© 2005 Oxford University Press
ARTICLE |
Sequence Variants in Toll-Like Receptor Gene Cluster (TLR6-TLR1-TLR10) and Prostate Cancer Risk
Affiliations of authors: Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC (JS, SLZ, BC, LL, GL, WL, AT, ART, DAM, JX); Department of Radiation Sciences and Oncology, University of Umeå, Umeå, Sweden (FW, HG); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KB, H-OA); Department of Urology and Clinical Medicine, Örebro University Hospital, Örebro, Sweden, and Regional Oncological Center, University Hospital, Uppsala, Sweden (J-EJ); Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD (WBI)
Correspondence to: Jianfeng Xu, Dr PH, MD, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 (e-mail: jxu{at}wfubmc.edu).
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.
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