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 -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 language | English (US) |
|---|---|
| Pages (from-to) | 675-685 |
| Number of pages | 11 |
| Journal | Human Genetics |
| Volume | 129 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2011 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels. / Parikh, Hemang; Wang, Zhaoming; Pettigrew, Kerry A.; Jia, Jinping; Daugherty, Sarah; Yeager, Meredith; Jacobs, Kevin B.; Hutchinson, Amy; Burdett, Laura; Cullen, Michael; Qi, Liqun; Boland, Joseph; Collins, Irene; Albert, Thomas J.; Vatten, Lars J.; Hveem, Kristian; Njølstad, Inger; Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine; Virtamo, Jarmo; Thun, Michael J.; Feigelson, Heather Spencer; Diver, W. Ryan; Chatterjee, Nilanjan; Thomas, Gilles; Albanes, Demetrius; Chanock, Stephen J.; Hunter, David J.; Hoover, Robert; Hayes, Richard B.; Berndt, Sonja I.; Sampson, Joshua; Amundadottir, Laufey.
In: Human Genetics, Vol. 129, No. 6, 06.2011, p. 675-685.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels
AU - Parikh, Hemang
AU - Wang, Zhaoming
AU - Pettigrew, Kerry A.
AU - Jia, Jinping
AU - Daugherty, Sarah
AU - Yeager, Meredith
AU - Jacobs, Kevin B.
AU - Hutchinson, Amy
AU - Burdett, Laura
AU - Cullen, Michael
AU - Qi, Liqun
AU - Boland, Joseph
AU - Collins, Irene
AU - Albert, Thomas J.
AU - Vatten, Lars J.
AU - Hveem, Kristian
AU - Njølstad, Inger
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Valeri, Antoine
AU - Virtamo, Jarmo
AU - Thun, Michael J.
AU - Feigelson, Heather Spencer
AU - Diver, W. Ryan
AU - Chatterjee, Nilanjan
AU - Thomas, Gilles
AU - Albanes, Demetrius
AU - Chanock, Stephen J.
AU - Hunter, David J.
AU - Hoover, Robert
AU - Hayes, Richard B.
AU - Berndt, Sonja I.
AU - Sampson, Joshua
AU - Amundadottir, Laufey
PY - 2011/6
Y1 - 2011/6
N2 - 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 -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.
AB - 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 -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.
UR - http://www.scopus.com/inward/record.url?scp=79959749784&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959749784&partnerID=8YFLogxK
U2 - 10.1007/s00439-011-0953-5
DO - 10.1007/s00439-011-0953-5
M3 - Article
C2 - 21318478
AN - SCOPUS:79959749784
VL - 129
SP - 675
EP - 685
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 6
ER -