Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels.
BACKGROUND
Recent evidence suggests that genetic variation in the promoter of the prostate-specific antigen (PSA) gene may contribute to individual variation in serum PSA levels. However, polymorphisms associated with variations in PSA levels have not been identified.


METHODS
We used the polymerase chain reaction to amplify the promoter region of the PSA genes (nucleotide positions -3873 to -5749 with respect to the start of transcription) of 409 healthy white men at risk for lung disease. Polymerase chain reaction products were sequenced to identify polymorphisms in the PSA gene promoter and to genotype the men for common single nucleotide polymorphisms (SNPs) and were cloned into luciferase reporter constructs to assay PSA promoter activity in human LNCaP prostate cancer cells. Analysis of variance was used to test the association of polymorphism frequencies with mean serum PSA levels. All statistical tests were two-sided.


RESULTS
The -4643G/A SNP (G allele) had a 21.2% prevalence and was associated with increases in serum PSA levels (P =.017) and PSA promoter activity (P<.001). The -5412C/T SNP (C allele) had a 22.0% prevalence and was associated with an increase in serum PSA levels (P =.0015). The -5429T/G SNP (G allele) had a 23.0% prevalence, was associated with an increase in serum PSA levels (P =.021), and was in linkage disequilibrium with the -5412C/T SNP. The promoter activity of the -5412 C/-5429 G haplotype was higher than that of the -5412 T/-5429 T haplotype (P<.001).


CONCLUSIONS
Genetic variations in the PSA promoter are associated with serum PSA levels in men without prostatic disease. PSA promoter genotype information may help to refine models of PSA cutoff values.
Cramer
Scott D
SD
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. scramer@wfubmc.edu
Chang
Bao-Li
BL
Rao
Anuradha
A
Hawkins
Gregory A
GA
Zheng
S Lilly
SL
Wade
Wendy N
WN
Cooke
Roger T
RT
Thomas
Leanne N
LN
Bleecker
Eugene R
ER
Catalona
William J
WJ
Sterling
David A
DA
Meyers
Deborah A
DA
Ohar
Jill
J
Xu
Jianfeng
J
D000368:Aged; D022981:Allelic Imbalance / Q000235:genetics*; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000235:genetics*; D003001:Cloning, Molecular; D005784:Gene Amplification; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000276:immunology*; D017422:Sequence Analysis, DNA; D001616:beta-Galactosidase / Q000235:genetics
D014408:Biomarkers, Tumor; D005819:Genetic Markers; D008156:Luciferases; D001616:beta-Galactosidase; D017430:Prostate-Specific Antigen