Revealing Antihypertensive Drugs for Reducing NAFLD Risk: Genetic Evidence from a Mendelian Randomization Study.

Area of Science:

• Pharmacogenomics
• Cardiovascular Research
• Hepatology

Background:

• Observational studies link hypertension and Nonalcoholic Fatty Liver Disease (NAFLD), but causality is unclear.
• Antihypertensive therapy's effect on NAFLD progression requires robust investigation.
• Mendelian randomization (MR) addresses confounding in observational data.

Purpose of the Study:

• To test the causal effect of antihypertensive drug targets on NAFLD risk using MR.
• To evaluate the safety and potential adverse outcomes of these drug targets.
• To provide genetic evidence for novel NAFLD therapeutic strategies.

Main Methods:

• Utilized 37 antihypertensive drug targets from genome-wide association studies (GWAS).
• Employed MR to estimate causal relationships between drug targets and NAFLD risk.
• Conducted heterogeneity tests, pleiotropy assessments, leave-one-out analyses, and meta-analysis for robustness.
• Performed phenome-wide association studies (PheWAS) to assess target safety.

Main Results:

• Genetic proxies for ADRB1 antagonists, SLC12A1 inhibitors, and NEU1 inhibitors showed association with reduced NAFLD risk.
• MR and meta-analysis identified significant associations for these drug targets.
• Combined MR and PheWAS indicated ADRB1 antagonists and SLC12A1 inhibitors may have favorable safety profiles.

Conclusions:

• Provides the first genetic evidence linking antihypertensive drug targets to reduced NAFLD risk.
• ADRB1 and SLC12A1 inhibition show promise as therapeutic targets for NAFLD.
• NEU1 inhibition requires careful evaluation to balance efficacy and safety for NAFLD treatment.