Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cardiovasc Diabetol. 2024 Apr 13;23(1):126. doi: 10.1186/s12933-024-02222-1.
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.
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.
Genetically predicted levels of 14 circulating proteins were associated with visceral and ectopic fat (P < 4.99 × 10, 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.
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.
内脏和异位脂肪的积累是代谢性心血管疾病的主要原因。然而，用于减少不必要的内脏和异位脂肪的新型药物靶点仍然有限。我们的研究旨在使用孟德尔随机化（MR）方法，全面研究血浆蛋白质组对内脏和异位脂肪的因果影响。
我们基于 2656 种血浆蛋白的五个大型全基因组关联研究（GWAS）汇总统计数据，进行了两样本 MR 分析，以筛选这些蛋白与 30000 多名欧洲血统参与者的内脏和异位脂肪特征之间的因果关联，并评估通过结局风险因素的中介效应。共定位分析用于检查鉴定的蛋白质和结局是否共享因果变异。
遗传预测的 14 种循环蛋白水平与内脏和异位脂肪有关（P < 4.99 × 10 ，在 Bonferroni 校正阈值下）。共定位分析优先考虑了十个对结果有影响的蛋白靶点，包括 FST、SIRT2、DNAJB9、IL6R、CTSA、RGMB、PNLIPRP1、FLT4、PPY 和 IL6ST。MR 分析显示，有七个风险因素与内脏和异位脂肪有关（P < 0.0024）。此外，CTSA、DNAJB9 和 IGFBP1 与主要结局的关联由 HDL-C 和 SHBG 介导。敏感性分析表明，多效性的证据很少。
我们的研究确定了候选蛋白，这些蛋白显示出潜在的因果作用，可能成为内脏和异位脂肪积累的潜在治疗靶点，并概述了进一步预防下游代谢性心血管疾病的因果途径。
