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Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies.

ABSTRACT: Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports.We did a pooled analysis combining genotype data from three case-control studies, Cancer of the Prostate in Sweden, the Health Professionals Follow-up Study, and the Prostate, Lung, Colon and Ovarian Cancer Screening Trial, with data from 3,101 prostate cancer cases and 2,523 controls. We did imputation to obtain dense coverage of the genes and comparable genotype data for all cohorts. In total, 58 single nucleotide polymorphisms in TLR4 and 96 single nucleotide polymorphisms in TLR6-1-10 were genotyped or imputed and analyzed in the entire data set. We did a cohort-specific analysis as well as meta-analysis and pooled analysis. We also evaluated whether the analyses differed by age or disease severity.We observed no overall association between genetic variation at the TLR4 and TLR6-1-10 loci and risk of prostate cancer.Common germ line genetic variation in TLR4 and TLR6-1-10 did not seem to have a strong association with risk of prostate cancer.This study suggests that earlier associations between prostate cancer risk and TLR4 and TLR6-1-10 sequence variants were chance findings. To definitely assess the causal relationship between TLR sequence variants and prostate cancer risk, very large sample sizes are needed.

SUBMITTER: Lindstrom S

PROVIDER: S-EPMC2837532 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies.

Lindström Sara S Hunter David J DJ Grönberg Henrik H Stattin Pär P Wiklund Fredrik F Xu Jianfeng J Chanock Stephen J SJ Hayes Richard R Kraft Peter P

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20100303 3

<h4>Background</h4>Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports.<h4>Methods</h4>We did a pooled analysis combining genotype data from three case-control studies, Cancer of the Prostate in Sweden, the Health Professionals Follow-up Study, and the Prostate, Lung, Colon and Ovarian Cancer Screening Trial, with data fr ...[more]

PMID: 20200442

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Project description:BACKGROUND:Prothymosin ? (ProT?) (isoform 2: iso2) is a widely distributed, small acidic protein with intracellular and extracellular-associated functions. Recently, we identified two new ProT? variants with potent anti-HIV activity from CD8+ T cells and cervicovaginal lavage. The first is a splice variant of the ProT? gene known as isoB and the second is the product of ProT? pseudogene 7 (p7). Similarly to iso2, the anti-HIV activity of both variants is mediated by type I IFN. Here we tested whether the immunomodulatory activity of isoB and p7 are also TLR4 dependent and determined their kinetic of release in response to HIV-1 infection. METHODS:Type I, type III, TNF-? and IL-6 mRNA inducing activity was determined in macrophages from wild type and TLR4 knockout mice treated with recombinant ProT? variants. Supernatants from mock and HIV infected cells were analyzed by mass spectrometry in positive and negative modes for the presence of ProT? variants. In silico structural and functional analysis of ProT? variants were performed. RESULTS:We show that both isoB and p7 upregulate IFN-?, IFN-?1, IL-6, TNF-? and RANTES mRNAs in primary human macrophages. The potent stimulation of IFN-? by the recombinant ProT? variants in human macrophages is dependent on the TLR4 pathway, whereas the induction of TNF-? and IL-6 may also occur independently of TLR4, suggesting the interaction of ProT? variants with other signaling molecules/receptors. In silico analyses confirmed that the novel isoB and p7 variants are intrinsically disordered proteins, which lack the NLS and mass spectrometry showed release of ProT? variants within minutes post HIV-1 infection. These features are consistent with the function of ProT? variants as damage associate molecular patterns (DAMPs). CONCLUSIONS:Our findings indicate that ProT? variants strongly inhibit viral replication mainly, but not exclusively, through TLR4 signaling and that they are released within minutes of viral infection suggesting that they may function as DAMPs.

Dataset Information

Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies.

Publications

Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies.

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