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

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Authors
Gudmundsson, Julius
Besenbacher, Soren
Sulem, Patrick
Gudbjartsson, Daniel F
Olafsson, Isleifur
Arinbjarnarson, Sturla
Agnarsson, Bjarni A
Benediktsdottir, Kristrun R
Isaksson, Helgi J
Kostic, Jelena P
Gudjonsson, Sigurjon A
Stacey, Simon N
Gylfason, Arnaldur
Sigurdsson, Asgeir
Holm, Hilma
Bjornsdottir, Unnur S
Eyjolfsson, Gudmundur I
Navarrete, Sebastian
Fuertes, Fernando
Garcia-Prats, Maria D
Polo, Eduardo
Checherita, Ionel A
Jinga, Mariana
Badea, Paula
Aben, Katja K
Schalken, Jack A
van Oort, Inge M
Sweep, Fred C
Helfand, Brian T
Davis, Michael
Donovan, Jenny L
Hamdy, Freddie C
Kristjansson, Kristleifur
Gulcher, Jeffrey R
Masson, Gisli
Kong, Augustine
Catalona, William J
Mayordomo, Jose I
Geirsson, Gudmundur
Einarsson, Gudmundur V
Barkardottir, Rosa B
Jonsson, Eirikur
Jinga, Viorel
Mates, Dana
Kiemeney, Lambertus A
Neal, David E
Thorsteinsdottir, Unnur
Rafnar, Thorunn
Stefansson, Kari
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Issue Date
2010-12-15

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Citation
Sci Transl Med. 2010, 2(62):62ra92
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.
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http://dx.doi.org/10.1126/scitranslmed.3001513
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564581/
ae974a485f413a2113503eed53cd6c53
10.1126/scitranslmed.3001513
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