title: Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers.
abstract: We investigated associations of serum α- and γ-tocopherols and their effect modification by polymorphisms in oxidative stress regulatory enzymes in relation to prostate cancer risk. In a nested case-control study in the Carotene and Retinol Efficacy Trial, prerandomized serum α- and γ-tocopherol were assayed among 684 men with incident prostate cancer [375 nonaggressive and 284 aggressive cancer (stage III/IV or Gleason score ≥7)] and 1441 controls. Manganese superoxide dismutase Ala-16Val (rs4880), glutathione peroxidase 1 Pro200Leu (rs1050450), catalase -262 C > T (rs1001179), and myeloperoxidase (MPO) G-463A (rs2333227) were genotyped. A multivariate-adjusted inverse association of serum α-tocopherol with total prostate cancer risk was observed in current smokers (OR = 0.62, 95% CI = 0.40-0.96, 4th vs. 1st quartiles). High (≥median) compared to low serum concentrations of α- and γ-tocopherol were inversely associated with aggressive prostate cancer in current smokers (OR = 0.50, 95% CI = 0.32-0.78 and OR = 0.64, 95% CI = 0.43-0.95, respectively). The association was stronger among those with MPO G/A+A/A genotypes. Among current smokers with low serum α-tocopherol concentrations, MPO G/A+A/A, the genotypes downregulating oxidative stress, were associated with an increased risk for aggressive prostate cancer (OR = 2.06, 95% CI = 1.22-3.46). Conversely, current smokers with these genotypes who had high α-tocopherol concentrations had a reduced risk for aggressive prostate cancer (OR = 0.34, 95% CI = 0.15-0.80; P-interaction = 0.001). In conclusion, among current smokers, both high serum α- and γ-tocopherol concentrations were associated with reduced risks of aggressive prostate cancer. The α-tocopherol-associated risks are modified by polymorphism in MPO G-463A.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, Seattle, WA, USA.
authors.forename: Ting-Yuan David
authors.initials: TY
authors.lastname: Cheng
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Barnett
authors.forename: Alan R
authors.initials: AR
authors.lastname: Kristal
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Irena B
authors.initials: IB
authors.lastname: King
authors.forename: Mark D
authors.initials: MD
authors.lastname: Thornquist
authors.forename: Gary E
authors.initials: GE
authors.lastname: Goodman
authors.forename: Marian L
authors.initials: ML
authors.lastname: Neuhouser
mesh_terms: D016022:Case-Control Studies; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D018384:Oxidative Stress / Q000235:genetics; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D012907:Smoking / Q000097:blood*; D024502:alpha-Tocopherol / Q000097:blood*; D024504:gamma-Tocopherol / Q000097:blood
chemical_list: D024504:gamma-Tocopherol; D009195:Peroxidase; D024502:alpha-Tocopherol