Yun Dabin, Yang Jung-Ho, Sim Jin-Ah, Kim Minjung, Park Ji Won, Jeong Seung Yong, Shin Aesun, Kweon Sun-Seog, Song Nan
College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Korea.
Department of Preventive Medicine, Chonnam National University Medical School, Hwasun-Gun, Jeollanam-Do, Korea.
J Transl Med. 2025 May 14;23(1):543. doi: 10.1186/s12967-025-06491-6.
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, P = 5.90 × 10), MMP14 (rs3751489, 14q11.2, beta (log odds ratio) = - 1.91, P = 2.31 × 10). 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.
全基因组关联研究（GWAS）及后续的功能解释已被用于识别易感基因和潜在的药物重新定位候选物。本研究旨在识别与结直肠癌（CRC）相关的基因和潜在的药物重新定位候选物。
首尔国立大学医院（SNUH，发现研究）和全南国立大学医院（CNUH，重复研究）的CRC患者被纳入病例组。韩国基因组与流行病学研究（KoGES）的参与者被纳入对照组。从血液来源的DNA中提取单核苷酸多态性（SNP，N = 409,063）。应用基于SNP的逻辑回归模型。此外，还进行了GWAS后分析。使用预训练的深度神经网络和药物可及性评估工具识别药物重新定位候选物。
在发现研究中，我们进行了一项年龄和性别1:3匹配的病例对照研究，包括500例CRC病例（平均年龄63.0±7.15岁）和1500例健康对照（平均年龄62.9±7.07岁），每组男性和女性各占50%。重复研究纳入了4860例CRC患者和46384例健康对照。两阶段GWAS揭示了MKLN1（rs75170436，7q32.3，β（对数优势比）=-0.90，P = 5.90×10）、MMP14（rs3751489，14q11.2，β（对数优势比）=-1.91，P = 2.31×10）之间具有统计学意义的关联。GWAS后功能分析揭示了两个基因上的强关联，突出了有害效应和基因表达增加。药物重新定位分析确定GW0742（PPARβ/δ激动剂）对MMP14的结合分数和药物可及性分数最高，参考等位基因为（12.06，0.85）。
通过GWAS发现MKLN1和MMP14与CRC发生相关，并且基于MKLN1和MMP14，我们确定GW0742（PPARβ/δ激动剂）为CRC潜在的药物重新定位候选物。这些发现增进了对CRC发生的理解，并为CRC治疗的新治疗靶点和候选物提供了见解。
