A Functional Polymorphism (rs2494752) in the AKT1 Promoter Region and Gastric Adenocarcinoma Risk in an Eastern Chinese Population

Abstract

AKT is an important signal transduction protein that plays a crucial role in cancer development. Therefore, we evaluated associations between single nucleotide polymorphisms (SNPs) in the AKT promoter region and gastric cancer (GCa) risk in a case-control study of 1,110 GCa patients and 1,114 matched cancer-free controls. We genotyped five SNPs (AKT1 rs2494750G >C, AKT1 rs2494752A >G, AKT1 rs10138227C >T, AKT2 rs7254617G>A and AKT2 rs2304186G >T) located in the 5' upstream regulatory, first intron or promoter regions. In the logistic regression analysis, a significantly elevated GCa risk was associated with the rs2494752 AG/GG variant genotypes (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02-1.42) under a dominant genetic model, and this risk was more evident in subgroups of ever drinkers. The luciferase reporter assay showed that the rs2494752 G allele significantly increased luciferase activity. Our results suggest that the potentially functional AKT1 rs2494752 SNP may affect GCa susceptibility, likely by modulating the AKT1 promoter transcriptional activity. Larger, independent studies are warranted to validate our findings.

Figure 1. Effect of the AKT1 rs2494752 polymorphism on the AKT1 promoter activity.

(A) Schematic representation of reporter plasmids containing the AKT1 rs2494752 A or G allele, which was inserted at upstream of the luciferase reporter gene in the pGL3-Basic plasmid. (B) The two constructs were transiently transfected into the Hela, SGC-7901, HGC-27 and AGS cells, respectively. All of the constructs were cotransfected with pRL-SV40 to standardize the transfection efficiency. Values were means ± SD from more than 3 separate experiments that were each performed in triplicate.

Figure 2. Linkage disequilibrium (LD) blocks of the AKT1/AKT2 genes.

(A) Pairwise LD among three selected AKT1 SNPs. The value within each diamond represents the pairwise correlation between SNPs (measured as r²) defined by the upper left and the upper right sides of the diamond. The red-to-white gradient reflects higher to lower LD values. (B) Pairwise LD among two selected SNPs of AKT2.