title: Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels.
abstract: Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case-control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10(-4), per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67-0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P = 4.72 × 10(-5), per-allele trend OR = 0.68, 95% CI = 0.57-0.82) and not for advanced cases with Gleason score >8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49-1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96-1.28) (P = 9.70 × 10(-5)). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20877, USA.
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pettigrew
authors.forename: Jinping
authors.initials: J
authors.lastname: Jia
authors.forename: Sarah
authors.initials: S
authors.lastname: Daugherty
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jacobs
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.forename: Laura
authors.initials: L
authors.lastname: Burdett
authors.forename: Michael
authors.initials: M
authors.lastname: Cullen
authors.forename: Liqun
authors.initials: L
authors.lastname: Qi
authors.forename: Joseph
authors.initials: J
authors.lastname: Boland
authors.forename: Irene
authors.initials: I
authors.lastname: Collins
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Albert
authors.forename: Lars J
authors.initials: LJ
authors.lastname: Vatten
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cancel-Tassin
authors.forename: Olivier
authors.initials: O
authors.lastname: Cussenot
authors.forename: Antoine
authors.initials: A
authors.lastname: Valeri
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Heather Spencer
authors.initials: HS
authors.lastname: Feigelson
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Diver
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Joshua
authors.initials: J
authors.lastname: Sampson
authors.forename: Laufey
authors.initials: L
authors.lastname: Amundadottir
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000235:genetics*
chemical_list: C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen