Dr John Reynolds and colleagues from the United Kingdom investigated the association of genetic polymorphisms of the interleukin-18 (IL-18) pathway to Barrett's esophagus and esophageal adenocarcinoma.
Most cases of esophageal adenocarcinoma arise in a background of reflux-induced Barrett's esophagus.
Genetic influences in this pathway are poorly understood.
IL-18 is a multifunctional cytokine implicated in anti-tumor immunity.
|CC genotype was associated with an increased risk of Barrett's esophagus|
|American Journal of Gastroenterology|
A number of polymorphisms of the IL-18 and IL-18 receptor-accessory protein (IL-18RAP) genes have been reported to alter gene expression and have recently been linked to inflammatory processes and various tumors, but have not heretofore been studied in Barrett's esophagus and esophageal adenocarcinoma.
The research team analzyed 2 IL-18 promoter polymorphisms −137 G/C and −607 C/A, (rs187238 and rs1946518), and 1 IL-18RAP polymorphism (rs917997, C/T).
Each single-nucleotide polymorphism was genotyped in separate groups.
The team evaluated esophageal adenocarcinoma, Barrett's esophagus, reflux esophagitis, and controls for association with disease status.
The IL-18RAP rs917997C allele is strongly associated with a protective effect in Barrett's esophagus and esophageal adenocarcinoma, which approaches genome-wide levels of significance for allele association without incurring significant multiple testing.
The CC genotype at IL-18RAP locus rs917997 was associated with a protective effect against esophageal disease.
The genotype frequencies of IL-18−607 C/A were weakly associated with Barrett's esophagus, and this trend was also seen between controls and esophageal adenocarcinoma.
The researchers found that CC genotype was associated with an increased risk of Barrett's esophagus, and approached significance for esophageal adenocarcinoma.
Allele and genotype frequencies at these loci were not significantly different between the reflux esophagitis group and controls.
The team noted that although no significant association was observed between the disease groups at the –137 G/C locus, the −137G/−607C haplotype was associated with increased risk of Barrett's esophagus with haplotype frequencies of 55% in controls and 65% in Barrett's esophagus.
Dr Reynolds' team concludes, "These data show a strong association of the IL-18RAP single-nucleotide polymorphism rs917997 locus with Barrett's esophagus and esophageal adenocarcinoma and suggestive association of the Barrett's population with the IL-18−607 C/A promoter polymorphism."
"As both of these single-nucleotide polymorphisms have been demonstrated as expression quantitative trait loci affecting expression of the respective genes, this strongly implicates IL-18 signaling in susceptibility to Barrett's esophagus and esophageal adenocarcinoma."