Selenium may affect prostate cancer risk via its plasma carrier selenoprotein P 
which shows dramatically reduced expression in prostate cancer tumors and cell 
lines. The selenoprotein P (SEPP1) Ala234 single nucleotide polymorphism (SNP) 
allele is associated with lower plasma selenoprotein P in men, reducing the 
concentration/activity of other antioxidant selenoproteins. Selenium status also 
modifies the effect of the mitochondrial superoxide dismutase (SOD2) SNP 
Ala16Val on prostate cancer risk. We investigated the relationship of these SNPs 
with prostate cancer risk. DNA from 2,975 cases and 1,896 age-matched controls 
from the population-based Prostate Cancer in Sweden study were genotyped using 
TaqMan assays. Cases were designated aggressive or nonaggressive prostate 
cancers at diagnosis by clinical criteria. Association with prostate cancer was 
investigated by logistic regression; gene-gene interaction using a general 
linear model. The mean plasma selenium concentration measured in 169 controls 
was relatively low (76.0 +/- 17.2 microg/L). SNP genotype distributions were in 
Hardy-Weinberg equilibrium. SOD2-Ala16+ men were at a greater risk of prostate 
cancer [odds ratios (OR), 1.19; 95% confidence intervals (CI), 1.03-1.37] 
compared with SOD2-Val16 homozygotes. Men homozygous for SEPP1-Ala234 who were 
also SOD2-Ala16+ had a higher risk of prostate cancer (OR, 1.43; 95% CI, 
1.17-1.76) and aggressive prostate cancer (OR, 1.60; 95% CI, 1.22-2.09) than 
those who were SOD2-Val16 homozygotes (interaction, prostate cancer P = 0.05; 
aggressive prostate cancer P = 0.01). This interaction was stronger in 
ever-smokers: SOD2-Ala16+ men homozygous for SEPP1-Ala234 had an almost doubled 
risk of prostate cancer (OR, 1.97; 95% CI, 1.33-2.91; interaction P = 0.001). In 
a low-selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at an 
increased risk of prostate cancer/aggressive prostate cancer especially if 
ever-smokers, because they are likely to produce more mitochondrial H(2)O(2) 
that they cannot remove, thereby promoting prostate tumor cell proliferation and 
migration.