In this integrative analysis of the association of advanced prostate cancer risk with candidate genes involved in innate immunity and inflammation, we studied 320 SNPs and their joint effects across genes and sub-pathways. Taken as a whole, the overall innate immunity and inflammation pathway seems to be involved in advanced prostate cancer, but the individual elements of this association are not clear. Indeed, the whole set of 320 SNPs is significantly associated with advanced prostate cancer risk. However, none of the other evaluated associations with sub-pathways, genes, or individual SNPs were significant, when correcting for multiple testing by making permutation based estimates of the family-wise error rate.
Nonetheless, our results suggest that the extracellular pattern recognition, the intracellular antiviral molecules, and the eicosanoid signaling (ie, COX-2) could be components that play a potential role in advanced prostate cancer risk. Within those sub-pathways, 5 genes (TLR1, TLR6, OAS1, OAS2, and COX-2) were nominally associated with advanced prostate cancer risk. Moreover, these genes harbor several SNPs nominally associated with advanced prostate cancer risk.
encode members of the toll-like receptor family. Their role is to recognize molecular patterns associated to infectious pathogens. Both are highly conserved from Drosophilia
to humans and share structural and functional similarities. Moreover, TLR1 and TLR6 also share the ability to form a heterodimer with TLR2 to recognize peptidoglycan and lipoproteins on pathogens. TLR1 is specialized in the recognition of gram-positive bacteria. Several studies have reported prostate cancer associations with members of the toll-like receptor family 
. In particular Sun et al. 
observed multiple SNPs in strong linkage disequilibrium located on TLR1
, and TLR10
associated with prostate cancer. In our dataset, we observed the same association with rs5743551on TLR1
and rs5743795 on TLR6
encode for two enzymes of the 2–5A synthetase family, involved in the innate immune response to viral infections. These molecules are induced by interferons and activate RNase L (product of RNASEL
) which degrades viral RNA and inhibits replication. Recently, Molinaro et al. 
showed that RNA fractions of prostate cancer cell lines are able to bind and activate OAS molecules, whereas RNA fractions of normal prostate epithelial cells cannot. Also, viral infections, sexually transmitted diseases 
, and infections with Propionibacterium acnes
, a gram positive bacterium, 
have 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 
. 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 
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 
. The association of genetic variants with prostate cancer risk has also been outlined in previous studies, including in the same dataset 
. 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 
Our results are concordant with those reported by Zheng et al. 
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 
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 in advanced prostate cancer, it would decrease the sample size –and consequently the power– drastically. Third, our selection of SNPs cannot exclude the possibility for rare functional variants in these candidate genes to play a role in advanced prostate cancer risk. Third, although the SKAT method provides an ideal framework to test for association with sets of potentially correlated SNPs, it does not measure the increase in risk associated with variants in the set of SNPs.
In conclusion, this study furthers research into prostate cancer genetics by studying SNPs in a candidate pathway at multiple levels of information: whole pathway, sub-pathways, genes, and SNPs. Our results suggest that although it may not be central in the etiology of advanced prostate cancer, the innate immunity and inflammation pathway could play a role in prostate cancer through different genetic variants.