Clinically relevant plasma proteome for adiposity depots: evidence from systematic mendelian randomization and...

Area of Science:

• Genetics
• Metabolomics
• Cardiovascular Disease Research

Background:

• Visceral and ectopic fat accumulation are primary drivers of cardiometabolic diseases.
• Limited drug targets exist for reducing excess visceral and ectopic fat.
• Plasma proteome's role in fat accumulation requires further investigation.

Purpose of the Study:

• To comprehensively investigate the causal effects of plasma proteins on visceral and ectopic fat.
• To identify novel therapeutic targets for reducing fat accumulation.
• To explore causal pathways for preventing cardiometabolic diseases.

Main Methods:

• Utilized a two-sample Mendelian randomization (MR) approach.
• Analyzed GWAS summary statistics for 2656 plasma proteins and fat traits in over 30,000 participants.
• Performed colocalization and mediation analyses to validate causal associations and identify risk factors.

Main Results:

• Identified 14 circulating proteins significantly associated with visceral and ectopic fat.
• Prioritized ten protein targets, including FST, SIRT2, DNAJB9, IL6R, CTSA, RGMB, PNLIPRP1, FLT4, PPY, and IL6ST.
• Discovered seven risk factors and identified mediation effects of HDL-C and SHBG for CTSA, DNAJB9, and IGFBP1.

Conclusions:

• Identified candidate proteins with putative causal effects on fat accumulation.
• Highlighted potential therapeutic targets for visceral and ectopic fat.
• Outlined causal pathways for the prevention of cardiometabolic diseases.