title: COX-2 gene promoter haplotypes and prostate cancer risk.
abstract: Cyclooxygenase-2 (COX-2) is a key rate-limiting enzyme that converts arachidonic acid into pro-inflammatory 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 that 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 CCAAT/enhancer binding protein alpha (C/EBP alpha) and NF-kappa B 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 a 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 suggest that variation of the COX-2 promoter may influence the risk and development of prostate cancer.
authors.affiliation: National Human Genome Center at Howard University, Washington, DC 20060, USA.
authors.forename: Ramesh C K
authors.initials: RC
authors.lastname: Panguluri
authors.forename: Layron O
authors.initials: LO
authors.lastname: Long
authors.forename: Weidong
authors.initials: W
authors.lastname: Chen
authors.forename: Songping
authors.initials: S
authors.lastname: Wang
authors.forename: Aoua
authors.initials: A
authors.lastname: Coulibaly
authors.forename: Flora
authors.initials: F
authors.lastname: Ukoli
authors.forename: Aaron
authors.initials: A
authors.lastname: Jackson
authors.forename: Sally
authors.initials: S
authors.lastname: Weinrich
authors.forename: Chiledum
authors.initials: C
authors.lastname: Ahaghotu
authors.forename: William
authors.initials: W
authors.lastname: Isaacs
authors.forename: Rick A
authors.initials: RA
authors.lastname: Kittles
mesh_terms: D001483:Base Sequence; D051546:Cyclooxygenase 2; D017931:DNA Primers; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D012307:Risk Factors
chemical_list: D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases