Genes of the interleukin-18 pathway are associated with susceptibility to barrett's esophagus and esophageal adenocarcinoma

Mahwash Babar, Anthony W. Ryan, Lesley A. Anderson, Ricardo Segurado, Graham Turner, Liam J. Murray, Seamus J. Murphy, Brian T. Johnston, Harry Comber, John V. Reynolds*, Ross McManus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Objectives:To investigate the association of genetic polymorphisms of the interleukin-18 (IL-18) pathway to Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Most cases of EAC arise in a background of reflux-induced BE. Genetic influences in this pathway are poorly understood. IL-18 is a multifunctional cytokine implicated in anti-tumor immunity. 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 BE and EAC.METHODS:Two IL-18 promoter polymorphisms 137 G/C and 607 C/A, (rs187238 and rs1946518) and one IL-18RAP polymorphism (rs917997, C/T) were analyzed. Each single-nucleotide polymorphism (SNP) was genotyped in the following groups: EAC, BE, reflux esophagitis (RE), and controls and analyzed for association with disease status.RESULTS:The IL-18RAP rs917997C allele is strongly associated with a protective effect in BE (P0.0002) and EAC (P6 × 10 7), 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 (P6 × 10 4, odds ratio (OR)0.59, and 95% confidence interval (CI) 0.43-0.80 for BE; and P2 × 10 6, OR0.46, and 95% CI 0.34-0.64 for EAC). The genotype frequencies of IL-18607 C/A were weakly associated with BE (P0.02), and this trend was also seen between controls and EAC (P0.07). The CC genotype was associated with an increased risk of BE (OR1.45, 95% CI 1.07-1.98) and approached significance for EAC (OR1.34, 95% CI 0.98-1.82). Allele and genotype frequencies at these loci were not significantly different between the RE group and controls. 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 BE (P0.006) with haplotype frequencies of 55% in controls and 65% in BE.CONCLUSIONS:These data show a strong association of the IL-18RAP SNP rs917997 locus with BE and EAC and suggestive association of the Barrett's population with the IL-18607 C/A promoter polymorphism. As both of these SNPs have been demonstrated as expression quantitative trait loci affecting expression of the respective genes, this strongly implicates IL-18 signaling in susceptibility to BE and EAC.

Original languageEnglish
Pages (from-to)1331-1341
Number of pages11
JournalAmerican journal of gastroenterology
Volume107
Issue number9
Early online date5 Jun 2012
DOIs
Publication statusPublished - Sep 2012

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