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

BACKGROUND: The accumulation of visceral and ectopic fat comprise a major cause of cardiometabolic diseases. However, novel drug targets for reducing unnecessary visceral and ectopic fat are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on visceral and ectopic fat using Mendelian randomization (MR) approach.

METHODS: We performed two-sample MR analyses based on five large genome-wide association study (GWAS) summary statistics of 2656 plasma proteins, to screen for causal associations of these proteins with traits of visceral and ectopic fat in over 30,000 participants of European ancestry, as well as to assess mediation effects by risk factors of outcomes. The colocalization analysis was conducted to examine whether the identified proteins and outcomes shared casual variants.

RESULTS: Genetically predicted levels of 14 circulating proteins were associated with visceral and ectopic fat (P < 4.99 × 10- 5 , at a Bonferroni-corrected threshold). Colocalization analysis prioritized ten protein targets that showed effect on outcomes, including FST, SIRT2, DNAJB9, IL6R, CTSA, RGMB, PNLIPRP1, FLT4, PPY and IL6ST. MR analyses revealed seven risk factors for visceral and ectopic fat (P < 0.0024). Furthermore, the associations of CTSA, DNAJB9 and IGFBP1 with primary outcomes were mediated by HDL-C and SHBG. Sensitivity analyses showed little evidence of pleiotropy.

CONCLUSIONS: Our study identified candidate proteins showing putative causal effects as potential therapeutic targets for visceral and ectopic fat accumulation and outlined causal pathways for further prevention of downstream cardiometabolic diseases.