Te cancer risk supports the proposed role of the corresponding proteins in GNF-7 site prostate function and/or tumour development. It would be interesting to determine if genetic variations in these two genes affect individual response to chemopreventive agents such as thioredoxin reductase inhibitors. In addition, SelK has been proposed to play a role in the regulation of Ca2+ flux [32] and changes in Ca2+ flux have been suggested to be involved in the progression to hormone-insensitive prostate cancer [33]. The association of SNPs in TXNRD1 and TXNRD2 with disease risk was only observed in advanced stage or high grade cancers and not in localized low-grade cases. This may reflect a role for these selenoproteins in the progression of prostate cancers rather that initiation, especially in view of the reported relationship between thioredoxin reductase activity and tumour aggressiveness [29]; alternatively, there may be different etiologies for the localized, low grade and the advanced, high grade cancers with different roles for the selenoproteins in the two disease situations. We hypothesize that sub-optimal Se status and altered activity of TR1, TR2 and SelK modify the ability of prostate cells to combat oxidative and inflammatory challenges and so affect their growth and tumour progression. Selenoprotein expression in response to Se supplementation has been found to vary between individuals and some of these effects have been attributed to genetic polymorphisms in selenoproteins [34,35,36]. Synthesis of different selenoproteins responds differentially to sub-optimal Se intake [15,37,38] and since the protective effects of Se are thought to occur through selenoprotein biosynthesis one would expect potential genetic effects on prostate cancer risk to be modulated by Se status and vice versa. Since Se content of most foods depends on their geographical source Se intake is difficult to assess [1], but Se status can be assessed by measurement of blood biomarkers such as serum Se, plasma GPx or plasma SePP. SePP has been reported to be a better marker of status over a wider range of intake [12] than GPx3 but a MedChemExpress CP21 recent systematic review concluded that more information is needed to evaluate their strengths and weaknesses as biomarkers of Se status [11]. Therefore, in this study we measured three markers of Se status and analysed them independently. There were significant interactions between Se status and TXNRD1, TXNRD2 and SELK genotype with respect to high-grade or advanced stage prostate cancer, so emphasising the importance of the combination of Se intake and genotype in determining prostate cancer risk. Our observations that effects of Se-related SNPs on prostate cancer risk were observed only in combination with Se status provide a likely explanation of why gene variants in selenoprotein genes have not been identified as risk factors in a recent genome-wide association study [25]. The lack of significant association of genotype for single SNPs in SEPP1 or SEP15 on prostate cancer risk is consistent with earlier reports that also found no association of specific SNPs in these genes with prostate cancer risk [17,18]. However, in a nested case control study [17] variants in SEP15 were observed to beassociated with prostate cancer mortality. In the present study we were unable to assess effects on mortality. Large-scale Se supplementation trials in the USA have given contradictory outcomes with regards to evidence for a relationship between lower Se i.Te cancer risk supports the proposed role of the corresponding proteins in prostate function and/or tumour development. It would be interesting to determine if genetic variations in these two genes affect individual response to chemopreventive agents such as thioredoxin reductase inhibitors. In addition, SelK has been proposed to play a role in the regulation of Ca2+ flux [32] and changes in Ca2+ flux have been suggested to be involved in the progression to hormone-insensitive prostate cancer [33]. The association of SNPs in TXNRD1 and TXNRD2 with disease risk was only observed in advanced stage or high grade cancers and not in localized low-grade cases. This may reflect a role for these selenoproteins in the progression of prostate cancers rather that initiation, especially in view of the reported relationship between thioredoxin reductase activity and tumour aggressiveness [29]; alternatively, there may be different etiologies for the localized, low grade and the advanced, high grade cancers with different roles for the selenoproteins in the two disease situations. We hypothesize that sub-optimal Se status and altered activity of TR1, TR2 and SelK modify the ability of prostate cells to combat oxidative and inflammatory challenges and so affect their growth and tumour progression. Selenoprotein expression in response to Se supplementation has been found to vary between individuals and some of these effects have been attributed to genetic polymorphisms in selenoproteins [34,35,36]. Synthesis of different selenoproteins responds differentially to sub-optimal Se intake [15,37,38] and since the protective effects of Se are thought to occur through selenoprotein biosynthesis one would expect potential genetic effects on prostate cancer risk to be modulated by Se status and vice versa. Since Se content of most foods depends on their geographical source Se intake is difficult to assess [1], but Se status can be assessed by measurement of blood biomarkers such as serum Se, plasma GPx or plasma SePP. SePP has been reported to be a better marker of status over a wider range of intake [12] than GPx3 but a recent systematic review concluded that more information is needed to evaluate their strengths and weaknesses as biomarkers of Se status [11]. Therefore, in this study we measured three markers of Se status and analysed them independently. There were significant interactions between Se status and TXNRD1, TXNRD2 and SELK genotype with respect to high-grade or advanced stage prostate cancer, so emphasising the importance of the combination of Se intake and genotype in determining prostate cancer risk. Our observations that effects of Se-related SNPs on prostate cancer risk were observed only in combination with Se status provide a likely explanation of why gene variants in selenoprotein genes have not been identified as risk factors in a recent genome-wide association study [25]. The lack of significant association of genotype for single SNPs in SEPP1 or SEP15 on prostate cancer risk is consistent with earlier reports that also found no association of specific SNPs in these genes with prostate cancer risk [17,18]. However, in a nested case control study [17] variants in SEP15 were observed to beassociated with prostate cancer mortality. In the present study we were unable to assess effects on mortality. Large-scale Se supplementation trials in the USA have given contradictory outcomes with regards to evidence for a relationship between lower Se i.