Carcinogenesis Advance Access published online on January 30, 2004
Carcinogenesis, doi:10.1093/carcin/bgh100
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 National Human Genome Center at Howard University, Washington, DC 20060; National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR
* Corresponding author. E-mail: rkittles{at}howard.edu.
Received 26 September 2003
; revised 12 January 2004
; accepted 17 January 2004
Cyclooxygenase-2 (COX-2) is a key rate-limiting enzyme that converts arachidonic acid into proinflamatory prostaglandins. COX-2 expression is strongly correlated with increased tumor microvasculature density and plays an important role in inhibiting apoptosis, stimulating angiogenesis and promoting tumor cell metastasis and invasion. However, little is known about the role sequence variation of the COX-2 gene contributes to prostate cancer. Thus, we searched for polymorphisms in the promoter region of the COX-2 gene using denaturing high performance liquid chromatography. Four single nucleotide polymorphisms (SNPs), -1285A/G, -1265G/A, -899G/C and -297C/G, were detected and confirmed by direct sequencing. Three of the SNPs in the promoter region of COX-2 gene create at least three putative transcription factor binding sites and eliminate C/EBPalpha and NF-kb binding sites. A case-control study of the four SNPs in African American (N=288), Bini Nigerian (N=264), and European American (N=184) prostate cancer cases and age matched controls revealed that SNP -297G was associated with decreased risk for prostate cancer (Odds Ratio [OR]=0.49; CI=0.2-0.9; P=0.01). The effect on risk was observed in both African Americans (OR=0.51; CI=0.2-0.9; P=0.01) and European Americans (OR=0.33; CI=0.1-0.9; P=0.02). In addition, SNPs -1265A and -899C were associated with increased prostate cancer risk in African Americans (OR=2.72; CI=1.3-5.8; P=0.007 and OR=3.67; CI=1.4-9.9; P=0.007, respectively). Haplotype analyses revealed modest effects on susceptibility to prostate cancer across populations. Haplotype GGCC conferred increased risk in the African American and Nigerian populations. Conversely, haplotype AGGG exhibited a negative association with prostate cancer risk in African Americans (OR=0.4; CI = 0.1-0.9; P=0.02) and European Americans (OR=0.2; CI=0.1-0.9; P=0.03). These data suggests that variation of the COX-2 promoter may influence the risk and development of prostate cancer.
COX-2, African Americans, prostate cancer, single nucleotide polymorphisms (SNP), haplotypes
COX-2 gene promoter haplotypes and prostate cancer risk
2 National Human Genome Center at Howard University, Washington, DC 20060; Divison of Urology, Howard University Hospital, Washington, DC 20060; Howard University Cancer Center, Washington, DC 20060
3 National Human Genome Center at Howard University, Washington, DC 20060
4 Howard University Cancer Center, Washington, DC 20060
5 Divison of Urology, Howard University Hospital, Washington, DC 20060
6 School of Nursing, University of Louisville, Louisville, Kentucky 40292
7 Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21287
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