AUTHOR=Jiao Mingwen , Cui Yuying , Qiu Xiaodong , Liang Xuezhen , Li Junhan , Guo Congcong , Tian Hu 

TITLE=Causal relationship between complement C1QB and colorectal cancer: a drug target Mendelian randomization study

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1403509

DOI=10.3389/fgene.2024.1403509

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>Colorectal cancer is influenced by several factors such as unhealthy habits and genetic factors. <italic>C1QB</italic> has been linked to a number of malignancies. However, uncertainty surrounds the connection between <italic>C1QB</italic> and CRC. Therefore, this study aimed to explore a bidirectional causal relationship of <italic>C1QB</italic> as a drug target in CRC through Mendelian randomization (MR) analysis.</p></sec><sec><title>Methods</title><p>The GWASs for <italic>C1QB</italic> and CRC were obtained from the Integrative Epidemiology Unit Open GWAS database. There were five strategies to investigate MR. Sensitivity analysis was carried out via tests for heterogeneity, horizontal pleiotropy and leave-one-out effects to evaluate the dependability of the MR analysis results. Furthermore, colocalization analysis of <italic>C1QB</italic> and CRC, protein-protein interaction network and drug prediction according to exposure factors as well as phenotype scanning were performed.</p></sec><sec><title>Results</title><p>The results of forward MR analysis demonstrated that <italic>C1QB</italic> was a risk factor for CRC (OR = 1.104, <italic>p</italic> = 0.033). However, we did not find a causal relationship between CRC and <italic>C1QB</italic> (reverse MR). Rs294180 and rs291985 corresponded to the same linkage interval and had the potential to influence <italic>C1QB</italic> and CRC, respectively. The PPI results demonstrated that <italic>C1QB</italic> interacted with 10 genes (<italic>C1QA</italic>, <italic>C1QC</italic>, <italic>C1R</italic>, <italic>C1S</italic>, <italic>C2</italic>, <italic>C4A</italic>, <italic>C4B</italic>, <italic>CALR</italic>, <italic>SERPING1</italic>, and <italic>VSIG4</italic>). Additionally, 21 medications were predicted to match <italic>C1QB</italic>. Molecular docking data, including for benzo(a)pyrene, 1-naphthylisothiocyanate, calcitriol and medroxyprogesterone acetate, revealed excellent binding for drugs and proteins. Moreover, we identified 29 diseases that were associated with <italic>C1QB</italic> and related medicines via disease prediction and intersection methods. As a therapeutic target for CRC, phenotypic scanning revealed that <italic>C1QB</italic> does not significantly affect weight loss, liver cirrhosis, or nonalcoholic fatty liver disease, but might have protective impacts on ovarian cancer and melanoma.</p></sec><sec><title>Conclusion</title><p>The results highlight a causal relationship between <italic>C1QB</italic> and CRC and imply an oncogenic role for <italic>C1QB</italic> in CRC, as potential drug targets. Drugs designed to target <italic>C1QB</italic> have a greater chance of success in clinical trials and are expected to help prioritize CRC drug development and reduce drug development costs. That provided a theoretical foundation and reference for research on CRC and <italic>C1QB</italic> in MR.</p></sec>