Causal effect of porphyria biomarkers on alcohol-related hepatocellular carcinoma through Mendelian Randomization

PLoS One. 2024 Mar 20;19(3):e0299536. doi: 10.1371/journal.pone.0299536. eCollection 2024.


Purpose: According to some cohort studies, an association exists between acute intermittent porphyria (AIP) and liver cancer. However, establishing a definitive causal relationship between porphyria and hepatocellular carcinoma (HCC) remains challenging. Prexisting studies regarding porphyria biomarkers and alcohol-related hepatocellular carcinoma (AR-HCC) make possible an entry point. In this study, we aimed to investigate the causal relationships between biomarkers of two types of porphyria, AIP and congenital erythropoietic porphyria (CEP), and AR-HCC.

Methods: Single-nucleotide polymorphisms (SNPs) associated with porphobilinogen deaminase (PBGD) and uroporphyrinogen-III synthase (UROS), along with outcome data on AR-HCC, were extracted from public genome-wide association studies (GWAS). The GWAS data were then used to explore the potential causal relationships via a two-sample Mendelian randomization (MR) analysis. The effect estimates were calculated using the random-effect inverse-variance-weighted (IVW) method. Additionally, the Cochrane's Q test, MR-Egger test, and leave-one-out analysis were conducted to detect heterogeneity and pleiotropy in the MR results.

Results: Using the IVW method as the primary causal effects model in the MR analyses, we found that both PBGD (effect estimate = 1.51; 95% CI, from 1.08 to 2.11, p = 0.016) and UROS (effect estimate = 1.53; 95% CI, from 1.08 to 2.18, p = 0.018) have a significant causal effect on AR-HCC.

Conclusion: Our findings revealed a causal effect of both PBGD and UROS on AR-HCC, suggesting that both AIP and CEP have a causal association with AR-HCC.

MeSH terms

  • Animals
  • Biomarkers
  • Carcinoma, Hepatocellular* / genetics
  • Genome-Wide Association Study
  • Humans
  • Liver Neoplasms* / genetics
  • Mendelian Randomization Analysis
  • Porifera*
  • Porphyria, Acute Intermittent*
  • Porphyrias*


  • Biomarkers

Grants and funding

This study was funded by the National Natural Science Foundation of China (No. 81472331), Natural Science Foundation of Anhui Province (No. 2108085MH289), and the Project of Scientific Research Foundation of Anhui Medical University (No. 2019xkj146).