Interactions between environmental factors and polymorphisms in angiogenesis pathway genes in esophageal adenocarcinoma risk: A case‐only study

Abstract

BACKGROUND Gastroesophageal reflux symptoms (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma (EA). However, how angiogenic gene polymorphisms and environmental factors jointly affect EA development remains unclear. METHODS Using a case-only design (n = 335), we examined interaction between 141 functional/tagging angiogenic SNPs and environmental factors (GERD, BMI, smoking) in modulating EA risk. Gene-environment interactions were assessed by a two-step approach. First, we applied random forest (RF) to screen for important SNPs that had either main or interaction effects. Second, we used case-only logistic regression (LR) to assess the effects of gene-environment interactions on EA risk, adjusting for covariates and false-discovery rate (FDR). RESULTS RF analyses identified three sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent LR analyses, interactions between 3 SNPs (rs2295778 of HIF1AN, rs133376 of TSC2, and rs2519757 of TSC1) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 (VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs3756309 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with EA development (all FDR ≤0.10). Moreover, these interactions tended to have a SNP dose-response effects for increased EA risk with increasing number of combined risk genotypes. CONCLUSIONS These findings suggest that genetic variations in angiogenic genes may modify EA susceptibility through interactions with environmental factors in a SNP dose-response manner.

Challenges and opportunities in genome-wide environmental interaction (GWEI) studies

“…The authors used a simple solution to handle family structure within their data by considering a binary family indicator as covariate for building the random forest. Similarly, Zhai et al (2011) performed a 2-step approach with initial screening for SNPs associated to environmental measures by random forest and further analysis based on case-only logistic regression to obtain parameter estimates for the selected variables.…”

Neoangiogenesis. Assessment in Esophageal Adenocarcinomas

“…The association of chronic inflammation with carcinogenesis has been reported in the literature [5] as well as the association of risk factors to neoangiogenesis for Barrett's esophagus [6]. The relation between neoangiogenesis and inflammatory process may be considered a prominent aspect of esophageal adenocarcinoma.…”

A Newly Identified Susceptibility Locus nearFOXP1Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

“…Several previous studies have pursued candidate-based GxE analyses of EA, and described potential interactions between GERD, smoking, or BMI and variants in a number of different genes related to detoxification, angiogenesis, DNA repair, apoptosis, and extracellular matrix degradation (27–31). These studies, however, were all limited by small sample sizes and lack of independent confirmation, and interactions in relation to risk of BE were not examined.…”

“…Some gene-exposure interactions have also been identified using the candidate gene approach, e.g. smoking and variants of GSTM1 , GSTT1 and VEGF (26–31). Few of the previously reported variants have been replicated and more systematic studies are warranted.…”