manuscript writing; Wu Y, Sun Y, Liu LY and Tian MM carried out part of the experiments; Feng GS performed the data analysis; You WC and Li JY designed the study and revised the manuscript.
Correspondence to: Ji-You Li, Professor, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, China. lijiyou@263.net
Telephone: +86-10-88192450 Fax: +86-10-88192437
Received December 16, 2009; Revised January 20, 2010; Accepted January 27, 2010;
Abstract
AIM: To investigate the effects of interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF) gene polymorphisms, Helicobacter pylori (H. pylori) infection, on the risk of developing severe chronic atrophic gastritis (SCAG) and intestinal metaplasia (IM).
METHODS: A total of 372 cases were selected from a cohort study in Linqu County, a high risk area for gastric cancer (GC) in northern China. To obtain a sufficient group size, patients with normal or superficial gastritis were included. Based on an average follow-up period of 56 mo, the 372 cases were divided into no progression group (no histological progression from normal or superficial gastritis, n = 137), group?I?(progressed from normal or superficial gastritis to SCAG, n = 134) and group II (progressed from normal or superficial gastritis to IM, n = 101). IL-8, MIF gene polymorphisms were detected by polymerase chain reaction-based denaturing high-performance liquid chromatography analysis and DNA sequencing.
RESULTS: An increased risk of SCAG was found in subjects with IL-8-251 AA genotype [odds ratio (OR) = 2.62, 95% CI: 1.23-5.72] or IL-8-251 A allele carriers (AA + AT) (OR = 1.81, 95% CI: 1.06-3.09). An elevated risk of IM was found in subjects with IL-8-251 AT genotype (OR = 2.27, 95% CI: 1.25-4.14) or IL-8-251 A allele carriers (OR = 2.07, 95% CI: 1.16-3.69). An increased risk of SCAG was found in subjects with MIF-173 GC genotype (OR = 2.36, 95% CI: 1.38-4.02) or MIF-173 C allele carriers (GC + CC) (OR = 2.07, 95% CI: 1.21-3.55). An elevated risk of IM was found in subjects with MIF-173 CC genotype (OR = 2.27, 95% CI: 1.16-4.46) or MIF-173 C allele carriers (OR = 3.84, 95% CI: 1.58-9.34). The risk of SCAG and IM was more evident in subjects carrying IL-8-251 A allele (OR = 6.70, 95% CI: 1.29-9.78) or MIF-173 C allele (OR = 6.54, 95% CI: 2.97-14.20) and positive for H. pylori infection.
CONCLUSION: IL-8-251 and MIF-173 gene polymorphisms are significantly associated with the risk of SCAG and IM in a population with a high risk of GC in Linqu County, Shandong Province, China.
Keywords: Chronic atrophic gastritis, Gene polymorphisms, Helicobacter pylori, Interleukin-8, Intestinal metaplasia, Macrophage migration inhibitory factor
INTRODUCTION
Atrophic gastritis (AG) and intestinal metaplasia (IM) are two important precursor lesions of intestinal type gastric cancer (GC)[1]. These precursor lesions may significantly elevate the risk of intestinal type GC[2,3].
Some bacterial factors, such as the pathogenic island of Helicobacter pylori (H. pylori) including cagA, sIm1 vacA, babA2, sabA, and oipA, are correlated with the severity of atrophic gastritis and occurrence of IM[4-9]. However, bacterial factors alone are not sufficient to explain the diverse results of H. pylori-related diseases. Our previous study has shown that the proportion of cagA + H. pylori strains in children living in Linqu County, an area with a high risk of GC in China, is very high (88.5%)[10]. It has also been demonstrated that almost 100% of H. pylori strains isolated from Chinese population are cagA positive[11].
There is increasing evidence that host inflammation-related cytokines and their gene polymorphisms are related with atrophic gastritis and IM[12,13]. Interleukin-8 (IL-8), a member of Cys-X-Cys (CXC) chemokine family, is an activator and chemoattractant of neutrophils and lymphocytes[14]. Gastric mucosal levels of IL-8 increase significantly after H. pylori infection and parallel to the severity of gastritis[15]. Macrophage migration inhibitory factor (MIF), an important activator of T lymphocytes and macrophages, plays a pivotal role in inflammatory and immune diseases[16,17]. H. pylori infection is associated with an increased expression of MIF mRNA and protein in gastric epithelial and inflammatory cells. Increased expression of the MIF protein correlates with histological severity of GC and its precursor[18].
As these inflammatory cytokines and their gene polymorphisms may potentially influence the outcome of H. pylori infection, a few studies have investigated the association of gene polymorphisms in these inflammatory cytokines with the risk of atrophy and IM[15,19,20].
However, these studies were limited by their single time-point assessment for pathological diagnosis. Therefore, we conducted a prospective study to investigate the association of IL-8 gene polymorphisms with the risk of atrophic gastritis, and MIF gene polymorphisms with IM, showing that the high expressing genotypes of IL-8 are significantly associated with the increased risks of severe chronic atrophic gastritis, and MIF is significantly associated with IM.