Carcinogenesis Advance Access originally published online on January 12, 2008
Carcinogenesis 2008 29(5):926-931; doi:10.1093/carcin/bgm241
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A pro-inflammatory genotype predisposes to Barrett's esophagus
Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, the Netherlands
1 Department of Health Risk Analysis and Toxicology, University of Maastricht, Postbus 616, 6200 MD Maastricht, the Netherlands
2 Department of Gastroenterology, IJsselland Hospital, 2906 ZC C Capelle aan den IJssel, the Netherlands
* To whom correspondence should be addressed. Tel: +31 10 4632792; Fax: +31 10 4632793; Email: hkusters{at}tergooiziekenhuizen.nl
Introduction: Severity of mucosal inflammation is shown to be associated with Barrett's esophagus (BE) development in animals. It has therefore been postulated that a strong pro-inflammatory host response predisposes to BE. Aim: To determine the impact of cytokine gene polymorphisms on the development of BE. Methods: The multiplex SNaPshotTM method was used to determine interleukin (IL)-12B (A+1188C), IL-10 (C–592A, C–819T, A–1082G), IL-8 (A–251T), IL-6 (G–174C) and IL-2 (G–330T) gene polymorphisms in 255 patients with BE and 247 patients with reflux esophagitis (RE). Results: The presence of the IL-12B C-allele, which is associated with increased IL-12p70 expression, was more frequently observed in BE than in RE patients [odds ratio (OR) 1.8; 95% confidence interval (CI) 1.2–2.7; P = 0.007). The risk of BE was increased in patients in whom the IL-12B C-allele coincided with a hiatal hernia (OR 2.9; 95% CI 1.32–6.58; P = 0.008). The IL-10–1082 GG genotype, which is associated with higher IL-10 levels, was also associated with a decreased risk of BE when it was associated with the IL-12B C-allele, indicating IL-10-dependent down-regulation of IL-12p70 expression. A combination of the IL-12B AA genotype and the IL-10 AA or AG genotypes was associated with RE (OR 1.4; 95% CI 1.05–1.85; P = 0.011). Conclusion: A genetic profile predisposing to a strong pro-inflammatory host response, mediated by IL-12p70 and partially dependent on IL-10, is associated with BE. This risk further increases when this genotype coincides with a hiatal hernia, suggesting that exposure to gastroesophageal reflux in the presence of a pro-inflammatory genetic background is a driving force in the development of BE.
Abbreviations: BE, Barrett's esophagus; CI, confidence interval; IL, interleukin; OR, odds ratio; PCR, polymerase chain reaction; RE, reflux esophagitis; SNP, single-nucleotide polymorphism
Received March 19, 2007; revised October 22, 2007; accepted October 24, 2007.
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