title: Association between Prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data.
abstract: BACKGROUND
  Kallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease.
  
  
  OBJECTIVE
  We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis.  METHODS AND DATA SOURCES: Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study.
  
  
  RESULTS
  Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p<0.05) but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77-0.93; p = 2.7×10(-4)). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells.
  
  
  CONCLUSIONS
  Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.
authors: Australian Prostate Cancer Research Centre-Queensland and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. jyotsna.batra@qut.edu.au
authors: Jyotsna
authors: J
authors: Batra
authors: Felicity
authors: F
authors: Lose
authors: Tracy
authors: T
authors: O'Mara
authors: Louise
authors: L
authors: Marquart
authors: Carson
authors: C
authors: Stephens
authors: Kimberly
authors: K
authors: Alexander
authors: Srilakshmi
authors: S
authors: Srinivasan
authors: Rosalind A
authors: RA
authors: Eeles
authors: Douglas F
authors: DF
authors: Easton
authors: Ali Amin
authors: AA
authors: Al Olama
authors: Zsofia
authors: Z
authors: Kote-Jarai
authors: Michelle
authors: M
authors: Guy
authors: Kenneth
authors: K
authors: Muir
authors: Artitaya
authors: A
authors: Lophatananon
authors: Aneela A
authors: AA
authors: Rahman
authors: David E
authors: DE
authors: Neal
authors: Freddie C
authors: FC
authors: Hamdy
authors: Jenny L
authors: JL
authors: Donovan
authors: Suzanne
authors: S
authors: Chambers
authors: Robert A
authors: RA
authors: Gardiner
authors: Joanne
authors: J
authors: Aitken
authors: John
authors: J
authors: Yaxley
authors: Mary-Anne
authors: MA
authors: Kedda
authors: Judith A
authors: JA
authors: Clements
authors: Amanda B
authors: AB
authors: Spurdle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002874:Chromosome Mapping; D019295:Computational Biology; D030541:Databases, Genetic; D003710:Demography; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011793:Queensland; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: C501608:KLK15 protein, human; D007610:Kallikreins