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

  1. Author:
    Parikh, H.
    Wang, Z. M.
    Pettigrew, K. A.
    Jia, J. P.
    Daugherty, S.
    Yeager, M.
    Jacobs, K. B.
    Hutchinson, A.
    Burdett, L.
    Cullen, M.
    Qi, L. Q.
    Boland, J.
    Collins, I.
    Albert, T. J.
    Vatten, L. J.
    Hveem, K.
    Njolstad, I.
    Cancel-Tassin, G.
    Cussenot, O.
    Valeri, A.
    Virtamo, J.
    Thun, M. J.
    Feigelson, H. S.
    Diver, W. R.
    Chatterjee, N.
    Thomas, G.
    Albanes, D.
    Chanock, S. J.
    Hunter, D. J.
    Hoover, R.
    Hayes, R. B.
    Berndt, S. I.
    Sampson, J.
    Amundadottir, L.

  2. Author Address

    [Amundadottir, L] NIH, Lab Translat Genom, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [Parikh, H; Pettigrew, KA; Jia, JP; Collins, I; Amundadottir, L] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA [Wang, ZM; Yeager, M; Jacobs, KB; Hutchinson, A; Burdett, L; Cullen, M; Qi, LQ; Boland, J] SAIC Frederick Inc, Core Genotyping Facil, NCI Frederick, Frederick, MD 21702 USA [Pettigrew, KA] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7BL, Antrim, North Ireland [Albert, TJ] Roche NimbleGen, Madison, WI 53711 USA [Vatten, LJ; Hveem, K] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway [Njolstad, I] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [Cancel-Tassin, G; Cussenot, O; Valeri, A] Hop Tenon, AP HP, Ctr Rech Pathol Prostat CeRePP, F-75020 Paris, France [Virtamo, J] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00300, Finland [Thun, MJ; Feigelson, HS; Diver, WR] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA [Thomas, G] Ctr Leon Berard, INSERM, U590, F-69373 Lyon 08, France [Hunter, DJ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA [Hayes, RB] NYU, Sch Med, Div Epidemiol, Dept Environm Med, New York, NY 10016 USA;Amundadottir, L (reprint author), NIH, Lab Translat Genom, Div Canc Epidemiol & Genet, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA;amundadottirl@mail.nih.gov
    1. Year: 2011
    2. Date: Jun
  2. Journal: Human Genetics
    1. 129
    2. 6
    3. Pages: 675-685
  4. Type of Article: Article
  5. ISSN: 0340-6717
  1. 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 x 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 x 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 a parts per thousand yenIII (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 x 10(-5)). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.

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  2. DOI: 10.1007/s00439-011-0953-5
  3. View record in Web of Science®
  4. WOS: 000290540900009

Library Notes

  1. Fiscal Year: FY2010-2011
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