Abstract
BackgroundToll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews.MethodsWe performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls.ResultsUsing random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity.Conclusions TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.
Highlights
Prostate cancer (PCa) is the most common malignancy since 1984, the most frequently diagnosed cancer, and the second leading cause of cancer-related deaths in 2013 among men in the USA [1]
The eicosanoid pathway activated by cyclooxygenase 2 (COX-2) has been suggested to be involved in the pathogenesis of aggressive prostate cancer (PCa) by a recent study [10]
Science Citation Index, and Online Mendelian Inheritance in Man databases for all genetic association studies published before February 2013, using combinations of the search terms ‘‘tolllike receptor 4,’’ odds ratios (ORs) ‘‘toll-like receptor 4 gene,’’ OR ‘‘TLR,’’ OR ‘‘TLR gene,’’ OR ‘‘Toll-like receptor 4 (TLR4),’’ OR ‘‘TLR4 gene,’’ AND ‘‘prostate cancer,’’ OR ‘‘prostatic neoplasms.’’ GWASs were searched using combinations of the search terms ‘‘genome-wide association study,’’ OR ‘‘GWAS,’’ AND ‘‘prostate cancer,’’ OR ‘‘prostatic neoplasms.’’ In addition, we manually searched the reference lists from reviews and original articles to retrieve other papers relevant to the topic
Summary
Prostate cancer (PCa) is the most common malignancy since 1984, the most frequently diagnosed cancer, and the second leading cause of cancer-related deaths in 2013 among men in the USA [1]. Chronic inflammation has been linked to the pathogenesis of PCa in both epidemiologic studies and molecular pathology investigations [5,6]. Several pathways linking inflammation and PCa have been identified: an intrinsic one driven by genetic events that cause neoplasia, and an extrinsic one driven by inflammatory conditions that predispose to cancer [9]. The eicosanoid pathway activated by cyclooxygenase 2 (COX-2) has been suggested to be involved in the pathogenesis of aggressive PCa by a recent study [10]. Despite the available evidence on the role of the inflammatory response in PCa onset and progression, the association between genetic variants of innate immune genes and the risk of aggressive PCa remains unclear. TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews
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