Journal of the National Cancer Institute Advance Access originally published online on October 9, 2007
JNCI Journal of the National Cancer Institute 2007 99(20):1525-1533; doi:10.1093/jnci/djm169
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Association Between Two Unlinked Loci at 8q24 and Prostate Cancer Risk Among European Americans
Affiliations of authors: Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC (SLZ, JS, YC, GL, FCH, YZ, BLC, WL, JWK, ART, JX); Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD (MG, GY, SDI, KEW, JS, RG, LAM, BJT, AWP, PCW, WBI); Department of Mathematical Sciences, Michigan Technological University, Houghton, MI (HSC); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (HG); Translational Genomics Research Institute (TGen), Phoenix, AZ (DD, JDC)
Correspondence to: William B. Isaacs, PhD, Marburg 115, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287 (e-mail: wisaacs{at}jhmi.edu) or Jianfeng Xu, MD, DrPH, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (e-mail: jxu{at}wfubmc.edu).
Background: Recent studies have provided evidence of associations between genetic markers at human chromosome 8q24 and an increased risk of prostate cancer. We examined whether multiple independent risk variants exist in this region and whether the strength of observed associations differs as a function of disease aggressiveness.
Methods: We evaluated associations between 18 single-nucleotide polymorphisms (SNPs) in a 1-Mb interval at 8q24 and the risk of prostate cancer among 1563 case patients (1017 of whom had high-grade [Gleason score 
7] and/or non–organ-confined disease) and 576 control subjects of European American ancestry. Differences in genotype frequencies between case and control subjects were compared using logistic regression analysis, with adjustment for age, and the Wald chi-square test. All statistical tests were two-sided.
Results: We identified multiple SNPs in a 50-kb region (referred to as locus 1) that are in linkage disequilibrium with a previously reported risk-associated SNP at 8q24, rs1447295, but were more strongly associated with prostate cancer risk in our study population. We also identified a novel susceptibility SNP, rs6983267, at a second locus (locus 2) that is approximately 70 kb centromeric of rs1447295 and in linkage equilibrium with, and independent of, locus 1. Risk alleles at locus 2 were common in our study population (minor allele frequency 
50%, 25% homozygous for risk-associated allele). Analysis of the National Cancer Institute’s Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer association study database alone and in combination with our data provided further evidence for this second prostate cancer risk locus; in the combined analysis, the allele frequencies for rs6983267 differed statistically significantly between case patients and control subjects (P = 1.61 x 10-9). We also identified a third locus at 8q24, approximately 400 kb centromeric to locus 2, that was statistically significantly associated with prostate cancer risk in a combined analysis of our data and CGEMS study data (P = 6.8 x 10-4). A joint analysis of loci 1 and 2 indicated that 35% of the control subjects carried risk genotypes at one or both these loci; compared with men with the nonrisk genotype at both loci, men with risk genotypes at both loci had an odds ratio of prostate cancer of 2.68 (95% confidence interval [CI] = 1.62 to 4.43) and men with risk genotypes at either locus had an odds ratio of prostate cancer of 1.70 (95% CI = 1.39 to 2.07).
Conclusions: Three loci at 8q24 are independent genetic risk factors for prostate cancer.
| CONTEXT AND CAVEATS Prior knowledge Various studies have linked genetic markers at human chromosome 8q24 with an increased risk of prostate cancer, but a comprehensive analysis of single-nucleotide polymorphisms throughout the region and the eventual identification of the causal variant(s) are still needed. Study design A case–control study to assess associations between germline variants at 8q24 and prostate cancer risk among men of European American ancestry. Contribution Three independent loci at 8q24 were identified that are associated in an additive fashion with an increased risk of prostate cancer. Implications The finding of multiple unlinked prostate cancer risk loci at 8q24 may provide important clues about the molecular mechanisms behind this genetic association. Limitations Control subjects were men with a serum prostate-specific antigen (PSA) level of 4.0 ng/mL or lower, potentially resulting in selection bias because control subjects (but not case patients) with certain diseases that are associated with higher PSA levels may have been preferentially excluded. Population stratification could have accounted for the observed different allele frequencies of variants between case patients and control subjects. There was no adjustment for multiple testing.
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Manuscript received March 14, 2007; revised August 1, 2007; accepted August 29, 2007.
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