title: A large prospective study of SEP15 genetic variation, interaction with plasma selenium levels, and prostate cancer risk and survival.
abstract: The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R(2) > 0.8) within SEP15, as well as rs5859 in the 3' untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (P(interaction) = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. kpenney@hsph.harvard.edu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Haojie
authors.initials: H
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: J Steven
authors.initials: JS
authors.lastname: Morris
authors.forename: Tobias
authors.initials: T
authors.lastname: Kurth
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
mesh_terms: D016022:Case-Control Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics* / Q000401:mortality*; D012307:Risk Factors; D012643:Selenium / Q000097:blood*; D051140:Selenoproteins / Q000235:genetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: C495238:SELENOF protein, human; D051140:Selenoproteins; D012643:Selenium