Studies have reported prostate cancer associations with members of the toll-like receptor family [6,12,16]. In particular Sun et al. [12] observed multiple SNPs in strong linkage disequilibrium located on TLR1, TLR6, and TLR10 associated with prostate cancer. In our dataset, we observed the same association with rs5743551on TLR1 and rs5743795 on TLR6. OAS1 and OAS2 encode for two enzymes of the 2?A synthetase family, involved in the innate immune response to viral infections. These molecules are induced by 1676428 interferons and activate RNase L (product of RNASEL) which degrades viral RNA and inhibits replication. Recently, Molinaro et al. [44] showed that RNA fractions of prostate cancer cell lines are able to bind and activate OAS molecules, whereas RNA fractions of normal prostateepithelial cells cannot. Also, viral infections, sexually transmitted diseases [45,46,47,48,49,50], and infections with Propionibacterium acnes, a gram positive bacterium, [51,52] have 15481974 been suggested as triggers in prostate cancer. These infectious agents may be cleared after the acute infection. Nonetheless, these agents could possibly induce carcinogenesis through the activation of a chronic inflammatory response [53]. Only one study of the association between prostate cancer and OAS1 was done on a smaller sample size and 3 SNPs different from our Anlotinib supplier selection where an association with rs2660 was found [54]. COX-2 encodes for the enzyme cyclooxygenase-2 (COX-2). COX-2 converts buy AN-3199 arachidonic acid to prostaglandin H2, which is a precursor for other tissue-specific inflammatory molecules (prostanoids). COX-2 was found to be overexpressed in prostate cancer tissue compared to the surrounding normal prostate tissue [55,56,57]. The association of genetic variants with prostate cancer risk has also been outlined in previous studies, including in the same dataset [27,28,29,30,58]. However, reports on the association between elevated expression of COX-2 in prostate cancer tissues and high Gleason score and recurrence of the disease have mixed results [59,60,61]. Our results are concordant with those reported by Zheng et al. [62] who studied 9,275 SNPs in 1,086 inflammation genes using 200 familial cases and 200 controls of Swedish origin. They observed a significant enrichment in the number of nominal associations observed, suggesting the role of multiple genes with modest effects. However, by using the SKAT, our study is the first analysis of SNP sets pooled across genes and sub-pathways within the innate immunity and inflammation pathway. None of the SNPs or genes included in our study was reported in any of the genome-wide association studies of prostate cancer listed in the Catalog of Genome-Wide Association studies [63]. Nonetheless, our study has several limitations. First, the limited sample size, and thus limited power, could explain why the association with the whole set of genes is significant while none of the associations with the sub-pathways, genes, or SNPs are significant after correcting for multiple testing. With this sample, the minimum (or maximum for protective) odds ratio detectable with a power of 80 varies between 1.5 (or 0.67) and 2.19 (or 0.46) when the MAF varies between 0.5 and 0.05. Moreover, the limited sample size does not allow 
evaluating potential heterogeneous effects of variants by ethnicity or other covariates. Second, although a more stringent selection of cases would better describe the role of the innate immunity and inflammation pathway.Studies have reported prostate cancer associations with members of the toll-like receptor family [6,12,16]. In particular Sun et al. [12] observed multiple SNPs in strong linkage disequilibrium located on TLR1, TLR6, and TLR10 associated with prostate cancer. In our dataset, we observed the same association with rs5743551on TLR1 and rs5743795 on TLR6. OAS1 and OAS2 encode for two enzymes of the 2?A synthetase family, involved in the innate immune response to viral infections. These molecules are induced by 1676428 interferons and activate RNase L (product of RNASEL) which degrades viral RNA and inhibits replication. Recently, 
Molinaro et al. [44] showed that RNA fractions of prostate cancer cell lines are able to bind and activate OAS molecules, whereas RNA fractions of normal prostateepithelial cells cannot. Also, viral infections, sexually transmitted diseases [45,46,47,48,49,50], and infections with Propionibacterium acnes, a gram positive bacterium, [51,52] have 15481974 been suggested as triggers in prostate cancer. These infectious agents may be cleared after the acute infection. Nonetheless, these agents could possibly induce carcinogenesis through the activation of a chronic inflammatory response [53]. Only one study of the association between prostate cancer and OAS1 was done on a smaller sample size and 3 SNPs different from our selection where an association with rs2660 was found [54]. COX-2 encodes for the enzyme cyclooxygenase-2 (COX-2). COX-2 converts arachidonic acid to prostaglandin H2, which is a precursor for other tissue-specific inflammatory molecules (prostanoids). COX-2 was found to be overexpressed in prostate cancer tissue compared to the surrounding normal prostate tissue [55,56,57]. The association of genetic variants with prostate cancer risk has also been outlined in previous studies, including in the same dataset [27,28,29,30,58]. However, reports on the association between elevated expression of COX-2 in prostate cancer tissues and high Gleason score and recurrence of the disease have mixed results [59,60,61]. Our results are concordant with those reported by Zheng et al. [62] who studied 9,275 SNPs in 1,086 inflammation genes using 200 familial cases and 200 controls of Swedish origin. They observed a significant enrichment in the number of nominal associations observed, suggesting the role of multiple genes with modest effects. However, by using the SKAT, our study is the first analysis of SNP sets pooled across genes and sub-pathways within the innate immunity and inflammation pathway. None of the SNPs or genes included in our study was reported in any of the genome-wide association studies of prostate cancer listed in the Catalog of Genome-Wide Association studies [63]. Nonetheless, our study has several limitations. First, the limited sample size, and thus limited power, could explain why the association with the whole set of genes is significant while none of the associations with the sub-pathways, genes, or SNPs are significant after correcting for multiple testing. With this sample, the minimum (or maximum for protective) odds ratio detectable with a power of 80 varies between 1.5 (or 0.67) and 2.19 (or 0.46) when the MAF varies between 0.5 and 0.05. Moreover, the limited sample size does not allow evaluating potential heterogeneous effects of variants by ethnicity or other covariates. Second, although a more stringent selection of cases would better describe the role of the innate immunity and inflammation pathway.
