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Toll-Like Receptor 4 Genetic Variation and Advanced Prostate Cancer Risk

¹ Department of Epidemiology and Biostatistics and Center of Human Genetics, University of California at San Francisco, San Francisco, California and ² Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio

Requests for reprints: John S. Witte, Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94143-0794. E-mail: wittej{at}humgen.ucsf.edu

Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response primarily against Gram-negative bacteria. Two recent publications reported that variants in TLR4 were associated with risk of prostate cancer. To further investigate the role of TLR4 in prostate cancer susceptibility, we identified six tagging single-nucleotide polymorphisms that comprehensively captured the common genetic variation of the locus and tested these polymorphisms in our case-control study of 1,012 men. Two single-nucleotide polymorphisms showed nominally statistically significant associations with prostate cancer risk, with the strongest (rs10759932) associated with a 4-fold increased risk of disease (P = 0.006). We estimated through permutation analysis that a similarly strong result would occur by chance 2.5% of the time. Our findings support previous studies and suggest that inherited differences in TLR4 influence prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(2):352–40)