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


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.


CONCLUSIONS
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.
Zhai
Rihong
R
Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA. rzhai@hsph.harvard.edu
Chen
Feng
F
Liu
Geoffrey
G
Su
Li
L
Kulke
Matthew H
MH
Asomaning
Kofi
K
Lin
Xihong
X
Heist
Rebecca S
RS
Nishioka
Norman S
NS
Sheu
Chau-Chyun
CC
Wain
John C
JC
Christiani
David C
DC
D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D015992:Body Mass Index; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005163:Factor Analysis, Statistical; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D016013:Likelihood Functions; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
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