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No Association Between Common Chemokine and Chemokine Receptor Gene Variants and Prostate Cancer Risk

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No Association Between Common Chemokine and Chemokine Receptor Gene Variants and Prostate Cancer Risk 3615 Null Results in Brief No Association between Common Chemokine and Chemokine Receptor Gene Variants and Prostate Cancer Risk Desiree C. Petersen,1,3 Gianluca Severi,4,5 Hoa N. Hoang,4 Emma J.D. Padilla,3 Melissa C. Southey,6 Dallas R. English,4,5 John L. Hopper,5 Graham G. Giles,4,5 and Vanessa M. Hayes1,2,3 1Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Sydney Children’s Hospital and 2Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia; 3Cancer Genetics Group, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; 4Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia; 5Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology and 6Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia Abstract There is growing evidence that inflammation and CXCL12 +801G>A has previously been tested and infection play important roles in the etiology of found to be associated withprostate cancer risk. We prostate cancer. As the chemokine network is directly found no significant associations withprostate cancer involved in inflammation and infectious diseases, we risk (all P > 0.4). All per allele odds ratios ranged tested for an association between six common putative from 0.96 (95% confidence intervals, 0.80-1.16) to 1.06 functional variants and prostate cancer risk using an (95% confidence intervals, 0.90-1.23). This suggests that Australian case-control study. We measured CCL5 these common chemokine and chemokine receptor À403G>A, CXCL12 +801G>A, CCR2V64I (G>A), variants do not play a major, if any, role in suscepti- CCR5#32, CX3CR1V249I (G>A), and CX3CR1T280M bilitytoprostatecancer. (Cancer Epidemiol Bio- (C>T) for 815 cases and 738 controls. Of these, only markers Prev 2008;17(12):3615–17) Introduction Inflammation and infection are thought to play a major CXC chemokine ligand 12 (CXCL12, MIM#600835) +180 3¶ role in the pathogenesis of prostate cancer (1), fuelling untranslated regulatory variant (rs1801157G>A), CC studies into associations between genetic variation in chemokine receptor 2 (CCR2, MIM#601267) nonsynon- inflammatory genes and prostate cancer risk (2, 3). A ymous variant CCR2V64I (rs1799864G>A), chemokine subset of cytokines involved in the regulation of receptor 5 (CCR5, MIM#601373) 32 bp deletion variant inflammation and shown to modulate tumor behavior CCR5D32, and CX3C chemokine receptor (CX3CR1, are those involved in the chemokine network (4). We MIM#601470) nonsynonymous variants CX3CR1V249I hypothesize that functional variants within genes of this (rs3732379G>A) and CX3CR1T280M (rs3732378C>T). network could result in a balance shift of the chemokine The CXCL12 +801G>A polymorphism was recently and chemokine receptor system towards a favorable shown to be a risk factor for prostate cancer in a Japanese angiogenic, antiapoptotic, or metastatic response, pro- study (13). The remaining variants, although associated moting the initiation and development of prostate cancer. with many infectious diseases and cancers, have not yet To test our hypothesis, we screened six commonly been investigated in prostate cancer. studied genetic variants previously shown to have a measurable functional effect on the corresponding pro- tein (5–12). These include CC chemokine ligand 5 (CCL5, Materials and Methods MIM#187011) À403 promoter variant (rs2107538G>A), Study Population. We tested our hypotheses in the Australian Risk Factors for Prostate Cancer Study, a Received 9/24/08; accepted 9/30/08. population-based case-control study including 815 cases Grant support: Australian Cancer Research Foundation, Cancer Institute of New and 738 controls predominantly of European descent South Wales (V.M. Hayes is a Fellow), National Health and Medical Research Council (14). Eligible cases were newly diagnosed adenocarcino- (J.L. Hopper is an Australia Fellow and M.C. Southey is a Senior Research Fellow), and the Freedman Foundation (D.C. Petersen was a Postdoctoral Fellow), Australia. mas of the prostate notified to the State Cancer Registry Requests for reprints: Vanessa M. Hayes, Cancer Genetics Group, Children’s during 1994 to 1997 and histopathologically confirmed. Cancer Institute Australia, Level 1, Sydney Children’s Hospital, P.O. Box 81, High Cases were excluded if age at diagnosis was z70 years or Street, Randwick, New South Wales 2031, Australia. Phone: 61-29382-0229; Fax: 61-29382-1850. E-mail: [email protected] if tumor was well-differentiated (Gleason score < 5). Copyright D 2008 American Association for Cancer Research. Cases were classified into tumor stage groupings doi:10.1158/1055-9965.EPI-08-0896 according to the American Joint Committee on Cancer Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008 Downloaded from cebp.aacrjournals.org on September 29, 2021. © 2008 American Association for Cancer Research. 