Genetic correction of PSA values using sequence variants associated with PSA levels

Julius Gudmundsson*, Soren Besenbacher, Patrick Sulem, Daniel F. Gudbjartsson, Isleifur Olafsson, Sturla Arinbjarnarson, Bjarni A. Agnarsson, Kristrun R. Benediktsdottir, Helgi J. Isaksson, Jelena P. Kostic, Sigurjon A. Gudjonsson, Simon N. Stacey, Arnaldur Gylfason, Asgeir Sigurdsson, Hilma Holm, Unnur S. Bjornsdottir, Gudmundur I. Eyjolfsson, Sebastian Navarrete, Fernando Fuertes, Maria D. Garcia-PratsEduardo Polo, Ionel A. Checherita, Mariana Jinga, Paula Badea, Katja K. Aben, Jack A. Schalken, Inge M. Van Oort, Fred C. Sweep, Brian T. Helfand, Michael Davis, Jenny L. Donovan, Freddie C. Hamdy, Kristleifur Kristjansson, Jeffrey R. Gulcher, Gisli Masson, Augustine Kong, William J. Catalona, Jose I. Mayordomo, Gudmundur Geirsson, Gudmundur V. Einarsson, Rosa B. Barkardottir, Eirikur Jonsson, Viorel Jinga, Dana Mates, Lambertus A. Kiemeney, David E. Neal, Unnur Thorsteinsdottir, Thorunn Rafnar, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


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.

Original languageEnglish (US)
Article number62ra92
JournalScience translational medicine
Issue number62
StatePublished - Dec 15 2010

ASJC Scopus subject areas

  • General Medicine


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