Tahir Usman A, Reichart Daniel, Purohit Anisha, Barber Jacob L, Tiwari Gaurav, Farrell Laurie, Marine Julia, Roy Darius, Patel Joshen, Ireland Catherine, Ho Carolyn Y, Seidman Christine E, Gerszten Robert E, Lakdawala Neal K
Beth Israel Deaconess Medical Center, Boston, MA (U.A.T., J.L.B., G.T., L.F.).
Harvard Medical School, Boston, MA (U.A.T., C.Y.H., C.E.S., R.E.G., N.K.L.).
Circ Genom Precis Med. 2025 Jun 13:e004924. doi: 10.1161/CIRCGEN.124.004924.
Pathogenic variants in the () gene cause an aggressive form of dilated cardiomyopathy (DCM), marked by higher rates of advanced conduction disease, malignant ventricular tachyarrhythmias, and advanced heart failure compared with other causes of nonischemic cardiomyopathy. However, the mechanisms that drive the development and progression of DCM are incompletely understood.
To identify proteins and biological pathways associated with likely pathogenic/pathogenic variants, we measured ≈3000 plasma proteins using the OLINK platform in a genetic DCM cohort consisting of (n=41) and sarcomeric (n=18) DCM, along with phenotype-negative individuals from family-based cascade screening (n=55) with (, n=16; sarcomere, n=12) or without the family variant (genotype negative, n=27).
We identified several novel proteins associated with DCM compared with sarcomeric DCM, including EDA2R (ectodysplasin A2 receptor; per log2 fold change in relative protein abundance, β=3.0; =4×10³) and (myosin light chain 4; β=2.32; =5×10³). Among the proteins associated with DCM, 26 showed concordant differential gene expression from single-cell sequencing in cardiomyocytes from myocardial biopsies in advanced heart failure compared with control hearts (false discovery rate, <5%). We performed principal component analyses on these 26 proteins to identify proteomic signatures of DCM and found the first principal component to be associated with left ventricular ejection fraction and complete heart block in the DCM cohort. Six proteins-EDA2R, MYL4, CRIM1 (cysteine-rich transmembrane BMP regulator 1), TPR (translocated promoter region), FSTL3 (follistatin-like 3), and NFYA (nuclear transcription factor Y)-were associated with pathogenic variants across phenotype-negative individuals, DCM, and their respective cardiomyocyte RNA expression profiles in advanced heart failure.
Proteomic profiling in individuals with likely pathogenic/pathogenic variants illuminated integral pathways across the spectrum of DCM. These findings may help advance genotype-driven biomarker discovery and tailored therapeutic development in DCM.
（）基因中的致病性变异会导致一种侵袭性扩张型心肌病（DCM），与其他非缺血性心肌病病因相比，其特征为高级传导疾病、恶性室性心律失常和晚期心力衰竭的发生率更高。然而，驱动DCM发生和发展的机制尚未完全明确。
为了鉴定与可能的致病性/致病性变异相关的蛋白质和生物学途径，我们使用OLINK平台在一个遗传性DCM队列中测量了约3000种血浆蛋白，该队列包括（n = 41）和肌节（n = 18）DCM患者，以及来自基于家系的级联筛查的表型阴性个体（n = 55），其中携带（，n = 16；肌节，n = 12）或不携带家族变异（基因型阴性，n = 27）。
与肌节性DCM相比，我们鉴定出了几种与DCM相关的新蛋白质，包括EDA2R（外胚层发育不良蛋白A2受体；相对蛋白丰度的每log2倍变化，β = 3.0； = 4×10³）和（肌球蛋白轻链4；β = 2.32； = 5×10³）。在与DCM相关的蛋白质中，26种在晚期心力衰竭心肌活检的心肌细胞单细胞测序中显示出与对照心脏一致的差异基因表达（错误发现率，<5%）。我们对这26种蛋白质进行了主成分分析，以鉴定DCM的蛋白质组学特征，发现第一主成分与DCM队列中的左心室射血分数和完全性心脏传导阻滞相关。六种蛋白质——EDA2R、MYL4、CRIM1（富含半胱氨酸的跨膜BMP调节因子1）、TPR（易位启动子区域）、FSTL3（卵泡抑素样3）和NFYA（核转录因子Y）——与表型阴性个体、DCM及其在晚期心力衰竭中的各自心肌细胞RNA表达谱中的致病性变异相关。
对可能的致病性/致病性变异个体进行蛋白质组学分析揭示了DCM整个谱系中的重要途径。这些发现可能有助于推进基因型驱动的生物标志物发现以及DCM的个性化治疗开发。
