Identification of a SNP  in the KLK3 gene which predisposes to prostate cancer – the first coding SNP to be discovered in this disease


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Zsofia Kote-Jarai1,Ali Amin Al Olama2,Daniel Leongamornlert1,Malgorzata Tymrakiewicz1,Edward Saunders1,Nathan Brown1,Michelle Guy1,Graham Giles3,Gianluca Severi3,John Hopper3,Melissa Southey3,Freddy Hamdy4,David Neal2,Jenny Donovan5,Kenneth Muir6,Douglas Easton2,Rosalind Eeles1
1The Institute of Cancer Research, Sutton, United Kingdom,2The University of Cambridge, Cambridge, United Kingdom,3University of Melbourne, Melbourne, Australia,4University of Oxfrod, Oxford, United Kingdom,5University of Bristol, Bristol, United Kingdom,6University of Warrick, Warrick, United Kingdom

Background

To identify common PrCa susceptibilility alleles, we conducted a multistaged genome-wide association study (GWAS). In the first stage (stage 1) 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected PrCa diagnosed at <60 years or having family history of disease, and 1,894 population screened controls with low PSA level from the UK. We have identified 7 novel PrCa susceptibility loci one of which contains a strong candidate susceptibility gene KLK3 which codes for PSA. PSA is widely used as a biomarker for PrCa detection and disease monitoring and our tag-SNP in this region lies between KLK2 and KLK3.

Method

To refine the association of PrCa with variants in this region we imputed SNPs from HapMap2 that were not in our GWAS. We used MACH 1.0 software and the HapMap CEU population as a reference panel.

Results

At the location of KLK3 on 19q13.3 we found a previously unidentified SNP, rs17632542, associated with PrCa at genome-wide significance, (P =5.9x10-26). Using a Taqman assay we genotyped this novel SNP in our stage 1 and an additional stage 2 sample set of 3650 PrCa cases and 3940 controls from the UK and Australia. The combined analysis showed that the association was significantly stronger between PrCa risk and this new SNP when compared with the original tag-SNP (P value 1.6x 10-24 compared to P value 2.3x10-17). The newly identified variant is a non-synonymous coding SNP in the KLK3 gene causing an Ile to Thre substitution at aa179. Molecular modelling suggests that this substitution might affect the stability of the protein.

Conclusion

We conclude that this novel association signal is a strong candidate for a functionally important SNP within the KLK3 gene and that this alteration at 19q13.3 has potential to be the causative variant influencing PrCa risk.