The Kallikrein-Related Peptidases hK2 and PSA with Emphasis on Genetic Variation, Secretion, and Sperm Motility

University dissertation from Lund University

Abstract: Prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) are secreted by the prostate into seminal plasma and through leakage into blood. This leakage increases rapidly in prostate disease, and PSA is used worldwide as a marker of prostate cancer. PSA is activated in vitro by hK2, and cleaves the semenogelins in semen, which releases motile sperm, and low levels of PSA have been associated with low sperm motility. The present objective was to evaluate factors that might influence release of hK2 and PSA, and to study those two proteins with regard to their levels in seminal plasma and blood, and their association with sperm motility in young healthy men without prostate disease. PSA and hK2 were measured by immunofluorometric assay. Genomic DNA was prepared from peripheral leukocytes, and genotyping was performed with the Sequenom Mass Array System. Levels of hK2 and PSA were found to be associated with variants in the genes encoding hK2 (KLK2) and PSA (KLK3) in young men (mean age 18 years). The single-nucleotide polymorphisms (SNPs) rs198972, rs198977, rs198978, and “SNP2” in KLK2 were associated with lower hK2 levels in seminal plasma and serum in carriers of the TT genotype. In KLK3, the AA genotype in rs266882 in combination with CAG > 22 were correlated with higher total PSA (tPSA) in serum; rs2271094 and “SNP1" were associated with lower tPSA concentrations in seminal plasma from subjects homozygous for the common allele (A or G, respectively). Carriers of the common T allele in rs1058205 in KLK3, had higher amounts of tPSA in seminal plasma, higher concentrations of tPSA in serum, and a lower ratio of free to tPSA (%fPSA). Free PSA (fPSA) in blood showed ~17% co-variation with PSA in semen, whereas no relationship was found between levels of complexed PSA (cPSA) in blood and PSA in semen. In blood, levels of cPSA, but not fPSA, increased with age, which may reflect an increasing incidence of prostate disease. In men 19–40 years, an age when reproduction most commonly takes place, correlations were found between hK2 and PSA in seminal plasma (p < 0.001, r = 0.47) and between hK2 and age (p = 0.01, r = –0.20). Men in that age group who were in the lowest quartile with respect to amount of PSA in seminal plasma, semen volume, and zinc concentration had, respectively, 5.8%, 4.1%, and 3.9% fewer progressively motile sperm. These findings suggest that a decrease in secretory function of the prostate can impair sperm motility. The present results obtained by analysing the allelic variants of KLK2 and KLK3 might be useful for refining models of PSA cut-off values in PCa testing.

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