Sequence Variants of Toll-Like Receptor 4 Are Associated with Prostate Cancer Risk: Results from the CAncer Prostate in Sweden Study

Inflammation has been implicated as an etiological factor in several human cancers. Growing evidence suggests that chronic inflammation may also play a role in the etiology of prostate cancer. Considering that genetic susceptibility is a major risk factor for this disease, we hypothesize that sequence variants in genes that regulate inflammation may modify individual susceptibility to prostate cancer. The lipopolysaccharide receptor Toll-like receptor 4 (TLR4) is a central player in the signaling pathways of the innate immune response to infection by Gram-negative bacteria and is an important candidate inflammatory gene. We performed a systematic genetic analysis of TLR4 sequence variants by evaluating eight single-nucleotide polymorphisms that span the entire gene among 1383 newly diagnosed prostate cancer patients and 780 age- and residence-matched controls in Sweden. We found an association between a sequence variant (11381G/C) in the 3′-untranslated region of the TLR4 gene and prostate cancer risk. The frequency of the variant genotypes (CG or CC) was significantly higher in the patients (24.1%) than in the controls (19.7%; P = 0.02). The frequency of risk genotypes among patients diagnosed before the age of 65 years was even higher (26.3%). Compared with men who had the wild-type genotype of this single-nucleotide polymorphism (GG), those with GC or CC genotypes had a 26% increased risk for prostate cancer (odds ratio, 1.26; 95% confidence interval, 1.01-1.57) and 39% increased risk increased risk for early onset prostate cancer (before age 65 years; odds ratio, 1.39; 95% confidence interval, 1.02-1.91). The risk attributable to this variant for prostate cancer in Sweden was estimated to be 4.9%. Although the biological mechanism of the observed association remains to be elucidated, our finding supports a role for a bacteria-associated response pathway, possibly acting via inflammation, in the development of prostate cancer.