Interactions among genetic variants in apoptosis pathway genes, reflux symptoms, body mass index, and smoking indicate two distinct etiologic patterns of esophageal adenocarcinoma

Abstract

Purpose: Apoptosis pathway, gastroesophageal reflux symptoms (reflux), higher body mass index (BMI), and tobacco smoking have been individually associated with esophageal adenocarcinoma (EA) development. However, how multiple factors jointly affect EA risk remains unclear.

Patients and methods: In total, 305 patients with EA and 339 age- and sex-matched controls were studied. High-order interactions among reflux, BMI, smoking, and functional polymorphisms in five apoptotic genes (FAS, FASL, IL1B, TP53BP, and BAT3) were investigated by entropy-based multifactor dimensionality reduction (MDR), classification and regression tree (CART), and traditional logistic regression (LR) models.

Results: In LR analysis, reflux, BMI, and smoking were significantly associated with EA risk, with reflux as the strongest individual factor. No individual single nucleotide polymorphism was associated with EA susceptibility. However, there was a two-way interaction between IL1B + 3954C>T and reflux (P = .008). In both CART and MDR analyses, reflux was also the strongest individual factor for EA risk. In individuals with reflux symptoms, CART analysis indicated that strongest interaction was among variant genotypes of IL1B + 3954C>T and BAT3S625P, higher BMI, and smoking (odds ratio [OR], 5.76; 95% CI, 2.48 to 13.38), a finding independently found using MDR analysis. In contrast, for participants without reflux symptoms, the strongest interaction was found between higher BMI and smoking (OR, 3.27; 95% CI, 1.88 to 5.68), also echoed by entropy-based MDR analysis.

Conclusion: Although a history of reflux is an important risk for EA, multifactor interactions also play important roles in EA risk. Gene-environment interaction patterns differ between patients with and without reflux symptoms.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Classification and regression tree analysis of reflux, body mass index (BMI), smoking, and genetic polymorphisms in apoptosis pathway. Terminal nodes show number of esophageal adenocarcinoma (EA) patients/number of controls. Single nucleotide polymorphisms were classified as wild type (w) and variant genotype (v); smoking was defined as ever and never smoking; BMI was categorized as ≥ 25 and

Fig A1.

Interaction map for esophageal adenocarcinoma risk. Values in nodes represent information gain (IG) of individual attribute (main effect). Values between nodes are IGs of each pairwise combination of attributes (interaction effects). A positive entropy (plotted in red or orange) indicates interaction while a negative (plotted in green or blue) indicates redundancy. (A) Overall interaction map; (B) interaction map for subjects with reflux symptoms; (C) interaction map for individuals without reflux symptoms. GERD, gastroesophageal reflux disease; BMI, body mass index.