KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness

Sci Rep. 2021 Apr 29;11(1):9264. doi: 10.1038/s41598-021-85169-7.


Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10-9) and 3145 (P < 1 × 10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers, Tumor / genetics
  • Epistasis, Genetic
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Kallikreins / genetics*
  • Male
  • Polymorphism, Single Nucleotide
  • Prostate-Specific Antigen / genetics*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology


  • Biomarkers, Tumor
  • KLK3 protein, human
  • Kallikreins
  • Prostate-Specific Antigen