The −251T Allele of the Interleukin-8 Promoter Is Associated with Increased Risk of Gastric Carcinoma Featuring Diffuse-Type Histopathology in Chinese Population

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Abstract
Purpose: Persistent interleukin-8 (IL-8) production contributes to chronic inflammation of the stomach. The proinflammatory IL-1β polymorphisms, which enhance the cytokine production, are associated with increased risk of gastric cancer. The −251A/T polymorphism of the IL-8 promoter is involved in several human diseases. Particularly, the −251A is associated with decreased risk of colorectal cancer. We aimed to determine whether the −251 allele resulting in high IL-8 expression was associated with increased risk of gastric carcinoma.Experimental Design: The −251A/T promoters were cloned and analyzed by luciferase assay. Binding of nuclear proteins to the −251A/T promoters was analyzed by electrophoretic mobility shift assay. The −251A/T promoters were differentiated by PCR-RFLP. Comparison of gastric cancer risk between the −251A/T promoters was done by a case-control study.Results: The −251T allele possessed transcriptional activity 2- to 5-fold stronger than the −251A counterpart. Electrophoretic mobility shift assay showed that the −251A promoter had strong ability to bind to an unknown protein or multiprotein complex. The −251T allele was associated with increased risk of noncardia (Ptrend = 0.012) and cardia (Ptrend = 0.029) carcinomas. Gastric carcinoma patients with the low-risk AA genotype had a tendency to sustain intestinal-type carcinomas (χ2 = 6.816; P = 0.033); however, the high-risk −251T allele was associated with >2-fold increased risk of diffuse-type (AA versus AT + TT: odds ratio, 2.52; 95% confidence interval, 1.16-5.49; P = 0.017) and mixed-type (AA versus AT + TT: odds ratio, 2.22; 95% confidence interval, 1.12-4.40; P = 0.019) carcinomas.Conclusions: The IL-8 −251T allele is significantly associated with increased risk of gastric carcinoma, particularly the diffuse and mixed types in Chinese population.