Causal associations of MICB, CTSA, and MMP9 proteins with oral cancer: Mendelian randomization study

Abstract

Abstract Oral cancer (ORCA) is the most prevalent histological subtype of oral malignancies in which immune modulation is relevant. The goal of this work was to employ Mendelian randomization (MR) to investigate the causal connection between the immune-related proteins MICB, CTSA, MMP9, and ORCA. The Open GWAS database of the Integrative Epidemiology Unit (IEU) was accessed to collect GWAS data for ORCA (ieu-b-4961), MICB (prot-a-1898), CTSA (prot-a-717) and MMP9 (prot-a-1921). From 372,373 samples, the ORCA dataset comprises 7,723,107 single nucleotide polymorphisms (SNPs). MICB, CTSA, and MMP9 all have 10,534,735 SNPs and 3,301 sample sizes. Then, the primary SVMR implementation approaches were weighted mode, simple mode, inverse variance weighted (IVW), weighted median, and MR-Egger. IVW was the most effective technique. A sensitivity study was also carried out to assess the correctness of SVMR data, with special focus devoted to heterogeneity, horizontal pleiotropy, and Leave-One-Out (LOO). MVMR was eventually implemented as well. A Mendelian randomization analysis of the three exposure factors in the dataset (ieu-b-94, ebi-a-GCST012237) was also performed to validate the study results. According to the SVMR results, there was a noteworthy causal interaction between ORCA and MICB (P = 0.0014), MMP9 (P = 0.0343), and CTSA (P = 0.0003). Furthermore, odds ratios (ORs) values revealed that MMP9 (OR = 1.0005) was an ORCA risk factor, whereas MICB (OR = 0.9994) and CTSA (OR = 0.9993) were security factors. The robustness of the SVMR findings was confirmed by the p-values of the heterogeneity and horizontal pleiotropy, both of which were greater than 0.05. The MVMR result did not affect any of the safety or hazard features of these three exposure factors. However, the P value for MMP9 was greater than 0.05, implying that MICB and CTSA may have a greater influence on ORCA than MMP9. The validation outcomes in both datasets harmonized with the findings from previous research, thereby solidifying the reliability of results. Our investigation provided a crucial resource for further research on the subject by demonstrating a causal relationship between ORCA and MICB, CTSA, and MMP9.

Keywords

• Oral cancer
• Mendelian randomization
• Causal relationship
• GWAS
• MICB
• CTSA