Causal Effects and Immune Cell Mediators of Prescription Analgesic Use and Risk of Liver Cancer and Precancerosis in European Population: A Mendelian Randomization Study

Abstract

Diverse clinical observations and basic studies have been conducted to explore the implications of analgesic medications in liver diseases. However, the direct causal relationship between prescription analgesic use (PAU) and the risk of liver cancer and precancerosis remains unclear. Thus, we aimed to reveal the conceivable causal effect of PAU on liver cancer and precancerosis, with immune cells as mediating factors. Two-sample Mendelian randomization (MR) analyses were performed to ascertain the causality of PAU on liver cancer and precancerosis. Sensitivity analysis approaches were employed to assess the heterogeneity and pleiotropy of results. Our findings revealed a causal correlation between different PAUs and the risk of liver cancer and alcoholic liver disease (ALD). Specifically, salicylic acid derivatives (SADs) and anilide medications were found to have a protective effect on liver cancer. And non-steroidal anti-inflammatory drugs (NSAIDs) and anilide medications showed a causal impact on ALD. Finally, mediation analyses found that anilide medications influence liver cancer through different immune cell phenotypes. Our research provides new genetic evidence for the causal impact of PAU on liver cancer and precancerosis, with the mediating role of immune cells demonstrated, offering a valuable foundation for researching analgesic medications in liver cancer and precancerosis treatment.

Keywords: analgesics; immune cell; liver cancer and precancerosis; mendelian randomization.

Figure 1

Directed acyclic graph of the MR framework analyzing the causal effect of PAU on liver cancer and precancerosis. Abbreviation: SNPs, single-nucleotide polymorphisms; IVs, instrumental variables; NSAIDs, non-steroidal anti-inflammatory drugs; SAD, salicylic acid derivative; AP, antimigraine preparations.

Figure 2

Relationship between analgesic and the risk of liver cancer and precancerosis with immune cells as mediators in the Mendelian randomization. Abbreviations: ALD, alcoholic liver disease.

Figure 3

Summary of forest plots showing the significant causal effect of PAU on liver cancer and precancerosis. OR, odds ratio; CI, confidence interval; nsnp, number of single-nucleotide polymorphism; LFC, liver fibrosis and cirrhosis; ALD, alcoholic liver disease.

Figure 4

Reverse MR analysis to rule out reverse causation. OR, odds ratio; CI, confidence interval; nsnp, number of single-nucleotide polymorphisms; ALD, alcoholic liver disease.

Figure 5

Summary of forest plots showing the significant mediating effect of immune cell phenotypes in the relationship between anilides and liver cancer risk. OR, odds ratio.

Figure 6

Summary of forest plots showing the significant causal effect of SAD on liver cancer risk in East Asian populations. OR, odds ratio; CI, confidence interval; nsnp, number of single-nucleotide polymorphism.