3616 Chemokine Variants and Prostate Cancer Risk Table 1. Allele and genotype distribution of CCL5, CXCL12, CCR2, CCR5 and CX3CR1 polymorphisms in 829 prostate cancer cases and 739 controls from the Australian Risk Factors for Prostate Cancer Study x Gene NCBI ID Minor allele Per allele P Heterozygous Homozygous P P c b k k { polymorphism* frequencies (n) OR (95% CI) OR (95% CI) OR (95% CI) (recessive) (dominant)** Cases Control CCL5 À403 (G/A) rs2107538 0.17 (801) 0.18 (727) 0.96 (0.80-1.16) 0.70 0.89 (0.71-1.12) 1.18 (0.68-2.03) 0.47 0.46 CXCL12 +801 (G/A) rs1801157 0.20 (815) 0.19 (727) 1.05 (0.88-1.24) 0.60 1.06 (0.85-1.33) 1.06 (0.67-1.69) 0.86 0.57 CCR2V64I (G/A) rs1799864 0.08 (813) 0.08 (738) 1.02 (0.79-1.32) 0.86 0.98 (0.74-1.30) 1.59 (0.46-5.46) 0.45 0.98 CCR5D32 — 0.11 (815) 0.11 (727) 1.00 (0.80-1.25) 0.98 1.00 (0.78-1.29) 0.97 (0.43-2.22) 0.95 0.99 CX3CR1V249I (G/A) rs3732379 0.29 (808) 0.27 (730) 1.06 (0.90-1.23) 0.49 1.05 (0.85-1.30) 1.12 (0.77-1.62) 0.62 0.54 CX3CR1T280M (C/T) rs3732378 0.17 (805) 0.18 (728) 0.99 (0.82-1.19) 0.89 0.98 (0.79-1.23) 0.98 (0.54-1.77) 0.96 0.88 *The second base pair indicates the minor allele. cMinor allele frequency and actual number for cases and controls. bORs and 95% CIs from unconditional logistic regression analysis for the additive model. xTest for association between genotype and prostate cancer risk for the additive model (likelihood ratio test). kORs and 95% CIs from unconditional logistic regression analysis for the codominant model. ORs are relative to homozygotes for the common allele. { Test for association between genotype and prostate cancer risk for the recessive model (likelihood ratio test). **Test for association between genotype and prostate cancer risk for the dominant model (likelihood ratio test). definition. Controls were randomly selected from the Genotype frequencies were consistent with Hardy- State Electoral Rolls and frequency matched to cases by Weinberg equilibrium for both cases and controls (all 5-year age group and city of residence. P > 0.05), whereas no association with age (all P > 0.05) was observed. Carriers of the rare allele for CCR5D32 Genotyping. TaqMan allelic discrimination assays were more prevalent in men born in Australia (23% (Applied Biosystems) were used to genotype single versus 15%, P = 0.006) whereas carriers of the rare allele nucleotide polymorphisms, CCL5 À403G>A, CXCL12 for CCR2V64I were less prevalent in men born in +801G>A, CCR2V64I (G>A), CX3CR1V249I (G>A), and Australia (14% versus 20%, P = 0.03). CX3CR1T280M (C>T), whereas gel-based amplicon size CX3CR1V249I and CX3CR1T280 were in almost differentiation was used for screening the deletion perfect linkage disequilibrium (D¶ = 1.00, P < 0.001, CCR5D32 (protocols available on request). Randomly, r2 = 0.54 for cases and controls combined). The remaining 20% of the study was replicated with 100% concordance. variants, including those in the CX3CR1, CCR5, and Statistical Analyses. Allele frequency estimates and CCR2 genes that are in close proximity (18), were not tests of deviation from Hardy-Weinberg equilibrium linked (all D¶ < 0.15). were carried out using standard procedures based on We found no evidence of association between any of asymptotic likelihood theory (15). Pairwise linkage the selected genetic variants and prostate cancer risk disequilibrium between variants was assessed using (all P > 0.4). The estimated per allele ORs ranged from Lewontin’s D¶ and r-squared (r2), estimated using R 0.96 (95% CI, 0.80-1.16) for CCL5 À403 to 1.06 (95% CI, (16).7 Fisher’s exact test was used to test for indepen- 0.90-1.23) for CX3CR1V249I. No OR was significantly dence between the single nucleotide polymorphisms and different in any of the recessive, dominant, codominant, age (<55, 55-64, 65-69) and country of birth (Australia, or additive models. Adjustment for known measured others). Polytomous logistic regression models were used risk factors (age of diagnosis, family history of prostate to estimate odds ratios (OR) by tumor stage (stage I-II cancer, and country of birth) did not significantly change and stage III-IV tumors), grade (moderate grade and high the OR estimates. ORs did not differ by tumor stage or grade tumors), and family history of prostate cancer grade (all P > 0.05). For CCR5D32, ORs increased with (affected first-degree relative and two or more first- the number of first degree-relatives affected (P = 0.04) degree relatives affected). Tests for association between with ORs per allele being 0.92 (95% CI, 0.73-1.17), 1.22 genotypes and case-control status were done under (95% CI, 0.82-1.82), and 2.30 (95% CI, 1.13-4.68) for none, dominant, recessive, codominant, and additive models.
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