Identification of MMP14 and MKLN1 as colorectal cancer susceptibility genes and drug-repositioning candidates from a genome-wide association study

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Abstract
Genome-wide association studies (GWAS) and subsequent functional interpretation have been used to identify susceptible genes and potential drug-repositioning candidates. This study aimed to identify genes associated with colorectal cancer (CRC) and potential drug-repositioning candidates. Patients with CRC at Seoul National University Hospital (SNUH, discovery study) and Chonnam National University Hospital (CNUH, replication study) were included as case groups. The Korean Genome and Epidemiology Study (KoGES) participants were included as a control group. Single-nucleotide polymorphisms (SNPs) were extracted from blood-derived DNA (N = 409,063). A SNP-based logistic regression model was applied. Furthermore, post-GWAS analysis was conducted. Drug-repositioning candidates were identified using a pre-trained deep neural network and the druggability assessment tool. In the discovery study, we conducted a 1:3 age- and sex-matched case–control study that included 500 CRC cases (mean age 63.0 ± 7.15 years) and 1,500 healthy controls (mean age 62.9 ± 7.07 years), each group comprising 50% males and 50% females. The replication study enrolled 4,860 patients with CRC and 46,384 healthy controls. The two-stage GWAS revealed statistically significant associations among MKLN1 (rs75170436, 7q32.3, beta (log odds ratio) = − 0.90, Pmeta = 5.90 × 10–13), MMP14 (rs3751489, 14q11.2, beta (log odds ratio) = − 1.91, Pmeta = 2.31 × 10–12). Post-GWAS functional analysis revealed strong associations on two genes highlighting deleterious effects and increased gene expression. Drug-repositioning analysis identified GW0742 (PPARβ/δ agonist) with the highest binding score and druggability score for MMP14 with a reference allele (12.06, 0.85). Using GWAS, MKLN1 and MMP14 were found to be associated with CRC development and we identified GW0742 (PPARβ/δ agonist) as a potential drug-repositioning candidate for CRC based on MKLN1 and MMP14. These findings improve the understanding of CRC development and provide insights into novel therapeutic targets and candidates for CRC treatment.
Funding Information
  • Ministry of Education (2021RIS-001)
  • Ministry of Science and ICT, South Korea (RS-2024-00440787, 2022R1C1C1009902, 2022R1F1A1074010, RS-2023-00251984, RS-2024-00358322)
  • Seoul National University Hospital Cohort Research Fund (2520140010)
  • Chonnam National University Hwasun Hospital (HCRI23004, HCRI21019)

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