Carcinogenesis Advance Access published online on January 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgm241
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A pro-inflammatory genotype predisposes to Barrett's esophagus
1 Department of Gastroenterology & Hepatology, Erasmus MC- University Medical Center Rotterdam, The Netherlands
2 Department of Health Risk Analysis & Toxicology, University of Maastricht, The Netherlands
3 Department of Gastroenterology, IJsselland Hospital, Capelle aan den IJssel, The Netherlands
* Corresponding author: Department of Gastroenterology & Hepatology, Erasmus MC - University Medical Center Rotterdam, L-459, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Phone: +31-10-4632792, Fax: +31-10-4632793, E-mail: 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 SNaP-shotTM method was used to determine 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.
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 reflux esophagitis patients (OR 1.8 95%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 downregulation of IL-12p70 expression. A combination of the IL-12B AA genotype and the IL-10 AA or AG genotypes was associated with reflux esophagitis (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.
Received March 19, 2007; revised October 22, 2007; accepted October 24, 2007.