title: Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.
abstract: How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene-environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene-environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08-2.58 times [interaction odds ratio (ORi)=2.08-2.58, adjusted P-value (Padj)=0.02-0.04]. Compared with patients carrying ≤1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi=1.89, Padj=0.016) or ≥3 (ORi=4.30, Padj<0.0001) risk genotypes. Compared with cases with ≤1 risk genotype, smoking-associated EA risk increased by 3.15 times when ≥2 risk genotypes were present (ORi=3.15, Padj<0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development.
authors.affiliation: Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, and Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rihong
authors.initials: R
authors.lastname: Zhai
authors.forename: Chen-yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Monica
authors.initials: M
authors.lastname: Ter-Minassian
authors.forename: Kofi
authors.initials: K
authors.lastname: Asomaning
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D017209:Apoptosis; D053179:Caspase 7 / Q000235:genetics; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D012306:Risk; D012907:Smoking / Q000009:adverse effects*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C505520:CASP7 protein, human; D053179:Caspase 7