Genome-wide association study identifies loci at ATF7IP and KLK2 associated with percentage of circulating free PSA.
BACKGROUND
Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy.


METHODS
To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml.


RESULTS
We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness.


CONCLUSIONS
These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.
Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Guangfu
G
Jin
Siqun Lilly
SL
Zheng
Hans
H
Lilja
Seong-Tae
ST
Kim
Sha
S
Tao
Zhengrong
Z
Gao
Tracey
T
Young
Fredrik
F
Wiklund
Junjie
J
Feng
William B
WB
Isaacs
Roger S
RS
Rittmaster
Henrik
H
Gronberg
Lynn D
LD
Condreay
Jielin
J
Sun
Jianfeng
J
Xu
D016022:Case-Control Studies; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics*; D012097:Repressor Proteins; D013548:Sweden; D020840:Tissue Kallikreins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
C501309:ATF7IP protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D020840:Tissue Kallikreins; D017430:Prostate-Specific Antigen