Identification of a SNP in the KLK3 gene which predisposes to prostate cancer the first coding SNP to be discovered in this disease
Session type: Proffered paper sessions
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.
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.
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.
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.