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

Authors' Affilliations: ¹ Division of Gastroenterology, Department of Medicine, ² Department of Pathology, and ³ Cancer Center, Taipei Veterans General Hospital; ⁴ Department and Institute of Biochemistry, ⁵ Department and Institute of Pharmacology, and ⁶ School of Medicine, National Yang-Ming University; and ⁷ Department of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan; and ⁸ The Liver Research Unit, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

Requests for reprints: Wei-Ping Lee, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201 Shi-Pai Road Section 2, Taipei 112, Taiwan. Phone: 886-2-28712121-2017; Fax: 886-2-2874-9425; E-mail: wleemc{at}yahoo.com.

Purpose: Persistent interleukin-8 (IL-8) production contributes to chronic inflammation of the stomach. The proinflammatory IL-1ß 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 (P_trend = 0.012) and cardia (P_trend = 0.029) carcinomas. Gastric carcinoma patients with the low-risk AA genotype had a tendency to sustain intestinal-type carcinomas (² = 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.

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