Sequence Variants in Toll-Like Receptor Gene Cluster (TLR6-TLR1-TLR10) and Prostate Cancer Risk

• Published in: JNCI : Journal of the National Cancer Institute Vol. 97; no. 7; pp. 525 - 532
• Main Authors: Sun, Jielin, Wiklund, Fredrik, Zheng, S. Lilly, Chang, Baoli, Bälter, Katarina, Li, Liwu, Johansson, Jan-Erik, Li, Ge, Adami, Hans-Olov, Liu, Wennuan, Tolin, Amy, Turner, Aubrey R., Meyers, Deborah A., Isaacs, William B., Xu, Jianfeng, Grönberg, Henrik
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 06.04.2005; Oxford Publishing Limited (England)
• Subjects: Biological and medical sciences; Case-Control Studies; Founder Effect; Gene Frequency; Genes; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Health risk assessment; Humans; Logistic Models; Male; Medical sciences; Membrane Glycoproteins - genetics; Nephrology. Urinary tract diseases; Odds Ratio; Polymorphism, Single Nucleotide; Prostate cancer; Prostatic Neoplasms - genetics; Receptors, Cell Surface - genetics; Sweden; Toll-Like Receptor 1; Toll-Like Receptor 10; Toll-Like Receptor 4; Toll-Like Receptor 6; Toll-Like Receptors; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Sweden; Europe; Human; Gene cluster; Urinary system disease; Genetic variability; Prostate disease; Genotype; Toll like receptor; Malignant tumor; Case control study; Epidemiology; Urology; Cancerology; Risk factor; Single nucleotide polymorphism; Male genital diseases; Prostate cancer; Public health; Biological receptor
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/dji070

Background: Chronic inflammation plays an important role in several human cancers and may be involved in the etiology of prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross-talk between innate immunity and adaptive immunity. Our previous finding of an association of TLR4 gene sequence variants and prostate cancer risk provides evidence for a role of TLRs in prostate cancer. In this study, we investigated whether sequence variants in the TLR6-TLR1-TLR10 gene cluster, residing within a 54-kb region on 4p14, were associated with prostate cancer risk. Methods: We selected 32 single-nucleotide polymorphisms (SNPs) covering these three genes and genotyped these SNPs in 96 control subjects from the Cancer Prostate in Sweden (CAPS) population-based prostate cancer case–control study. Five distinct haplotype blocks were inferred at this region, and we identified 17 haplotype-tagging SNPs (htSNPs) that could uniquely describe >95% of the haplotypes. These 17 htSNPs were then genotyped in the entire CAPS study population (1383 case subjects and 780 control subjects). Odds ratios of prostate cancer for the carriers of a variant allele versus those with the wild-type allele were estimated using unconditional logistic regression. Results: The allele frequencies of 11 of the 17 SNPs were statistically significantly different between case and control subjects (P = .04–.001), with odds ratios for variant allele carriers (homozygous or heterozygous) compared with wild-type allele carriers ranging from 1.20 (95% confidence interval [CI] = 1.00 to 1.43) to 1.38 (95% CI = 1.12 to 1.70). Phylogenetic tree analyses of common haplotypes identified a clade of two evolutionarily related haplotypes that are statistically significantly associated with prostate cancer risk. These two haplotypes contain all the risk alleles of these 11 associated SNPs. Conclusion: The observed multiple associated SNPs at the TLR6-TLR1-TLR10 gene cluster were dependent and suggest the presence of a founder prostate cancer risk variant on this haplotype background. The TLR6-TLR1-TLR10 gene cluster may play a role in prostate cancer risk, although further functional studies are needed to pinpoint the disease-associated variants in this gene cluster.