SPP1 rs4754 and its epistatic interactions with SPARC polymorphisms in gastric cancer susceptibility

The matricellular glycoprotein products of the SPP1 and SPARC genes play critical roles in many aggressive tumor phenotypes including gastric cancer. We sought to test whether the polymorphisms of these two genes, individually or jointly, influence gastric cancer susceptibility. Nine potentially functional, tagging single nucleotide polymorphisms (tagSNPs) of SPP1 and SPARC were selected and detected using the Kompetitive Allele Specific PCR method in 301 gastric cancer cases and 1441 healthy control subjects. We found that the genotype frequencies of SPP1 rs4754 in gastric cancer were significantly different from those in controls. The rs4754 TT genotype conferred an increased risk of gastric cancer, with unadjusted and adjusted ORs ranging from 1.75 to 1.95 (all P0.05). The assessment of the effect modifications of sex and age on the genetic effects also confirmed the statistically significant association of the rs4754 TT genotype with increased gastric cancer risk. Epistatic interactions were found between SPP1 rs4754 and SPARC rs1054204, rs3210714 and rs3549 (all P values for interaction0.05). During the assessment of the epistatic effects between pairs of interacting factors, increased gastric cancer risk was observed in the combined presence of the SPP1 rs4754 TT genotype and the common genotypes of interacting SPARC SNPs, with ORs ranging from 3.94 to 4.41. When the genetic influence of SPP1 rs4754 TT was excluded, the genetic effects of the SPARC rs1054204, rs3210714 and rs3549 common genotypes on gastric cancer susceptibility switched from being risky to beneficial. These data reveal an association between the SPP1 rs4754 polymorphism and altered risk of gastric cancer and highlight an important role of the epistatic effects of SPP rs4754 with SPARC polymorphisms in gastric carcinogenesis. Additional functional experiments and independent large-scale studies, especially in other ethnic populations, are needed to confirm our results.