Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels

Hemang Parikh, Zhaoming Wang, Kerry A. Pettigrew, Jinping Jia, Sarah Daugherty, Meredith Yeager, Kevin B. Jacobs, Amy Hutchinson, Laura Burdett, Michael Cullen, Liqun Qi, Joseph Boland, Irene Collins, Thomas J. Albert, Lars J. Vatten, Kristian Hveem, Inger Njølstad, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine ValeriJarmo Virtamo, Michael J. Thun, Heather Spencer Feigelson, W. Ryan Diver, Nilanjan Chatterjee, Gilles Thomas, Demetrius Albanes, Stephen J. Chanock, David J. Hunter, Robert Hoover, Richard B. Hayes, Sonja I. Berndt, Joshua Sampson, Laufey Amundadottir

Research output: Contribution to journalArticle

Abstract

Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case-control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10-4, per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67-0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P = 4.72 × 10-5, per-allele trend OR = 0.68, 95% CI = 0.57-0.82) and not for advanced cases with Gleason score >8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49-1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96-1.28) (P = 9.70 × 10 -5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.

Original languageEnglish (US)
Pages (from-to)675-685
Number of pages11
JournalHuman genetics
Volume129
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Parikh, H., Wang, Z., Pettigrew, K. A., Jia, J., Daugherty, S., Yeager, M., Jacobs, K. B., Hutchinson, A., Burdett, L., Cullen, M., Qi, L., Boland, J., Collins, I., Albert, T. J., Vatten, L. J., Hveem, K., Njølstad, I., Cancel-Tassin, G., Cussenot, O., ... Amundadottir, L. (2011). Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels. Human genetics, 129(6), 675-685. https://doi.org/10.1007/s00439-011-0953-5