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Variants of the IL8 and IL8RB Genes and Risk for Gastric Cardia Adenocarcinoma and Esophageal Squamous Cell Carcinoma

¹ Pediatric Oncology Branch and ² Cancer Prevention Studies Branch, Center for Cancer Research and ³ Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland and ⁴ Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China

Requests for reprints: Sharon A. Savage, Section on Genomic Variation, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Advanced Technology Center, 8717 Grovemont Circle, Gaithersburg, MD 20892-4605. Phone: 301-435-2746; Fax: 301-402-3134. E-mail: savagesh{at}mail.nih.gov

The population of Linxian in north central China is at high risk for gastric cardia adenocarcinoma (GCC) and esophageal squamous cell carcinoma (ESCC), and chronic inflammation may contribute to this risk. Interleukin-8 (IL8), a potent chemoattractant, has three well-characterized single nucleotide polymorphisms (SNP), one (–251) of which alters transcriptional activity. Four well-described SNPs in the two IL8 receptors, IL8RA and IL8RB, have been associated with inflammation. We conducted a case-cohort study in the Nutrition Intervention Trials (Linxian, China) to assess the association between these SNPs and incident GCC (n = 90) and ESCC (n = 131). IL8, IL8RA, and IL8RB SNPs were analyzed using a multiplex assay system, haplotypes were constructed, and risks were estimated using Cox proportional hazards models. The homozygous variants of IL8 –251 and +396 were associated with 2-fold increased relative risks for GCC, but the highest risk observed was for the AGT/AGC haplotype of IL8 –251/+396/+781 (relative risk, 4.14; 95% confidence interval, 1.31-13.1). Variation within IL8 was not associated with ESCC. Few subjects had variation at the IL8RA SNP and no significant associations were observed for IL8RB SNPs or haplotypes with either GCC or ESCC. We conclude that variation in IL8 seems to increase the risk for GCC but not ESCC in this high-risk population. These variants could confer an altered IL8 expression pattern or interact with environmental factors to increase the risk for inflammation and GCC.

Key Words: Interleukin-8 • Lymphokines, cytokinesis, chemokinesis, and growth factors • Gastrointestinal cancers: stomach • Polymorphisms related to inflammation, immune response, oxidative damage

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