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 journalArticle

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

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Toll-Like Receptor 4
Sweden
Prostatic Neoplasms
Genotype
Inflammation
Genes
Single Nucleotide Polymorphism
Odds Ratio
CD14 Antigens
Confidence Intervals
3' Untranslated Regions
Genetic Predisposition to Disease
Gram-Negative Bacteria
Innate Immunity
Bacteria
Infection

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zheng, S. L., Augustsson-Bälter, K., Chang, B., Hedelin, M., Li, L., Adami, H. O., ... Grönberg, H. (2004). Sequence Variants of Toll-Like Receptor 4 Are Associated with Prostate Cancer Risk: Results from the CAncer Prostate in Sweden Study. Cancer Research, 64(8), 2918-2922. https://doi.org/10.1158/0008-5472.CAN-03-3280

Sequence Variants of Toll-Like Receptor 4 Are Associated with Prostate Cancer Risk : Results from the CAncer Prostate in Sweden Study. / Zheng, S. Lilly; Augustsson-Bälter, Katarina; Chang, Baoli; Hedelin, Maria; Li, Liwu; Adami, Hans Olov; Bensen, Jeanette; Li, Ge; Johnasson, Jan Erik; Turner, Aubrey R.; Adams, Tamara S.; Meyers, Deborah A.; Isaacs, William B; Xu, Jianfeng; Grönberg, Henrik.

In: Cancer Research, Vol. 64, No. 8, 15.04.2004, p. 2918-2922.

Research output: Contribution to journalArticle

Zheng, SL, Augustsson-Bälter, K, Chang, B, Hedelin, M, Li, L, Adami, HO, Bensen, J, Li, G, Johnasson, JE, Turner, AR, Adams, TS, Meyers, DA, Isaacs, WB, Xu, J & Grönberg, H 2004, 'Sequence Variants of Toll-Like Receptor 4 Are Associated with Prostate Cancer Risk: Results from the CAncer Prostate in Sweden Study', Cancer Research, vol. 64, no. 8, pp. 2918-2922. https://doi.org/10.1158/0008-5472.CAN-03-3280
Zheng, S. Lilly ; Augustsson-Bälter, Katarina ; Chang, Baoli ; Hedelin, Maria ; Li, Liwu ; Adami, Hans Olov ; Bensen, Jeanette ; Li, Ge ; Johnasson, Jan Erik ; Turner, Aubrey R. ; Adams, Tamara S. ; Meyers, Deborah A. ; Isaacs, William B ; Xu, Jianfeng ; Grönberg, Henrik. / Sequence Variants of Toll-Like Receptor 4 Are Associated with Prostate Cancer Risk : Results from the CAncer Prostate in Sweden Study. In: Cancer Research. 2004 ; Vol. 64, No. 8. pp. 2918-2922.
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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.",
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