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-Prats; Eduardo 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

doi:10.1126/scitranslmed.3001513

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

Urology

Research output: Contribution to journal › Article › peer-review

136 Scopus citations

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.

Original language	English (US)
Article number	62ra92
Journal	Science translational medicine
Volume	2
Issue number	62
DOIs	https://doi.org/10.1126/scitranslmed.3001513
State	Published - Dec 15 2010

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Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/scitranslmed.3001513

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Gudmundsson, J., Besenbacher, S., Sulem, P., Gudbjartsson, D. F., Olafsson, I., Arinbjarnarson, S., Agnarsson, B. A., Benediktsdottir, K. R., Isaksson, H. J., Kostic, J. P., Gudjonsson, S. A., Stacey, S. N., Gylfason, A., Sigurdsson, A., Holm, H., Bjornsdottir, U. S., Eyjolfsson, G. I., Navarrete, S., Fuertes, F., ... Stefansson, K. (2010). Genetic correction of PSA values using sequence variants associated with PSA levels. Science translational medicine, 2(62), [62ra92]. https://doi.org/10.1126/scitranslmed.3001513

@article{cd183f890c1a410b868c5e7797ce24fa,

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 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.",

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

year = "2010",

month = dec,

day = "15",

doi = "10.1126/scitranslmed.3001513",

language = "English (US)",

volume = "2",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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Gudmundsson, J, Besenbacher, S, Sulem, P, Gudbjartsson, DF, Olafsson, I, Arinbjarnarson, S, Agnarsson, BA, Benediktsdottir, KR, Isaksson, HJ, Kostic, JP, Gudjonsson, SA, Stacey, SN, Gylfason, A, Sigurdsson, A, Holm, H, Bjornsdottir, US, Eyjolfsson, GI, Navarrete, S, Fuertes, F, Garcia-Prats, MD, Polo, E, Checherita, IA, Jinga, M, Badea, P, Aben, KK, Schalken, JA, Van Oort, IM, Sweep, FC, Helfand, BT, Davis, M, Donovan, JL, Hamdy, FC, Kristjansson, K, Gulcher, JR, Masson, G, Kong, A, Catalona, WJ, Mayordomo, JI, Geirsson, G, Einarsson, GV, Barkardottir, RB, Jonsson, E, Jinga, V, Mates, D, Kiemeney, LA, Neal, DE, Thorsteinsdottir, U, Rafnar, T & Stefansson, K 2010, 'Genetic correction of PSA values using sequence variants associated with PSA levels', Science translational medicine, vol. 2, no. 62, 62ra92. https://doi.org/10.1126/scitranslmed.3001513

TY - JOUR

T1 - Genetic correction of PSA values using sequence variants associated with PSA levels

AU - Gudmundsson, Julius

AU - Besenbacher, Soren

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F.

AU - Olafsson, Isleifur

AU - Arinbjarnarson, Sturla

AU - Agnarsson, Bjarni A.

AU - Benediktsdottir, Kristrun R.

AU - Isaksson, Helgi J.

AU - Kostic, Jelena P.

AU - Gudjonsson, Sigurjon A.

AU - Stacey, Simon N.

AU - Gylfason, Arnaldur

AU - Sigurdsson, Asgeir

AU - Holm, Hilma

AU - Bjornsdottir, Unnur S.

AU - Eyjolfsson, Gudmundur I.

AU - Navarrete, Sebastian

AU - Fuertes, Fernando

AU - Garcia-Prats, Maria D.

AU - Polo, Eduardo

AU - Checherita, Ionel A.

AU - Jinga, Mariana

AU - Badea, Paula

AU - Aben, Katja K.

AU - Schalken, Jack A.

AU - Van Oort, Inge M.

AU - Sweep, Fred C.

AU - Helfand, Brian T.

AU - Davis, Michael

AU - Donovan, Jenny L.

AU - Hamdy, Freddie C.

AU - Kristjansson, Kristleifur

AU - Gulcher, Jeffrey R.

AU - Masson, Gisli

AU - Kong, Augustine

AU - Catalona, William J.

AU - Mayordomo, Jose I.

AU - Geirsson, Gudmundur

AU - Einarsson, Gudmundur V.

AU - Barkardottir, Rosa B.

AU - Jonsson, Eirikur

AU - Jinga, Viorel

AU - Mates, Dana

AU - Kiemeney, Lambertus A.

AU - Neal, David E.

AU - Thorsteinsdottir, Unnur

AU - Rafnar, Thorunn

AU - Stefansson, Kari

PY - 2010/12/15

Y1 - 2010/12/15

N2 - 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.

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.

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U2 - 10.1126/scitranslmed.3001513

DO - 10.1126/scitranslmed.3001513

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C2 - 21160077

AN - SCOPUS:78650468754

SN - 1946-6234

VL - 2

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 62

M1 - 62ra92

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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