The Cumulative Effect of Gene-Gene and Gene-Environment Interactions on the Risk of Prostate Cancer in Chinese Men

Abstract

Prostate cancer (PCa) is a multifactorial disease involving complex genetic and environmental factors interactions. Gene-gene and gene-environment interactions associated with PCa in Chinese men are less studied. We explored the association between 36 SNPs and PCa in 574 subjects from northern China. Body mass index (BMI), smoking, and alcohol consumption were determined through self-administered questionnaires in 134 PCa patients. Then gene-gene and gene-environment interactions among the PCa-associated SNPs were analyzed using the generalized multifactor dimensionality reduction (GMDR) and logistic regression methods. Allelic and genotypic association analyses showed that six variants were associated with PCa and the cumulative effect suggested men who carried any combination of 1, 2, or ≥3 risk genotypes had a gradually increased PCa risk (odds ratios (ORs) = 1.79-4.41). GMDR analysis identified the best gene-gene interaction model with scores of 10 for both the cross-validation consistency and sign tests. For gene-environment interactions, rs6983561 CC and rs16901966 GG in individuals with a BMI ≥ 28 had ORs of 7.66 (p = 0.032) and 5.33 (p = 0.046), respectively. rs7679673 CC + CA and rs12653946 TT in individuals that smoked had ORs of 2.77 (p = 0.007) and 3.11 (p = 0.024), respectively. rs7679673 CC in individuals that consumed alcohol had an OR of 4.37 (p = 0.041). These results suggest that polymorphisms, either individually or by interacting with other genes or environmental factors, contribute to an increased risk of PCa.

Keywords: gene-environment interaction; gene-gene interaction; prostate cancer; single nucleotide polymorphism.

Figure 1

The best age-adjusted GMDR model for gene-gene interaction. The best model is composed of rs16901966, rs11986220, rs1983891, and rs339331. In each cell, the left bar represents a positive score, and the right bar a negative score. High-risk cells are indicated by dark shading, low-risk cells by light shading, and empty cells by no shading. The patterns of high-risk and low-risk cells differ across each of the different multilocus dimensions, presenting evidence of epistasis.

Figure 2

Gene-gene interaction dendrogram. The strongly interacting SNPs appear close together at the leaves of the tree (rs16901966 and 1983891), and the weakly interacting SNPs appear distant from each other.