title: Genetic variation in prostate-specific antigen-detected prostate cancer and the effect of control selection on genetic association studies.
abstract: BACKGROUND
  Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls.
  
  
  METHODS
  We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA < 0.5 ng/mL) or "high" (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA.
  
  
  RESULTS
  The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA.
  
  
  CONCLUSIONS
  Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA.
  
  
  CONCLUSIONS
  These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Duleeka W
authors.initials: DW
authors.lastname: Knipe
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC / University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC / University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, UK.|The Royal Marsden National Health Service Foundation Trust, Sutton, Surrey and London, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, UK.|The Royal Marsden National Health Service Foundation Trust, Sutton, Surrey and London, UK.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Cambridge, UK.
authors.forename: Ali Amin
authors.initials: AA
authors.lastname: Al Olama
authors.affiliation: Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Cambridge, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Benlloch
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.affiliation: Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom.
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: The Royal Marsden National Health Service Foundation Trust, Sutton, Surrey and London, UK.|Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC / University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Commissariat à l'Energie Atomique, Center National de Génotypage, Evry, France.|McGill University-Génome Québec Innovation Centre, Montreal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC / University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
mesh_terms: D000368:Aged; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics*
chemical_list: D017430:Prostate-Specific Antigen
references.citation: Nat Genet. 2009 Oct;41(10):1058-60
references.pmid: 19767752
references.citation: Nat Genet. 2009 Oct;41(10):1122-6
references.pmid: 19767754
references.citation: Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1196-203
references.pmid: 21467234
references.citation: Nat Genet. 2010 Sep;42(9):751-4
references.pmid: 20676098
references.citation: Nat Genet. 2011 Jul 10;43(8):785-91
references.pmid: 21743467
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 Nov;21(11):2048-58
references.pmid: 22923026
references.citation: Cancer Res. 2009 Jan 1;69(1):10-5
references.pmid: 19117981
references.citation: Eur Urol. 2003 Apr;43(4):327-32
references.pmid: 12667711
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120
references.citation: Nat Genet. 2011 Jun;43(6):570-3
references.pmid: 21602798
references.citation: Nat Genet. 2007 May;39(5):631-7
references.pmid: 17401366
references.citation: Nat Genet. 2008 Mar;40(3):310-5
references.pmid: 18264096
references.citation: J Natl Cancer Inst. 2007 Dec 19;99(24):1836-44
references.pmid: 18073375
references.citation: N Engl J Med. 2004 May 27;350(22):2239-46
references.pmid: 15163773
references.citation: Nat Genet. 2013 Apr;45(4):385-91, 391e1-2
references.pmid: 23535732
references.citation: Genet Epidemiol. 2010 Dec;34(8):816-34
references.pmid: 21058334
references.citation: Cancer. 1994 Jul 1;74(1):104-14
references.pmid: 7516262
references.citation: Nat Genet. 2007 Aug;39(8):977-83
references.pmid: 17603485
references.citation: Sci Transl Med. 2010 Dec 15;2(62):62ra92
references.pmid: 21160077
references.citation: Annu Rev Genomics Hum Genet. 2009;10:387-406
references.pmid: 19715440
references.citation: Eur J Cancer. 2010 Nov;46(17):3095-101
references.pmid: 21047592
references.citation: Clin Cancer Res. 2009 Mar 1;15(5):1787-93
references.pmid: 19223501
references.citation: Nat Genet. 2008 Mar;40(3):316-21
references.pmid: 18264097
references.citation: Cancer Biol Ther. 2011 Dec 1;12(11):997-1004
references.pmid: 22130093
references.citation: Hum Mol Genet. 2011 Oct 1;20(19):3867-75
references.pmid: 21743057
references.citation: Nat Genet. 2009 Oct;41(10):1116-21
references.pmid: 19767753