G-A variant in miR-200c binding site of EFNA1 alters susceptibility to gastric cancer.

MicroRNAs (miRNAs) post-transcriptionally modulate gene expression by binding to complementary sites at 3'-untranslated regions (3'UTRs) of their target messenger RNAs (mRNAs). Genetic variations in miRNA binding sites may alter individual susceptibilities to many cancers. However, whether miRNA binding site single nucleotide polymorphisms (SNPs) interfere with gastric cancer (GC) susceptibility has not been reported. In this case-control study including 525 GC patients and 501 controls, we selected three miRNA binding site SNPs located in 3'UTRs of genes involved in GC to investigated their associations with GC susceptibility. We identified that rs12904 in ephrin-A1 (EFNA1) gene was significantly associated with risk of GC, with the OR for carrying AG or GG genotype being 0.65 (P = 0.002, OR 0.65; 95% CI, 0.50-0.85) compared with AA genotype. Specifically, we found that rs12904 is in strong linkage disequilibrium (LD) with rs4072037, a susceptibility variant reported by previous genome-wide association study (GWAS). No significant associations were observed for the other two SNPs (rs699517 in TYMS and rs1042542 in BIRC5). Furthermore, luciferase assays indicated EFNA1 as the target of hsa-miR-200c and rs12904 G > A change resulted in altered regulation of luciferase expression. In addition, rs12904 AA genotype was associated with increased expression of EFNA1 mRNA compared with AG or GG genotype in the cancer tissues from 48 patients. Taken together, these findings indicate that the miR-200c binding site SNP (rs12904 G > A) in the 3'UTR of EFNA1 can modulate EFNA1 expression and is associated with GC susceptibility. Larger replication studies are needed to confirm our findings.