Chin J Cancer Res
Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Published: October 2024
Objective: Genome-wide association studies (GWAS) have identified over 150 risk loci linked to colorectal cancer (CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism (SNP) rs12603526 in the Asian population. However, the specific causal gene and the functional regulatory mechanisms in this region remain unresolved, necessitating further investigation to elucidate the underlying mechanisms of CRC.
Methods: We employed an RNA interference-based functional approach to identify genes critical for CRC cell proliferation at the GWAS locus 17p13.3. Bioinformatic fine-mapping analysis was conducted to prioritize causal variants. A large-scale study involving 7,013 cases and 7,329 controls from a Chinese population, along with another cohort of 5,158 cases and 20,632 controls from the UK Biobank, was performed to validate the association between the candidate variant and the gene. A series of biological experiments was conducted to explore the function of the candidate gene and its regulatory mechanisms.
Results: We identified as a key oncogene that promotes CRC cell proliferation, and confirmed its carcinogenic role through proliferation assays. The variant rs526835 was prioritized as a causal candidate for CRC risk, located in a functional region with enhancer properties, and showed a significant quantitative association with expression. The rs526835 [T] variant was associated with a 1.17-fold increase in CRC risk [95% confidence interval (95% CI): 1.11-1.23, P=1.23×10] in the large-scale Chinese cohort, which was further corroborated in the UK Biobank cohort. Mechanistically, we demonstrated that rs526835 enhances a promoter-enhancer interaction mediated by the transcription factor JUN, leading to increased expression of .
Conclusions: We reveal the underlying mechanisms of CRC predisposition at the GWAS locus 17p13.3. Additionally, our findings highlight the critical role of in CRC pathogenesis and introduce a novel enhancer-promoter interaction between and rs526835, which could inform future precision prevention and personalized cancer therapies.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2024.05.08 | DOI Listing |
J Affect Disord
January 2025
Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu 610041, China. Electronic address:
Background: Major depressive disorder (MDD) is associated with gastrointestinal tract (GIT) disorders, while genetic correlation, pleiotropic loci and shared risk genes remain to be explored.
Methods: Leveraging genome-wide association study statistics for MDD (n = 170,756), peptic ulcer disease (PUD; n = 16,666), gastroesophageal reflux disease (GORD; n = 54,854), PUD and/or GORD and/or medications (PGM; n = 90,175), irritable bowel syndrome (IBS; n = 28,518), and inflammatory bowel disease (IBD; n = 7045), we determined global and local genetic correlations, identified pleiotropic loci, performed gene-level evaluations, and inferred causal associations using bidirectional Mendelian randomization.
Results: We found global correlation of MDD with PUD (r = 0.
Bioinformatics
January 2025
Department of Biostatistics, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong, China.
Motivation: Fine-mapping aims to prioritize causal variants underlying complex traits by accounting for the linkage disequilibrium of GWAS risk locus. The expanding resources of functional annotations serve as auxiliary evidence to improve the power of fine-mapping. However, existing fine-mapping methods tend to generate many false positive results when integrating a large number of annotations.
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January 2025
Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
Background: Mounting evidence suggests that Parkinson's disease (PD) and inflammatory bowel disease (IBD) are closely associated and becoming global health burdens. However, the causal relationships and common pathogeneses between them are uncertain. Furthermore, they are uncurable.
View Article and Find Full Text PDFMol Cancer
January 2025
Molecular Epidemiology (MOLE), Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
VTRNA2-1 is a polymorphically imprinted locus. The proportion of individuals with a maternally imprinted VTRNA2-1 locus is consistently approximately 75% in populations of European origin, with the remaining circa 25% having a non-methylated VTRNA2-1 locus. Recently, VTRNA2-1 hypermethylation at birth was suggested to be a precursor of paediatric acute lymphoblastic leukaemia with biomarker potential.
View Article and Find Full Text PDFPharmacol Res
January 2025
Centre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK. Electronic address:
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