Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk

Jielin Sun; Fredrik Wiklund; S. Lilly Zheng; Baoli Chang; Katarina Bälter; Liwu Li; Jan Erik Johansson; Ge Li; Hans Olov Adami; Wennuan Liu; Amy Tolin; Aubrey R. Turner; Deborah A. Meyers; William B. Isaacs; Jianfeng Xu; Henrik Grönberg

doi:10.1093/jnci/dji070

Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk

Jielin Sun, Fredrik Wiklund, S. Lilly Zheng, Baoli Chang, Katarina Bälter, Liwu Li, Jan Erik Johansson, Ge Li, Hans Olov Adami, Wennuan Liu, Amy Tolin, Aubrey R. Turner, Deborah A. Meyers, William B. Isaacs, Jianfeng Xu, Henrik Grönberg

School of Medicine

Research output: Contribution to journal › Article › peer-review

137 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	525-532
Number of pages	8
Journal	Journal of the National Cancer Institute
Volume	97
Issue number	7
DOIs	https://doi.org/10.1093/jnci/dji070
State	Published - Apr 6 2005

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1093/jnci/dji070

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Sun, J., Wiklund, F., Zheng, S. L., Chang, B., Bälter, K., Li, L., Johansson, J. E., Li, G., Adami, H. O., Liu, W., Tolin, A., Turner, A. R., Meyers, D. A., Isaacs, W. B., Xu, J., & Grönberg, H. (2005). Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. Journal of the National Cancer Institute, 97(7), 525-532. https://doi.org/10.1093/jnci/dji070

Sun, J, Wiklund, F, Zheng, SL, Chang, B, Bälter, K, Li, L, Johansson, JE, Li, G, Adami, HO, Liu, W, Tolin, A, Turner, AR, Meyers, DA, Isaacs, WB, Xu, J & Grönberg, H 2005, 'Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk', Journal of the National Cancer Institute, vol. 97, no. 7, pp. 525-532. https://doi.org/10.1093/jnci/dji070

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title = "Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk",

abstract = "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.",

author = "Jielin Sun and Fredrik Wiklund and Zheng, {S. Lilly} and Baoli Chang and Katarina B{\"a}lter and Liwu Li and Johansson, {Jan Erik} and Ge Li and Adami, {Hans Olov} and Wennuan Liu and Amy Tolin and Turner, {Aubrey R.} and Meyers, {Deborah A.} and Isaacs, {William B.} and Jianfeng Xu and Henrik Gr{\"o}nberg",

year = "2005",

month = apr,

day = "6",

doi = "10.1093/jnci/dji070",

language = "English (US)",

volume = "97",

pages = "525--532",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "7",

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TY - JOUR

T1 - Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk

AU - Sun, Jielin

AU - Wiklund, Fredrik

AU - Zheng, S. Lilly

AU - Chang, Baoli

AU - Bälter, Katarina

AU - Li, Liwu

AU - Johansson, Jan Erik

AU - Li, Ge

AU - Adami, Hans Olov

AU - Liu, Wennuan

AU - Tolin, Amy

AU - Turner, Aubrey R.

AU - Meyers, Deborah A.

AU - Isaacs, William B.

AU - Xu, Jianfeng

AU - Grönberg, Henrik

PY - 2005/4/6

Y1 - 2005/4/6

N2 - 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.

AB - 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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Sequence variants in toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk

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