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

Autor: Jarmo Virtamo, Laura Burdett, Robert N. Hoover, Gilles Thomas, Kevin B. Jacobs, Kerry A. Pettigrew, Zhaoming Wang, W. Ryan Diver, Geraldine Cancel-Tassin, Laufey T. Amundadottir, Sonja I. Berndt, Irene Collins, Hemang Parikh, Jinping Jia, Stephen J. Chanock, Olivier Cussenot, Demetrius Albanes, Joshua N. Sampson, Thomas J. Albert, Sarah E. Daugherty, Amy Hutchinson, Kristian Hveem, Lars J. Vatten, Heather Spencer Feigelson, Meredith Yeager, Antoine Valeri, Inger Njølstad, Michael J. Thun, Joseph Boland, Liqun Qi, Michael Cullen, Nilanjan Chatterjee, David J. Hunter, Richard B. Hayes
Rok vydání: 2011
Předmět:
Male
Oncology
medicine.medical_specialty
VDP::Medisinske Fag: 700::Basale medisinske
odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714
Locus (genetics)
Single-nucleotide polymorphism
VDP::Medical disciplines: 700::Basic medical
dental and veterinary science disciplines: 710::Medical genetics: 714
Biology
Polymorphism
Single Nucleotide
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Germline mutation
Internal medicine
Genetics
medicine
Humans
Genetics(clinical)
Genetic Predisposition to Disease
Germ-Line Mutation
Genetics (clinical)
Original Investigation
030304 developmental biology
0303 health sciences
Case-control study
Chromosome Mapping
Prostatic Neoplasms
Cancer
Odds ratio
Prostate-Specific Antigen
medicine.disease
3. Good health
Prostate-specific antigen
Endocrinology
Case-Control Studies
030220 oncology & carcinogenesis
Kallikreins
Chromosomes
Human
Pair 19
Zdroj: Human Genetics
ISSN: 1432-1203
0340-6717
Popis: 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 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. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-0953-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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