| Title: |
KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness |
| Authors: |
Lin, H-Y; Huang, P-Y; Cheng, C-H; Tung, H-Y; Fang, Z; Berglund, AE; Chen, A; French-Kwawu, J; Harris, D; Pow-Sang, J; Yamoah, K; Cleveland, JL; Awasthi, S; Rounbehler, RJ; Gerke, T; Dhillon, J; Eeles, R; Kote-Jarai, Z; Muir, K; Schleutker, J; Pashayan, N; Neal, DE; Nielsen, SF; Nordestgaard, BG; Gronberg, H; Travis, RC |
| Publisher Information: |
Nature Research |
| Publication Year: |
2026 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/s41598-021-85169-7 |
| Availability: |
https://doi.org/10.1038/s41598-021-85169-7; https://ora.ox.ac.uk/objects/uuid:6071ca1c-b274-47d7-8d99-2ab75ae247a1 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.4BE28375 |
| Database: |
BASE |