Abstract 928: Toll-Like Receptor 4 Polymorphisms Modify the Association between T. vaginalis Serostatus and Prostate Cancer Risk
Authors: Chen Yen-Ching , Huang Yi-Ling , Platz Elizabeth A. , Zheng Lu , Alderete John F. , Hunter David J. , Giovannucci Edward , Sutcliffe Siobhan 
Published: February 2011

Background. Our previously study in the Health Professionals Follow-Up Study (HPFS) reported that men who were seropositive for the protozoan Trichomonas vaginalis had a higher risk of prostate cancer (PCa) especially in men who did not regularly take aspirin over their life. In the HPFS, 10 SNPs (rs6478317, rs10116253, rs1927914, rs10759932, rs1927911, rs5030717, rs2149356, rs7873784, rs11536891 and rs1536898) and one haplotype in the innate immune gene, toll-like receptor 4 (TLR4), were significantly associated with decreased PCa risk. As T. vaginalis is recognized by TLR4 on the surface of macrophages, variations in TLR4 may attenuate the inflammatory response towards T. vaginalis and thus modify the risk of PCa. Therefore, we hypothesize that genetic polymorphisms of TLR4 modify the association between T. vaginalis infection and PCa risk, which has not been explored before.

Methods. A total of 690 incident PCa cases diagnosed between 1993 and 2000 and 692 matched controls were included in this study nested in the HPFS. We determined T. vaginalis serostatus by ELISA and genotyped 16 common TLR4 SNPs. Logistic regression was used to estimate the association between T. vaginalis seropositivity and PCa by TLR4 genotypes adjusting for potential confounders. Likelihood ratio tests were used to test for interactions.

Results. Among men with T. vaginalis seropositivity, non-variant carriers of TLR4 SNPs rs6478317, rs10116253, rs10759932, and rs1927911, were associated with an increased risk of PCa, whereas variant carriers were not associated with PCa (Pinteraction&lt;0.05). Interactions were stronger for high-grade PCa (rs11536858, rs6478317, rs10116253, rs1927914, rs10759932, rs1927911, and rs2149356, Pinteraction&lt;0.05) and much weaker for low-grade PCa (rs10759932, Pinteraction&lt;0.05) than for total PCa for some TLR4 SNPs. Interactions were also stronger among infrequent aspirin users with T. vaginalis seropositivity [rs10116253, rs1927911, rs11536878, rs7873784, and rs11536891, odds ratio (OR)=3.22-6.02, Pinteraction&lt;0.05], and weaker among moderate to regular lifetime aspirin users with T. vagianlis seropositivity (rs10759932, OR=1.54, Pinteraction&lt;0.05). Although the patterns of association between T. vaginalis infection and PCa risk seemed to differ between variant and non-variant carriers of some TLR4 haplotypes, none of these haplotypes significantly modified the association between T. vaginalis serostatus and the risk of total, high- or low-grade PCa. Results remained non-significant after stratification by lifetime frequency of aspirin use.

Conclusions. The positive association between T. vaginalis infection and PCa risk was modified by genetic variations in TLR4, and the effect was stronger for high-grade PCa and infrequent aspirin users. Our results support the hypothesis that infection-associated inflammation contributes to the etiology of PCa.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 928.