title: Interactions between environmental factors and polymorphisms in angiogenesis pathway genes in esophageal adenocarcinoma risk: a case-only study.
abstract: BACKGROUND
  Gastroesophageal reflux disease (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma. However, how angiogenic gene polymorphisms and environmental factors jointly affect esophageal adenocarcinoma development remains unclear.
  
  
  METHODS
  By using a case-only design (n = 335), the authors examined interactions between 141 functional/tagging angiogenic single nucleotide polymorphisms (SNPs) and environmental factors (GERD, BMI, smoking) in modulating esophageal adenocarcinoma risk. Gene-environment interactions were assessed by a 2-step approach. First, the authors applied random forest to screen for important SNPs that had either main or interaction effects. Second, they used case-only logistic regression to assess the effects of gene-environment interactions on esophageal adenocarcinoma risk, adjusting for covariates and false-discovery rate.
  
  
  RESULTS
  Random forest analyses identified 3 sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent logistic regression analyses, interactions between 2 SNPs (rs2295778 of HIF1AN, rs13337626 of TSC2) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 of VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs17708574 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with esophageal adenocarcinoma development (all false-discovery rates ≤0.10). Moreover, these interactions tended to have SNP dose-response effects for increased esophageal adenocarcinoma risk with increasing number of combined risk genotypes.
  
  
  CONCLUSIONS
  These findings suggest that genetic variations in angiogenic genes may modify esophageal adenocarcinoma susceptibility through interactions with environmental factors in an SNP dose-response manner.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115, USA. rzhai@hsph.harvard.edu
authors.forename: Rihong
authors.initials: R
authors.lastname: Zhai
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: Monica
authors.initials: M
authors.lastname: Ter-Minassian
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Wu
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Kofi
authors.initials: K
authors.lastname: Asomaning
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: John C
authors.initials: JC
authors.lastname: Wain
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology*; D042501:Angiogenic Proteins / Q000235:genetics*; D015992:Body Mass Index; D004273:DNA, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000209:etiology*; D005260:Female; D005764:Gastroesophageal Reflux / Q000209:etiology; D059647:Gene-Environment Interaction; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction; D012907:Smoking
chemical_list: D042501:Angiogenic Proteins; D004273:DNA, Neoplasm