Characterizing Associations and SNP-Environment Interactions for GWAS-Identified Prostate Cancer Risk Markers—Results from BPC3 Sara Lindstrom 1,2 , Fredrick Schumacher 3 , Afshan Siddiq 4 , Ruth C. Travis 5 , Daniele Campa 6 , Sonja I. Berndt 7 , W. Ryan Diver 8 , Gianluca Severi 9 , Naomi Allen 5 , Gerald Andriole 10 , Bas Bueno-de-Mesquita 11 , Stephen J. Chanock 7 , David Crawford 12 , J. Michael Gaziano 13,14 , Graham G. Giles 9,15 , Edward Giovannucci 16 , Carolyn Guo 1,2 , Christopher A. Haiman 3 , Richard B. Hayes 7,17 , Jytte Halkjaer 18 , David J. Hunter 1,19 , Mattias Johansson 20,21 , Rudolf Kaaks 22 , Laurence N. Kolonel 23 , Carmen Navarro 24,25 , Elio Riboli 4 , Carlotta Sacerdote 26 , Meir Stampfer 2,16,19 , Daniel O. Stram 3 , Michael J. Thun 8 , Dimitrios Trichopoulos 2,27 , Jarmo Virtamo 28 , Stephanie J. Weinstein 7 , Meredith Yeager 7 , Brian Henderson 3 , Jing Ma 19 , Loic Le Marchand 23 , Demetrius Albanes 7 , Peter Kraft 1,2,29 * 1 Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, 2 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, 3 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America, 4 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom, 5 Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, 6 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, 7 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 8 Department of Epidemiology, American Cancer Society, Atlanta, Georgia, United States of America, 9 Cancer Epidemiology Centre, Cancer Council Victoria and the Centre for Molecular, Genetic, Environmental, and Analytic Epidemiology, University of Melbourne, Melbourne, Australia, 10 Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America, 11 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands, 12 Urologic Oncology, University of Colorado at Denver Health Sciences Center, Denver, Colorado, United States of America, 13 Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC) and Geriatric Research, Education, and Clinical Center (GRECC), Boston Veterans Affairs Healthcare System, Boston, Massachusetts, United States of America, 14 Division of Aging, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America, 15 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia, 16 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America, 17 Division of Epidemiology, NYU Langone Medical Center, New York, New York, United States of America, 18 The Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark, 19 Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 20 International Agency for Research on Cancer, Lyon, France, 21 Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea ˚ University, Umea ˚, Sweden, 22 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, 23 Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, United States of America, 24 Department of Epidemiology, Regional Health Authority, Murcia, Spain, 25 CIBER Epidemiologı ´a y Salud Pu ´ blica (CIBERESP), Barcelona, Spain, 26 CPO-Piemonte Torino, and Human Genetics Foundation, Torino, Italy, 27 Center for Food and Nutrition Policies, Athens, Greece, 28 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland, 29 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America Abstract Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10 228 ). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade ,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined. PLoS ONE | www.plosone.org 1 February 2011 | Volume 6 | Issue 2 | e17142