Human tissue kallikreins (KLK), encoded by the largest contiguous cluster of protease genes located on chromosome 19q13.4, are secreted serine proteases with diverse expression patterns and physiological roles. Certain KLKs are implicated in many cancer-related processes such as invasion, proliferation, and metastasis, by acting individually or in cascades with other KLKs or proteases. In addition, they have potential or known applicability as biomarkers e.g. PSA/KLK3 for prostate cancer. We participated in a three stage genome-wide association study as a part of the PRACTICAL consortium, where a SNP (rs2735839) located close to KLK3 was found to be significantly associated with PrCa risk. Fine-mapping studies identified KLK3 nonsynonymous exonic SNP rs17632542 as the causal SNP underlying the association, and a large validation study of 25,000 PrCa patients and 25,000 healthy male controls carried out with the COGS consortium has refined the risk associated with the SNP to be OR=0.74, 95%CI=0.70-0.78. In addition, we have previously reported a significant association of KLK3, KLK14 and KLK15 SNPs with PrCa aggressiveness as defined by Gleason scores. To analyse the association of KLK SNPs with PrCa metastasis, we undertook a case-case analysis. Out of 17,680 patients with available data on PrCa seer-staging, 883 were identified with metastatic disease. Twenty-four SNPs within the KLK region previously found to be associated with risk or aggressiveness of PrCa were genotyped using Illumina infinium assay as a part of COGS chips. We identified rs1058205, rs17632542 and rs2735839 in KLK3 to be significantly associated with metastasis (p<0.01), where most significant results were observed for the rs17632542 (OR=1.5, 95%CI=1.3-1.8). These results are interesting as they indicate that while KLK3 minor allele has a protective role in PrCa predisposition, it is more prevalent in metastatic disease. We are now undertaking the suitable functional assays to validate the results of our prediction modelling. Our preliminary data suggested that the KLK3 non-synonymous SNP might affect protein stability, and thus could be the causal variant at the kallikrein locus to be associated with PrCa risk, aggressiveness and metastasis.