Novel functional variants locus in PLCE1 and susceptibility to esophageal squamous cell carcinoma: based on published genome-wide association studies in a central Chinese population.

A novel functional single nucleotide polymorphism (SNP) rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with the risk of esophageal squamous cell carcinoma (ESCC) by three large-scale genome-wide association studies (GWAS) in Chinese populations. In the present study, we validated this finding and also explored the risk of ESCC associated with other two unreported potentially functional SNPs (rs17417407 G>T and rs2274224 C>G) of PLCE1 in a population-based case-control study to investigate the association between these three potentially functional SNPs in PLCE1 and susceptibility to ESCC. A total of 381 ESCC cases and 420 controls matched by age and sex were recruited and successfully genotyped for three SNPs (rs17417407, rs2274223 and rs2274224) of the PLCE1 in a central Chinese population. SNP rs2274223 was independently associated with increased risk of ESCC (adjusted odds ratio [OR], 2.80; 95% confidence interval [95% CI], 1.45-5.39 for GG vs. AA), and SNP rs2274224 was found to be associated with decreased risk of ESCC (adjusted OR, 0.65; 95% CI, 0.46-0.91 for CG vs. CC). The combined effects of risk alleles for three SNPs (rs17417407T, rs2274223G and rs2274224G) were found to be associated with elevated risk of ESCC in a dose-dependent effect manner (Ptrend=0.005). The Grs17417407Ars2274223Crs2274224 haplotype decreased the risk of ESCC (adjusted OR, 0.76; 95% CI, 0.62-0.93), meanwhile the Grs17417407Grs2274223Crs2274224 and Trs17417407Grs2274223Crs2274224 haplotypes could increase the risk of ESCC (adjusted OR, 1.75; 95% CI, 1.33-2.18 and OR, 2.51; 95% CI, 1.15-2.49). Gene-environment interaction analysis presented a best model consisted of four factors (rs2274223, rs2274224, family history, and smoking) with testing balance accuracy (TBA): 0.66 and cross validation consistency (CVC): 7/10, which could increase the esophageal cancer risk in the "high risk group" with 3.67-fold (OR: 3.67, 95% CI: 2.74-4.92), compared to the "low risk group". Our results further confirmed that genetic variations in PLCE1 may contribute to ESCC risk associated with tobacco exposure in a central Chinese population. Further functional studies are needed to validate our results.