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

Area of Science:

• Genetics and Genomics
• Hepatology
• Cancer Research

Background:

• An association between acute intermittent porphyria (AIP) and liver cancer is suggested by cohort studies.
• Establishing a direct causal link between porphyria and hepatocellular carcinoma (HCC) remains challenging.
• Porphyria biomarkers and alcohol-related HCC (AR-HCC) offer a potential avenue for investigation.

Purpose of the Study:

• To investigate the potential causal relationships between biomarkers of AIP and congenital erythropoietic porphyria (CEP).
• To determine the causal effect of these porphyria biomarkers on alcohol-related hepatocellular carcinoma (AR-HCC).

Main Methods:

• Utilized a two-sample Mendelian randomization (MR) analysis.
• Extracted single-nucleotide polymorphisms (SNPs) for PBGD and UROS from public genome-wide association studies (GWAS).
• Employed the inverse-variance-weighted (IVW) method for effect estimation, with heterogeneity and pleiotropy analyses.

Main Results:

• The MR analysis indicated a significant causal effect of PBGD on AR-HCC (effect estimate = 1.51, p = 0.016).
• Similarly, UROS demonstrated a significant causal effect on AR-HCC (effect estimate = 1.53, p = 0.018).
• These findings were robust across primary analyses and sensitivity tests.

Conclusions:

• Both PBGD and UROS exhibit a causal influence on the development of AR-HCC.
• This suggests a causal association between AIP and CEP with AR-HCC.
• Highlights potential genetic predispositions to liver cancer in individuals with specific porphyrias.