Associations of genotypes and haplotypes of IL-17 with risk of gastric cancer in an eastern Chinese population.

Fei Zhou,Meng-Hong Sun,Ya-Nong Wang,Qing-Yi Wei,Jiu-Cun Wang,Ya-Jun Yang,Lei Cheng,Meng-Yun Wang,Li-Xin Qiu,Li Jin,Jin Li

doi:10.18632/oncotarget.11616

Abstract

Interleukin-17 plays a crucial role in inflammation-related carcinogenesis. We hypothesize that genetic variants in IL-17 are associated with gastric cancer (GCa) risk, and we genotyped five potentially functional single nucleotide polymorphisms (SNPs) (rs1974226 G > A, rs2275913 A > G, rs3819024 A > G, rs4711998 A > G, and rs8193036 C > T) of IL-17 in 1121 GCa patients and 1216 cancer-free controls in an eastern Chinese population. Logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Meta-analysis and genotype-mRNA expression correlation were performed to further validate positive associations. We found that an increased GCa risk was independently associated with rs1974226 (adjusted OR = 2.60, 95% CI = 1.27–5.32 for AA vs. GG + GA) and rs2275913 (adjusted OR = 1.33, 95% CI = 1.03–1.72 for GA + AA vs. GG), while a decreased GCa risk was independently associated with rs3819024 (adjusted OR = 0.72, 95% CI = 0.54–0.96 for GG vs. AA + AG). Additional meta-analyses confirmed the observed risk association with rs2275913. We also found that two IL-17 haplotypes (G-G-G-A-C) and (A-G-G-A-C) (in the order of rs1974226, rs2275913, rs3819024, rs4711998 and rs8193036) were associated with a reduced GCa risk (adjusted OR = 0.64, 95% CI = 0.46–0.89 and adjusted OR = 0.38, 95% CI = 0.17–0.81, respectively). However, the expression Quantitative Trait Locus (eQTL) analysis for the genotype-phenotype correlation did not find mRNA expression changes associated with either the genotypes. In conclusions, genetic variants of IL-17 are likely to be associated with risk of GCa, and additional larger studies with functional validation are needed to explore the molecular mechanisms underlying the observed associations.

Highlights

Despite the advances in its diagnosis and therapy, gastric cancer (GCa) remains a great burden worldwide as the fifth most diagnosed cancer and the third most common cause for cancer-related deaths [1]
We found that an increased GCa risk was independently associated with rs1974226 and rs2275913, while a decreased GCa risk was independently associated with rs3819024
We found that two IL-17 haplotypes (G-G-G-A-C) and (A-G-G-A-C) were associated with a reduced GCa risk

Summary

Introduction

Despite the advances in its diagnosis and therapy, gastric cancer (GCa) remains a great burden worldwide as the fifth most diagnosed cancer and the third most common cause for cancer-related deaths [1]. The development of GCa is closely associated with personal lifestyles, such as smoking consumption, alcohol drinking and diet habit [3], the majority of GCa cases is attributable to the infection of Helicobacter pylori (H. pylori) and some to Epstein-Barr virus (EBV) [4, 5]. Only a fraction of individuals who were exposed to these environmental factors eventually developed GCa, suggesting that genetic predisposition may have played an essential role in gastric carcinogenesis. IL-17 transcripts have been observed to be higher in mucosal biopsies of H. pylori-infected gastritis patients, for those with chronic inflammation [10]. As infection-induced chronic gastritis is a major factor in histological development of GCa [12, 13], IL-17 has been speculated to play an important role in gastric pathogenesis

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Conclusion