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.