Genetic Polymorphisms in Inflammation Pathway Genes and Prostate Cancer Risk

Background: Chronic inflammation is an important mechanism for the development and progression of prostate cancer (PC). To better understand the potential relationship between genes in the inflammation pathway and PC risk, we evaluated variants in 16 candidate genes. Methods: A total of 143 tagging and amino acid altering single nucleotide polymorphisms (SNPs) were genotyped in Caucasian and African American men participating in one of two population-based, case-control studies (n = 1,458 cases and 1,351 controls). The relative risk of PC was estimated using logistic and polytomous regression models. Results: Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P < 0.05) with risk of PC in Caucasians. The most significant effect on risk was seen with rs11574783 in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01-0.63). Cumulatively, four SNPs in genes interleukin 4 (IL4), IL6ST, PTGS2, and signal transducer and activator of transcription 3 (STAT3) conferred a three-fold elevation in PC risk among men carrying the maximum number of high-risk alleles (OR = 2.97, 95% CI: 1.41-6.25, P-trend = 0.0003). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (P-homogeneity < 0.05), with SNPs in AKT1, PIK3R1, and STAT3 independently associated with more aggressive PC; OR = 5.1 (95% CI: 2.29-11.40, P-trend = 3.8 x 10(-5)) for carriers of all high-risk genotypes. Conclusions: These results suggest that variants in genes within the inflammation pathway may play a role in the development of PC, however, further studies are needed to replicate our findings. Impact: These results underline the potential importance of the inflammation pathway in PC development and progression. Cancer Epidemiol Biomarkers Prev; 20(5); 923-33. (C)2011 AACR.