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

S. Lilly Zheng, Katarina Augustsson-Bälter, Baoli Chang, Maria Hedelin, Liwu Li, Hans Olov Adami, Jeanette Bensen, Ge Li, Jan Erik Johnasson, Aubrey R. Turner, Tamara S. Adams, Deborah A. Meyers, William B. Isaacs, Jianfeng Xu, Henrik Grönberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2918-2922
Number of pages5
JournalCancer Research
Volume64
Issue number8
DOIs
StatePublished - Apr 15 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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