KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness
Awasthi Shivanshu; Batra Jyotsna; Berglund Anders E.; Brenner Hermann; Cannon-Albright Lisa; Chen Ann; Cheng Chia-Ho; Clements Judith; Cleveland John L.; Cybulski Cezary; Dhillon Jasreman; Eeles Rosalind; Fang Zhide; French-Kwawu Jennifer; Gerke Travis; Giles Graham G.; Gronberg Henrik; Haiman Christopher A.; Harris Darian; Huang Po-Yu; Kaneva Radka; Khaw Kay-Tee; Kibel Adam S.; Kote-Jarai Zsofia; Lin Hui-Yi; Maier Christiane; Muir Kenneth; Neal David E.; Nielsen Sune F.; Nordestgaard Børge G.; Pandha Hardev; Park Jong Y.; UKGPCS collaborators; APCB(Australian Prostate Cancer BioResource); The PRACTICAL consortium; Pashayan Nora; Pow-Sang Julio; Rounbehler Robert J.; Schleutker Johanna; Srinivasan Srilakshmi; Stanford Janet L.; Teixeira Manuel R.; Thibodeau Stephen N.; Travis Ruth C.; Tung Heng-Yuan; Wiklund Fredrik; Yamoah Kosj
https://urn.fi/URN:NBN:fi-fe2021093048529
Tiivistelmä
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<3.5x10-9) and 3145 (P<1x10-5) 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.
Kokoelmat
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