克隆性造血的人血浆蛋白质组学图谱。

Human Plasma Proteomic Profile of Clonal Hematopoiesis.

作者信息

Yu Zhi, Vromman Amélie, Nguyen Ngoc Quynh H, Schuermans Art, Rentz Thiago, Vellarikkal Shamsudheen K, Uddin Md Mesbah, Niroula Abhishek, Griffin Gabriel, Honigberg Michael C, Lin Amy E, Gibson Christopher J, Katz Daniel H, Tahir Usman, Fang Shi, Haidermota Sara, Ganesh Shriienidhie, Antoine Tajmara, Weinstock Joshua, Austin Thomas R, Ramachandran Vasan S, Peloso Gina M, Hornsby Whitney, Ganz Peter, Manson JoAnn E, Haring Bernhard, Kooperberg Charles L, Reiner Alexander P, Bis Joshua C, Psaty Bruce M, Min Yuan-I, Correa Adolfo, Lange Leslie A, Post Wendy S, Rotter Jerome I, Rich Stephen S, Wilson James G, Ebert Benjamin L, Yu Bing, Ballantyne Christie M, Coresh Josef, Sankaran Vijay G, Bick Alexander G, Jaiswal Siddhartha, Gerszten Robert E, Libby Peter, Gupta Rajat M, Natarajan Pradeep

机构信息

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

出版信息

bioRxiv. 2024 Oct 31:2023.07.25.550557. doi: 10.1101/2023.07.25.550557.

DOI:10.1101/2023.07.25.550557

PMID:39554199

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11565774/

Abstract

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (, , and ). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic -/- vs wild-type mice validation, disentangled causal proteomic perturbations from CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

摘要

与血细胞亚临床体细胞突变相关的血浆蛋白质组学特征可能为下游临床后果提供新的见解。在此，我们探讨了具有不确定潜能的克隆性造血（CHIP）中的此类模式，CHIP与多种癌症和非癌症结局相关，包括冠状动脉疾病（CAD）。在来自美国国立心肺血液研究所（NHLBI）TOPMed和英国生物银行的61833名具有不同祖先的参与者（3881名患有CHIP）中，他们进行了基于血液的DNA测序和蛋白质组学测量（TOPMed中通过SomaScan检测1148种蛋白质，英国生物银行中通过Olink检测2917种蛋白质），我们分别从TOPMed和英国生物银行中鉴定出32种和345种与最常见的驱动基因（、和）相关的独特蛋白质。这些关联在驱动基因、性别和种族方面表现出显著的异质性，并且在免疫反应和炎症途径中富集。人类的孟德尔随机化研究，结合造血 -/- 与野生型小鼠的ELISA验证，从CHIP中解开了因果蛋白质组学扰动。最后，我们鉴定出了CHIP和CAD之间共有的血浆蛋白。