MiRNA-related SNPs and risk of esophageal adenocarcinoma and Barrett's esophagus: Post genome-wide association analysis in the BEACON consortium
Buas, Matthew Frank
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The incidence of esophageal adenocarcinoma (EA) has increased significantly in recent decades. Although several major risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, only limited knowledge exists regarding the role of inherited genetic variation and its interplay with environmental factors. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently completed a genome-wide association study (GWAS) of 1,517 EA cases, 2,416 BE cases, and 2,187 controls. Using this dataset, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), a class of small non-coding RNAs that regulate post-transcriptional gene expression and are deregulated in many cancers, including EA. Polymorphisms in three classes of genes were evaluated for their association with risk of EA or BE: 1) miRNA biogenesis genes (157 SNPs / 21 genes), 2) miRNA gene loci (234 SNPs / 210 genes), and 3) miRNA-targeted mRNAs (179 SNPs / 158 genes). 28 SNPs were nominally associated (P<0.05) with EA, and 34 with BE, compared to 29 expected by chance for each condition. A polymorphism located in a predicted miRNA-138 binding site of the DNA repair gene XRCC1 (rs1799782) was the top hit identified in either analysis (per allele OR 0.68 for EA, 95% CI 0.55-0.83, p=0.00025), with a p-value approaching but not reaching the Bonferroni threshold for significance (alpha=8.8 x 10-5) after correction for multiple comparisons. This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While chance alone may account for the reported findings, follow-up studies are underway using an expanded sample set with an additional 1,000 EA cases and 1,000 controls to further evaluate whether genetic variation in this pathway correlates with disease susceptibility and interacts with known risk factors.
- Epidemiology