Journal of the National Cancer Institute Advance Access originally published online on September 2, 2009
JNCI Journal of the National Cancer Institute 2009 101(19):1330-1336; doi:10.1093/jnci/djp287
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Replication of Prostate Cancer Risk Loci in a Japanese Case–Control Association Study
Affiliations of authors: Department of Urology, Jikei University School of Medicine, Tokyo, Japan (HY, TKi, HK, YK, SE); Department of Epidemiology, Harvard School of Public Health, Boston, MA (KLP); Department of Pathology, Jikei University School of Medicine, Tokyo, Japan (HT); Department of Public Health, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (TKa); Department of Hygiene and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan (YY); Department of Health Care, Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital, Tokyo, Japan (MY); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (MLF)
Correspondence to: Matthew L. Freedman, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115-6084 (e-mail: freedman{at}broad.mit.edu) or Shin Egawa, MD, Department of Urology, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan (e-mail: s-egpro{at}jikei.ac.jp).
Background: Two prostate cancer genome-wide scans in populations of European ancestry identified several genetic variants that are strongly associated with prostate cancer risk. The effect of these risk variants and their cumulative effect in other populations are unknown.
Methods: We evaluated the association of 23 risk single-nucleotide polymorphisms (SNPs) with prostate cancer risk and clinical covariates (Gleason score, tumor aggressiveness, and age at diagnosis) in men of Japanese ancestry (311 case subjects and 1035 control subjects) using unconditional logistic regression. We also used logistic regression to test the association between increasing numbers of independently associated risk alleles and the risk of prostate cancer, prostate cancer aggressiveness, and age at diagnosis. All statistical tests were two-sided.
Results: Seven of the 23 SNPs (five independent loci) were associated with prostate cancer risk (P values ranged from .0084 to 2.3 x 10–8 and effect sizes [estimated as odds ratios, ORs] ranged from 1.35 to 1.82). None of the seven SNPs was associated with Gleason score or aggressive disease. rs6983561 and rs4430796 were associated with age at diagnosis (Ps = .0188 and .0339, respectively). Men with six or more risk alleles (27% of case patients and 11% of control subjects) had a higher risk of prostate cancer than men with two or fewer risk alleles (7% of case patients and 20% of control subjects) (OR = 6.22, P = 1.5 x 10–12).
Conclusions: These results highlight the critical importance of considering ancestry in understanding how risk alleles influence disease and suggest that risk estimates and variants differ across populations. It is important to perform studies in multiple ancestral populations so that the composite genetic architecture of prostate cancer can be rigorously addressed.
| CONTEXT AND CAVEATS Prior knowledge Previously, 23 single-nucleotide polymorphisms were identified as being associated with prostate cancer risk in European populations. Study design Genetic association case–control study of the 23 single-nucleotide polymorphisms in a Japanese population; associations between disease aggressiveness and age at diagnosis were included. Associations per allele and of several alleles in combination were studied. Contributions A total of seven of the 23 single-nucleotide polymorphisms were associated with increased risk of prostate cancer in this study population, but no associations were found with disease aggressiveness or age at diagnosis. Men with six or more risk alleles had higher risk for prostate cancer than men with two or fewer alleles. Implications The findings in the Japanese population were somewhat different from those performed in European populations, although seven of the 23 single-nucleotide polymorphisms that were previously identified in the European population were associated with prostate cancer risk in the Japanese population in this study. Limitations Because of the multiple alleles tested, their rare frequency, and the population size, statistical power was limited. From the Editors
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H. Yamada and K. L. Penney contributed equally to this work.
Manuscript received October 21, 2008; revised July 6, 2009; accepted July 28, 2009.
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J Natl Cancer Inst 2009 101: 1293.