Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript

Z. Kote-Jarai, A. Amin Al Olama, D. Leongamornlert, M. Tymrakiewicz, E. Saunders, M. Guy, G. G. Giles, G. Severi, M. Southey, J. L. Hopper, K. C. Sit, J. M. Harris, J. Batra, A. B. Spurdle, J. A. Clements, F. Hamdy, D. Neal, J. Donovan, K. Muir, P. D P Pharoah & 11 others S. J. Chanock, N. Brown, S. Benlloch, E. Castro, N. Mahmud, L. O'Brien, A. Hall, E. Sawyer, R. Wilkinson, D. F. Easton, R. A. Eeles

Research output: Contribution to journalArticle

Abstract

Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10-22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10-34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

Original languageEnglish (US)
Pages (from-to)687-694
Number of pages8
JournalHuman Genetics
Volume129
Issue number6
DOIs
StatePublished - Jun 2011
Externally publishedYes

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Prostatic Neoplasms
Genome-Wide Association Study
Prostate-Specific Antigen
Single Nucleotide Polymorphism
Genes
RNA Splicing
Molecular Dynamics Simulation
Genetic Predisposition to Disease
Genetic Markers
Biomarkers
Genotype
Genome
Neoplasms
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Kote-Jarai, Z., Amin Al Olama, A., Leongamornlert, D., Tymrakiewicz, M., Saunders, E., Guy, M., ... Eeles, R. A. (2011). Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Human Genetics, 129(6), 687-694. https://doi.org/10.1007/s00439-011-0981-1

Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. / Kote-Jarai, Z.; Amin Al Olama, A.; Leongamornlert, D.; Tymrakiewicz, M.; Saunders, E.; Guy, M.; Giles, G. G.; Severi, G.; Southey, M.; Hopper, J. L.; Sit, K. C.; Harris, J. M.; Batra, J.; Spurdle, A. B.; Clements, J. A.; Hamdy, F.; Neal, D.; Donovan, J.; Muir, K.; Pharoah, P. D P; Chanock, S. J.; Brown, N.; Benlloch, S.; Castro, E.; Mahmud, N.; O'Brien, L.; Hall, A.; Sawyer, E.; Wilkinson, R.; Easton, D. F.; Eeles, R. A.

In: Human Genetics, Vol. 129, No. 6, 06.2011, p. 687-694.

Research output: Contribution to journalArticle

Kote-Jarai, Z, Amin Al Olama, A, Leongamornlert, D, Tymrakiewicz, M, Saunders, E, Guy, M, Giles, GG, Severi, G, Southey, M, Hopper, JL, Sit, KC, Harris, JM, Batra, J, Spurdle, AB, Clements, JA, Hamdy, F, Neal, D, Donovan, J, Muir, K, Pharoah, PDP, Chanock, SJ, Brown, N, Benlloch, S, Castro, E, Mahmud, N, O'Brien, L, Hall, A, Sawyer, E, Wilkinson, R, Easton, DF & Eeles, RA 2011, 'Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript', Human Genetics, vol. 129, no. 6, pp. 687-694. https://doi.org/10.1007/s00439-011-0981-1
Kote-Jarai Z, Amin Al Olama A, Leongamornlert D, Tymrakiewicz M, Saunders E, Guy M et al. Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Human Genetics. 2011 Jun;129(6):687-694. https://doi.org/10.1007/s00439-011-0981-1
Kote-Jarai, Z. ; Amin Al Olama, A. ; Leongamornlert, D. ; Tymrakiewicz, M. ; Saunders, E. ; Guy, M. ; Giles, G. G. ; Severi, G. ; Southey, M. ; Hopper, J. L. ; Sit, K. C. ; Harris, J. M. ; Batra, J. ; Spurdle, A. B. ; Clements, J. A. ; Hamdy, F. ; Neal, D. ; Donovan, J. ; Muir, K. ; Pharoah, P. D P ; Chanock, S. J. ; Brown, N. ; Benlloch, S. ; Castro, E. ; Mahmud, N. ; O'Brien, L. ; Hall, A. ; Sawyer, E. ; Wilkinson, R. ; Easton, D. F. ; Eeles, R. A. / Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. In: Human Genetics. 2011 ; Vol. 129, No. 6. pp. 687-694.
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abstract = "Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10-22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10-34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.",
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AU - Kote-Jarai, Z.

AU - Amin Al Olama, A.

AU - Leongamornlert, D.

AU - Tymrakiewicz, M.

AU - Saunders, E.

AU - Guy, M.

AU - Giles, G. G.

AU - Severi, G.

AU - Southey, M.

AU - Hopper, J. L.

AU - Sit, K. C.

AU - Harris, J. M.

AU - Batra, J.

AU - Spurdle, A. B.

AU - Clements, J. A.

AU - Hamdy, F.

AU - Neal, D.

AU - Donovan, J.

AU - Muir, K.

AU - Pharoah, P. D P

AU - Chanock, S. J.

AU - Brown, N.

AU - Benlloch, S.

AU - Castro, E.

AU - Mahmud, N.

AU - O'Brien, L.

AU - Hall, A.

AU - Sawyer, E.

AU - Wilkinson, R.

AU - Easton, D. F.

AU - Eeles, R. A.

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N2 - Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10-22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10-34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

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