RT Journal Article
SR Electronic
T1 Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 62ra92
OP 62ra92
DO 10.1126/scitranslmed.3001513
VO 2
IS 62
A1 Gudmundsson, Julius
A1 Besenbacher, Soren
A1 Sulem, Patrick
A1 Gudbjartsson, Daniel F.
A1 Olafsson, Isleifur
A1 Arinbjarnarson, Sturla
A1 Agnarsson, Bjarni A.
A1 Benediktsdottir, Kristrun R.
A1 Isaksson, Helgi J.
A1 Kostic, Jelena P.
A1 Gudjonsson, Sigurjon A.
A1 Stacey, Simon N.
A1 Gylfason, Arnaldur
A1 Sigurdsson, Asgeir
A1 Holm, Hilma
A1 Bjornsdottir, Unnur S.
A1 Eyjolfsson, Gudmundur I.
A1 Navarrete, Sebastian
A1 Fuertes, Fernando
A1 Garcia-Prats, Maria D.
A1 Polo, Eduardo
A1 Checherita, Ionel A.
A1 Jinga, Mariana
A1 Badea, Paula
A1 Aben, Katja K.
A1 Schalken, Jack A.
A1 van Oort, Inge M.
A1 Sweep, Fred C.
A1 Helfand, Brian T.
A1 Davis, Michael
A1 Donovan, Jenny L.
A1 Hamdy, Freddie C.
A1 Kristjansson, Kristleifur
A1 Gulcher, Jeffrey R.
A1 Masson, Gisli
A1 Kong, Augustine
A1 Catalona, William J.
A1 Mayordomo, Jose I.
A1 Geirsson, Gudmundur
A1 Einarsson, Gudmundur V.
A1 Barkardottir, Rosa B.
A1 Jonsson, Eirikur
A1 Jinga, Viorel
A1 Mates, Dana
A1 Kiemeney, Lambertus A.
A1 Neal, David E.
A1 Thorsteinsdottir, Unnur
A1 Rafnar, Thorunn
A1 Stefansson, Kari
YR 2010
UL http://stm.sciencemag.org/content/2/62/62ra92.abstract
AB 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 Pcombined <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.