© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 11, 812-818,
June 4, 2003
© 2003 Oxford University Press
ARTICLE |
New Paraoxonase 1 Polymorphism I102V and the Risk of Prostate Cancer in Finnish Men
Affiliations of authors: M. Marchesani, J. Kaikkonen, P. Uimari, Oy Jurilab Ltd., Kuopio, Finland; A. Hakkarainen, T.-P. Tuomainen, Research Institute of Public Health, University of Kuopio, Kuopio; E. Pukkala, Finnish Cancer Registry, Helsinki, Finland; E. Seppälä, M. Matikainen, J. Schleutker, Laboratory of Cancer Genetics, University of Tampere and Tampere University Hospital, Tampere, Finland; O.-P. Kallioniemi, Medical Biotechnology Group, Technical Research Centre of Finland and University of Turku, Turku, Finland; T. Lehtimäki, Laboratory of Atherosclerosis Genetics, Tampere University Hospital, Tampere; J. T. Salonen, Research Institute of Public Health, University of Kuopio, Kuopio, and Inner Savo Health Centre, Suonenjoki, Finland.
Correspondence to: Professor Jukka T. Salonen, M.D., Ph.D., M.Sc.P.H., Research Institute of Public Health, University of Kuopio, Box 1627, 70211 Kuopio, Finland (e-mail: jukka.salonen{at}uku.fi).
Background: Human serum paraoxonase eliminates carcinogenic lipid-soluble radicals. Because expression of the main human paraoxonase gene PON1 varies widely in humans, certain PON1 polymorphisms might be associated with increased risks of cancer. We sought new functional mutations in PON1 and determined whether known or new PON1 mutations were associated with the risk for prostate cancer in a prospective, random, population-based sample of Finnish men and in a case–control study. Methods: Serum paraoxonase activity was measured in 835 healthy men in the Kuopio Ischaemic Heart Disease Risk Factor Study. PON1 mutations were identified by hierarchical phenotype-targeted sequencing in DNAs from the 100 men with the lowest paraoxonase activity in this cohort, and 1595 men in the cohort were genotyped for PON1 mutations by restriction fragment length polymorphism. Multivariable analysis was used to investigate the association of known and new PON1 mutations with incident prostate cancer in 1569 cancer-free men in the cohort followed for 9–14 years. In a case–control study of Finnish men, the association of prostate cancer with the PON1 mutation identified in the cohort study was investigated in 69 case patients with familial prostate cancer and 69 unmatched healthy control subjects. Results: We identified a new single-nucleotide PON1 polymorphism associated with decreased serum paraoxonase activity that caused an isoleucine
valine change at codon 102 in exon 4 (I102V). Of the 1569 men cancer-free at baseline, 56 (3.6%) were carriers of the I102V mutation. After adjusting for age and cholesterol-lowering medications, the relative risk for developing prostate cancer during follow-up was 6.3 (95% confidence interval [CI] = 2.1 to 19.2) among 102V allele carriers compared with noncarriers. Other PON1 alleles were not statistically significantly associated with prostate cancer. In the case–control study, patients with familial prostate cancer were more likely to be carriers of the PON1 I102V mutation than control subjects (odds ratio = 4.3, 95% CI = 0.9 to 21.5). Conclusion: The PON1 102V allele appears to be associated with an increased risk for prostate cancer.
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