Association of Interleukin-18 Gene Promoter −607 C>A and −137G>C Polymorphisms with Cancer Risk: A Meta-Analysis of 26 Studies

BACKGROUND: Evidence suggest that IL-18 gene polymorphisms may be risk factors for several cancers. Increasing studies investigating the association between IL-18 gene promoter polymorphisms (−607 C>A and −137G>C) and cancer risk have yielded conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: We performed a meta-analysis of 26 studies including 4096 cases and 5222 controls. We assessed the strength of the association of IL-18 gene promoter −607 C>A and −137G>C polymorphisms with cancer risk and performed sub-group analyses by cancer types, ethnicities, source of controls and sample size. The pooled results revealed a significant increased risk of cancer susceptibility for −607 C>A (CA vs. CC: OR = 1.19, 95%CI: 1.04, 1.37, P(heterogeneity) = 0.033; CA/AA vs. CC: OR = 1.17, 95% CI: 1.01, 1.34, P(heterogeneity) = 0.007), but no significant association for −137 G>C was observed with overall cancer risk. Sub-group analyses revealed that an increased risk of nasopharyngeal carcinoma was both found for −607 C>A (CA/AA vs. CC: OR = 1.32, 95% CI: 1.04, 1.69, P(heterogeneity) = 0.823) and −137G>C (GC/CC vs. GG: OR = 1.57, 95%CI: 1.26, 1.96, P(heterogeneity) = 0.373). Consistent with the results of the genotyping analyses, the −607A/−137C and −607C/−137C haplotypes were associated with a significantly increased risk of nasopharyngeal carcinoma as compared with the −607C/−137G haplotype (−607A/−137C vs. −607C/−137G: OR = 1.26, 95%CI: 1.13, 1.40; P(heterogeneity) = 0.569; −607C/−137C vs. −607C/−137G: OR = 1.14, 95%CI: 1.03, 1.27; P(heterogeneity) = 0.775). As for gastrointestinal cancer, we also found that −607 C>A polymorphism was significantly associated with increased cancer risk (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50, P(heterogeneity) = 0.458). Further sub-group analysis revealed that −137G>C polymorphism contributed to cancer risk in Asians but not in Caucasians (GC/CC vs. GG: OR = 1.31, 95%CI: 1.05, 1.64, P(heterogeneity)<0.001). CONCLUSIONS: The meta-analysis results suggest that IL-18 gene promoter −607 C>A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the −137 G>C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increases the risk of nasopharyngeal carcinoma.