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Circulating citrate as a mediator in the relationship between HMGCR inhibitors and chronic hepatitis B: a Mendelian

Lili Zhang1, Yuming Li2, Ying Li3

  • 1Department of Ultrasonography, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, Jilin, People's Republic of China.

Scientific Reports
|April 14, 2025
PubMed

Insights

HMGCR inhibitors show promise in treating chronic hepatitis B (CHB). This study suggests citrate may mediate the protective effect of these drugs against CHB, offering insights into treatment mechanisms.

Area of Science:

  • Pharmacogenomics
  • Metabolomics
  • Hepatology

Background:

  • Observational studies suggest HMGCR inhibitors are effective for chronic viral hepatitis.
  • The precise mechanism by which HMGCR inhibitors exert therapeutic effects in Chronic Hepatitis B (CHB) remains incompletely understood.

Purpose of the Study:

  • To investigate the causal relationship between HMGCR inhibitors and CHB.
  • To explore the mediating role of circulating metabolites in the association between HMGCR inhibitors and CHB.

Main Methods:

  • Two-sample, two-step Mendelian randomization (MR) analysis using GWAS data.
  • Inverse-variance weighted (IVW) as the primary method, supplemented by MR-Egger regression.
  • Pleiotropy and sensitivity analyses were performed using MR-Egger, MR-PRESSO, and leave-one-out methods.

Main Results:

  • Genetic variants in HMGCR inhibitor target genes were associated with reduced CHB and myocardial infarction risk.
  • Eight circulating metabolites showed a significant causal link with both HMGCR inhibitors and CHB.
  • Citrate was identified as a significant mediator, with a mediation effect of -0.015 and a mediation ratio of 9.769%.

Conclusions:

  • HMGCR inhibitors significantly reduce the risk of CHB.
  • The circulating metabolite citrate may play a mediating role in the beneficial effects of HMGCR inhibitors on CHB.
  • Limitations include the inability to assess short-term effects and potential bias from GWAS data overlap.

Keywords:
Chronic hepatitis BCirculating metabolitesHydroxymethylglutaryl-CoA reductase inhibitorsMendelian randomization

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