Genetic evidence for the causal influence of inflammatory factors on intrahepatic cholangiocarcinoma risk

Figure 1 An overview of the current research process and the foundational assumptions of Mendelian randomization analyses. A: Diagram of the three core assumptions in Mendelian randomization; B: Overall flowchart of the study process. SNPs: Single nucleotide polymorphisms; MR: Mendelian randomization; BWMR: Bayesian weighted Mendelian randomization.

Figure 2  A circular heatmap illustrating the causal impact of inflammatory factors on intrahepatic cholangiocarcinoma risk, analyzed using five statistical methods: Inverse variance weighted, weighted median, Mendelian randomization-Egger, Simple mode, and weighted mode.

Figure 3 Forest plots illustrating the causal effects of specific inflammatory factors on intrahepatic cholangiocarcinoma risk. A: Mendelian randomization (MR) analysis results using the Inverse-Variance weighted method, showing odds ratios with corresponding 95%CI and P values for each inflammatory factor; B: Bayesian weighted MR analysis results, validating the causal associations identified by MR. BWMR: Bayesian weighted Mendelian randomization; IVW: Inverse-Variance weighted method; OR: Odds ratio; Nsnp: Number of SNPs.

Figure 4 Results of reverse Mendelian randomization analysis examining intrahepatic cholangiocarcinoma as the exposure and specific inflammatory factors as the outcomes. A: A forest plot displays the significant causal effects of intrahepatic cholangiocarcinoma (ICC) on programmed cell death 1 ligand 1 levels; B: Scatter plots were employed to illustrate the causal relationship between ICC and programmed cell death ligand 1 levels, using five different Mendelian randomization methods; C: Forest plots from "leave-one-out" sensitivity analyses, illustrating the influence of individual single nucleotide polymorphisms on the overall results. ICC: Intrahepatic cholangiocarcinoma; MR: Mendelian randomization; IVW: Inverse-Variance weighted method; OR: Odds ratio; SNPs: Single nucleotide polymorphisms; Nsnp: Number of SNPs.

Figure 5 Validation of causal associations between specific inflammatory factors and intrahepatic cholangiocarcinoma risk in an independent cohort. A: Forest plot showing the odds ratios with 95%CI for inflammatory factors previously identified in the discovery cohort, evaluated in the validation cohort using the Inverse-Variance weighted (IVW) Mendelian randomization (MR) method; B: Scatter plot illustrating the causal association between genetically predicted artemin levels and ICC risk, analyzed using five MR methods (IVW, weighted median, MR-Egger, simple mode, and weighted mode); C: Scatter plot illustrating the causal association between genetically predicted matrix metalloproteinase-10 levels and ICC risk, using the same five MR methods. ICC: Intrahepatic cholangiocarcinoma; MR: Mendelian randomization; IVW: Inverse-Variance weighted method; OR: Odds ratio; SNPs: Single nucleotide polymorphisms; Nsnp: Number of SNPs.

Figure 6 The meta-Mendelian randomization analysis was conducted to examine the association between artemin levels and matrix metalloproteinase-10 levels using data from both the training and validation sets. A: Meta-Mendelian randomization (MR) analysis of artemin levels was conducted based on intrahepatic cholangiocarcinoma (ICC) data from both the training and validation sets; B: Meta-MR analysis of matrix metalloproteinase-10 levels was conducted based on ICC data from both the training and validation sets. ICC: Intrahepatic cholangiocarcinoma; OR: Odds ratio; GWAS: Genome-wide association studies; Nsnp: Number of SNPs.