caa a22 4500 445861495 CHVBK 20180317145444.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00439-011-0981-1 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0981-1 Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript [Elektronische Daten] [Z. Kote-Jarai, A. Amin Al Olama, D. Leongamornlert, M. Tymrakiewicz, E. Saunders, M. Guy, G. Giles, G. Severi, M. Southey, J. Hopper, K. Sit, J. Harris, J. Batra, A. Spurdle, J. Clements, F. Hamdy, D. Neal, J. Donovan, K. Muir, P. Pharoah, S. Chanock, N. Brown, S. Benlloch, E. Castro, N. Mahmud, L. O'Brien, A. Hall, E. Sawyer, R. Wilkinson, D. Easton, R. Eeles] Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P=3.9×10−22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P=1.9×10−34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk. The Author(s), 2011 Kote-Jarai Z. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Amin Al Olama A. Department of Public Health and Primary Care, Centre for Cancer Epidemiology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut Leongamornlert D. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Tymrakiewicz M. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Saunders E. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Guy M. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Giles G. Cancer Epidemiology Centre, The Cancer Council Victoria, 100 Drummond Street, 3053, Carlton, VIC, Australia aut Severi G. Cancer Epidemiology Centre, The Cancer Council Victoria, 100 Drummond Street, 3053, Carlton, VIC, Australia aut Southey M. Cancer Epidemiology Centre, The Cancer Council Victoria, 100 Drummond Street, 3053, Carlton, VIC, Australia aut Hopper J. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston Street, 3053, Carlton, VIC, Australia aut Sit K. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut Harris J. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut Batra J. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut Spurdle A. Genetics and Population Health Division, Queensland Institute of Medical Research, 300 Herston Rd, 4006, Herston, QLD, Australia aut Clements J. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut Hamdy F. Nuffield Department of Surgery, University of Oxford, OX3 9DU, Oxford, UK aut Neal D. Surgical Oncology, Departments of Oncology and Surgery, University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, CB2 2QQ, Cambridge, UK aut Donovan J. Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK aut Muir K. Warwick Medical School, Warwick University, CV4 7AL, Coventry, UK aut Pharoah P. Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut Chanock S. Division of Cancer Epidemiology and Genetics, National Cancer Institute, 8717 Grovemont Circle, 20892-4605, Bethesda, MD, USA aut Brown N. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Benlloch S. Department of Public Health and Primary Care, Centre for Cancer Epidemiology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut Castro E. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Mahmud N. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut O'Brien L. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Hall A. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Sawyer E. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Wilkinson R. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Easton D. Department of Public Health and Primary Care, Centre for Cancer Epidemiology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut Eeles R. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut Human Genetics Springer-Verlag 129/6(2011-06-01), 687-694 0340-6717 129:6<687 2011 129 439 https://doi.org/10.1007/s00439-011-0981-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0981-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kote-Jarai Z. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Amin Al Olama A. Department of Public Health and Primary Care, Centre for Cancer Epidemiology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut NATIONALLICENCE 700 1- Leongamornlert D. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Tymrakiewicz M. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Saunders E. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Guy M. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Giles G. Cancer Epidemiology Centre, The Cancer Council Victoria, 100 Drummond Street, 3053, Carlton, VIC, Australia aut NATIONALLICENCE 700 1- Severi G. Cancer Epidemiology Centre, The Cancer Council Victoria, 100 Drummond Street, 3053, Carlton, VIC, Australia aut NATIONALLICENCE 700 1- Southey M. Cancer Epidemiology Centre, The Cancer Council Victoria, 100 Drummond Street, 3053, Carlton, VIC, Australia aut NATIONALLICENCE 700 1- Hopper J. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston Street, 3053, Carlton, VIC, Australia aut NATIONALLICENCE 700 1- Sit K. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut NATIONALLICENCE 700 1- Harris J. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut NATIONALLICENCE 700 1- Batra J. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut NATIONALLICENCE 700 1- Spurdle A. Genetics and Population Health Division, Queensland Institute of Medical Research, 300 Herston Rd, 4006, Herston, QLD, Australia aut NATIONALLICENCE 700 1- Clements J. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Urban Village, 4059, Kelvin Grove, QLD, Australia aut NATIONALLICENCE 700 1- Hamdy F. Nuffield Department of Surgery, University of Oxford, OX3 9DU, Oxford, UK aut NATIONALLICENCE 700 1- Neal D. Surgical Oncology, Departments of Oncology and Surgery, University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, CB2 2QQ, Cambridge, UK aut NATIONALLICENCE 700 1- Donovan J. Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK aut NATIONALLICENCE 700 1- Muir K. Warwick Medical School, Warwick University, CV4 7AL, Coventry, UK aut NATIONALLICENCE 700 1- Pharoah P. Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut NATIONALLICENCE 700 1- Chanock S. Division of Cancer Epidemiology and Genetics, National Cancer Institute, 8717 Grovemont Circle, 20892-4605, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Brown N. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Benlloch S. Department of Public Health and Primary Care, Centre for Cancer Epidemiology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut NATIONALLICENCE 700 1- Castro E. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Mahmud N. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- O'Brien L. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Hall A. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Sawyer E. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Wilkinson R. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 700 1- Easton D. Department of Public Health and Primary Care, Centre for Cancer Epidemiology, University of Cambridge, Strangeways Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK aut NATIONALLICENCE 700 1- Eeles R. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/6(2011-06-01), 687-694 0340-6717 129:6<687 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer