title: Genetic correction of PSA values using sequence variants associated with PSA levels.
abstract: Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
authors.affiliation: deCODE genetics, IS-101 Reykjavik, Iceland. julius@decode.is
authors.forename: Julius
authors.initials: J
authors.lastname: Gudmundsson
authors.forename: Soren
authors.initials: S
authors.lastname: Besenbacher
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.forename: Sturla
authors.initials: S
authors.lastname: Arinbjarnarson
authors.forename: Bjarni A
authors.initials: BA
authors.lastname: Agnarsson
authors.forename: Kristrun R
authors.initials: KR
authors.lastname: Benediktsdottir
authors.forename: Helgi J
authors.initials: HJ
authors.lastname: Isaksson
authors.forename: Jelena P
authors.initials: JP
authors.lastname: Kostic
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.forename: Unnur S
authors.initials: US
authors.lastname: Bjornsdottir
authors.forename: Gudmundur I
authors.initials: GI
authors.lastname: Eyjolfsson
authors.forename: Sebastian
authors.initials: S
authors.lastname: Navarrete
authors.forename: Fernando
authors.initials: F
authors.lastname: Fuertes
authors.forename: Maria D
authors.initials: MD
authors.lastname: Garcia-Prats
authors.forename: Eduardo
authors.initials: E
authors.lastname: Polo
authors.forename: Ionel A
authors.initials: IA
authors.lastname: Checherita
authors.forename: Mariana
authors.initials: M
authors.lastname: Jinga
authors.forename: Paula
authors.initials: P
authors.lastname: Badea
authors.forename: Katja K
authors.initials: KK
authors.lastname: Aben
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
authors.forename: Inge M
authors.initials: IM
authors.lastname: van Oort
authors.forename: Fred C
authors.initials: FC
authors.lastname: Sweep
authors.forename: Brian T
authors.initials: BT
authors.lastname: Helfand
authors.forename: Michael
authors.initials: M
authors.lastname: Davis
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: Kristleifur
authors.initials: K
authors.lastname: Kristjansson
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gulcher
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: William J
authors.initials: WJ
authors.lastname: Catalona
authors.forename: Jose I
authors.initials: JI
authors.lastname: Mayordomo
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Geirsson
authors.forename: Gudmundur V
authors.initials: GV
authors.lastname: Einarsson
authors.forename: Rosa B
authors.initials: RB
authors.lastname: Barkardottir
authors.forename: Eirikur
authors.initials: E
authors.lastname: Jonsson
authors.forename: Viorel
authors.initials: V
authors.lastname: Jinga
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D055088:Early Detection of Cancer / Q000379:methods*; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D007610:Kallikreins / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D029584:Prostatic Secretory Proteins / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics; D019098:Telomerase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D029584:Prostatic Secretory Proteins; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; C043076:beta-microseminoprotein; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C509186:TERT protein, human; D019098:Telomerase; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen