Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels

Scott D. Cramer, Bao Li Chang, Anuradha Rao, Gregory A. Hawkins, S. Lilly Zheng, Wendy N. Wade, Roger T. Cooke, Leanne N. Thomas, Eugene R. Bleecker, William J. Catalona, David Sterling, Deborah A. Meyers, Jill Ohar, Jianfeng Xu

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Abstract

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.

Original languageEnglish
Pages (from-to)1044-1053
Number of pages10
JournalJournal of the National Cancer Institute
Volume95
Issue number14
DOIs
StatePublished - 16 Jul 2003

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Genetic Polymorphisms
Prostate-Specific Antigen
Serum
Genes
Single Nucleotide Polymorphism
Alleles
Haplotypes
Genotype
Prostatic Diseases
Polymerase Chain Reaction
Gene Order
Linkage Disequilibrium
Luciferases
Genetic Promoter Regions
Human Activities
Lung Diseases
Prostatic Neoplasms
Analysis of Variance

Cite this

Cramer, Scott D. ; Chang, Bao Li ; Rao, Anuradha ; Hawkins, Gregory A. ; Zheng, S. Lilly ; Wade, Wendy N. ; Cooke, Roger T. ; Thomas, Leanne N. ; Bleecker, Eugene R. ; Catalona, William J. ; Sterling, David ; Meyers, Deborah A. ; Ohar, Jill ; Xu, Jianfeng. / Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels. In: Journal of the National Cancer Institute. 2003 ; Vol. 95, No. 14. pp. 1044-1053.
@article{6a913653b8e44e7da312fe30e7926c71,
title = "Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels",
abstract = "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.",
author = "Cramer, {Scott D.} and Chang, {Bao Li} and Anuradha Rao and Hawkins, {Gregory A.} and Zheng, {S. Lilly} and Wade, {Wendy N.} and Cooke, {Roger T.} and Thomas, {Leanne N.} and Bleecker, {Eugene R.} and Catalona, {William J.} and David Sterling and Meyers, {Deborah A.} and Jill Ohar and Jianfeng Xu",
year = "2003",
month = "7",
day = "16",
doi = "10.1093/jnci/95.14.1044",
language = "English",
volume = "95",
pages = "1044--1053",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
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Cramer, SD, Chang, BL, Rao, A, Hawkins, GA, Zheng, SL, Wade, WN, Cooke, RT, Thomas, LN, Bleecker, ER, Catalona, WJ, Sterling, D, Meyers, DA, Ohar, J & Xu, J 2003, 'Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels', Journal of the National Cancer Institute, vol. 95, no. 14, pp. 1044-1053. https://doi.org/10.1093/jnci/95.14.1044

Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels. / Cramer, Scott D.; Chang, Bao Li; Rao, Anuradha; Hawkins, Gregory A.; Zheng, S. Lilly; Wade, Wendy N.; Cooke, Roger T.; Thomas, Leanne N.; Bleecker, Eugene R.; Catalona, William J.; Sterling, David; Meyers, Deborah A.; Ohar, Jill; Xu, Jianfeng.

In: Journal of the National Cancer Institute, Vol. 95, No. 14, 16.07.2003, p. 1044-1053.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels

AU - Cramer, Scott D.

AU - Chang, Bao Li

AU - Rao, Anuradha

AU - Hawkins, Gregory A.

AU - Zheng, S. Lilly

AU - Wade, Wendy N.

AU - Cooke, Roger T.

AU - Thomas, Leanne N.

AU - Bleecker, Eugene R.

AU - Catalona, William J.

AU - Sterling, David

AU - Meyers, Deborah A.

AU - Ohar, Jill

AU - Xu, Jianfeng

PY - 2003/7/16

Y1 - 2003/7/16

N2 - 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.

AB - 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.

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U2 - 10.1093/jnci/95.14.1044

DO - 10.1093/jnci/95.14.1044

M3 - Article

VL - 95

SP - 1044

EP - 1053

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 14

ER -