caa a22 4500 44586141X CHVBK 20180317145444.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00439-011-0953-5 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0953-5 Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels [Elektronische Daten] [Hemang Parikh, Zhaoming Wang, Kerry Pettigrew, Jinping Jia, Sarah Daugherty, Meredith Yeager, Kevin Jacobs, Amy Hutchinson, Laura Burdett, Michael Cullen, Liqun Qi, Joseph Boland, Irene Collins, Thomas Albert, Lars Vatten, Kristian Hveem, Inger Njølstad, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine Valeri, Jarmo Virtamo, Michael Thun, Heather Feigelson, W. Diver, Nilanjan Chatterjee, Gilles Thomas, Demetrius Albanes, Stephen Chanock, David Hunter, Robert Hoover, Richard Hayes, Sonja Berndt, Joshua Sampson, Laufey Amundadottir] Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case-control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P=0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P=3.41×10−4, per-allele trend odds ratio (OR)=0.77, 95% CI=0.67-0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P=4.72×10−5, per-allele trend OR=0.68, 95% CI=0.57-0.82) and not for advanced cases with Gleason score >8 or stage ≥III (P=0.31, per-allele trend OR=1.12, 95% CI=0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61ng/ml, 95% CI=1.49-1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12ng/ml, 95% CI=0.96-1.28) (P=9.70×10−5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy. The Author(s), 2011 Parikh Hemang Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut Wang Zhaoming Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Pettigrew Kerry Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut Jia Jinping Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut Daugherty Sarah Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Yeager Meredith Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Jacobs Kevin Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Hutchinson Amy Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Burdett Laura Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Cullen Michael Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Qi Liqun Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Boland Joseph Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Collins Irene Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut Albert Thomas Roche NimbleGen, 53711, Madison, WI, USA aut Vatten Lars Department of Public Health and General Practice, Norwegian University of Science and Technology, 7489, Trondheim, Norway aut Hveem Kristian Department of Public Health and General Practice, Norwegian University of Science and Technology, 7489, Trondheim, Norway aut Njølstad Inger Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, 9037, Tromsø, Norway aut Cancel-Tassin Geraldine Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020, Paris, France aut Cussenot Olivier Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020, Paris, France aut Valeri Antoine Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020, Paris, France aut Virtamo Jarmo Department of Chronic Disease Prevention, National Institute for Health and Welfare, 00300, Helsinki, Finland aut Thun Michael Epidemiology Research Program, American Cancer Society, 30329, Atlanta, GA, USA aut Feigelson Heather Epidemiology Research Program, American Cancer Society, 30329, Atlanta, GA, USA aut Diver W. Epidemiology Research Program, American Cancer Society, 30329, Atlanta, GA, USA aut Chatterjee Nilanjan Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Thomas Gilles Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Albanes Demetrius Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Chanock Stephen Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Hunter David Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, 02115, Boston, MA, USA aut Hoover Robert Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Hayes Richard Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, 10016, New York, NY, USA aut Berndt Sonja Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Sampson Joshua Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut Amundadottir Laufey Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut Human Genetics Springer-Verlag 129/6(2011-06-01), 675-685 0340-6717 129:6<675 2011 129 439 https://doi.org/10.1007/s00439-011-0953-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0953-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Parikh Hemang Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Wang Zhaoming Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Pettigrew Kerry Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Jia Jinping Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Daugherty Sarah Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Yeager Meredith Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Jacobs Kevin Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Hutchinson Amy Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Burdett Laura Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Cullen Michael Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Qi Liqun Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Boland Joseph Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Collins Irene Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Albert Thomas Roche NimbleGen, 53711, Madison, WI, USA aut NATIONALLICENCE 700 1- Vatten Lars Department of Public Health and General Practice, Norwegian University of Science and Technology, 7489, Trondheim, Norway aut NATIONALLICENCE 700 1- Hveem Kristian Department of Public Health and General Practice, Norwegian University of Science and Technology, 7489, Trondheim, Norway aut NATIONALLICENCE 700 1- Njølstad Inger Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, 9037, Tromsø, Norway aut NATIONALLICENCE 700 1- Cancel-Tassin Geraldine Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020, Paris, France aut NATIONALLICENCE 700 1- Cussenot Olivier Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020, Paris, France aut NATIONALLICENCE 700 1- Valeri Antoine Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020, Paris, France aut NATIONALLICENCE 700 1- Virtamo Jarmo Department of Chronic Disease Prevention, National Institute for Health and Welfare, 00300, Helsinki, Finland aut NATIONALLICENCE 700 1- Thun Michael Epidemiology Research Program, American Cancer Society, 30329, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Feigelson Heather Epidemiology Research Program, American Cancer Society, 30329, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Diver W. Epidemiology Research Program, American Cancer Society, 30329, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Chatterjee Nilanjan Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Thomas Gilles Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Albanes Demetrius Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Chanock Stephen Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Hunter David Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, 02115, Boston, MA, USA aut NATIONALLICENCE 700 1- Hoover Robert Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Hayes Richard Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, 10016, New York, NY, USA aut NATIONALLICENCE 700 1- Berndt Sonja Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Sampson Joshua Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Amundadottir Laufey Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 20877, Bethesda, MD, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/6(2011-06-01), 675-685 0340-6717 129:6<675 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer