Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus

Abstract

Background & aims: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE.

Methods: We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions.

Results: For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10^-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10^-7, P = 1.83×10^-7, and P = 3.58×10^-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10^-7) and pack-years of smoking history (P = 2.82×10^-7), respectively.

Conclusion: The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

Keywords: Esophageal Neoplasm; Esophagus; Genetic Variants; Risk Factors.

Figure 1

Regional association plots for genotyped single nucleotide polymorphisms (SNPs) showing P values for interaction for (A) smoking status and (B) recurrent gastroesophageal reflux disease symptoms in esophageal adenocarcinoma and (C) body mass index and (D) pack-years of smoking exposure in Barrett’s esophagus. The SNPs in Table 2 are shown as a solid purple diamond, except in panel B where rs2341926 and rs13396805 are shown as circles near rs12465911. The color scheme indicates linkage disequilibrium between the SNP shown with a solid purple diamond and other SNPs in the region using the r² value calculated from the 1000 Genomes Project. The y axis is the −log10 interaction P value computed from 5388 cases (3104 Barrett’s esophagus, 2284 esophageal adenocarcinoma) and 2182 control subjects. The recombination rate from CEU HapMap data (right-side y axis) is shown in light blue. (A) Chromosome 2p25.1; (B) chromosome 2q23.3 region; (C) chromosome 1p34.3 region; (D) chromosome 15q14 region.