Zhou Fangli, Ding Yun, Chen Tao, Tang Qiming, Zhang Jingjing, Thyparambil Sheeno, Jin Bo, Han Zhi, Chou C James, Schilling James, Luo Ruben Y, Tian Haoming, Sylvester Karl G, Whitin John C, Cohen Harvey J, McElhinney Doff B, Tian Li, Ling Xuefeng B, Ren Yan
Department of Endocrinology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Research and Development Department, mProbe Inc., Rockville, MD 20850, United States.
Eur J Endocrinol. 2024 Nov 27;191(6):558-569. doi: 10.1093/ejendo/lvae148.
Primary aldosteronism (PA), a significant cause of secondary hypertension affecting ∼10% of patients with severe hypertension, exacerbates cardiovascular, and cerebrovascular complications even after blood pressure control. PA is categorized into two main subtypes: unilateral aldosterone-producing adenomas (APA) and bilateral hyperaldosteronism (BHA), each requiring distinct treatment approaches. Accurate subtype classification is crucial for selecting the most effective treatment. The goal of this study was to develop novel blood-based proteomic biomarkers to differentiate between APA and BHA subtypes in patients with PA.
Five subtyping differential protein biomarker candidates (APOC3, CD56, CHGA, KRT5, and AZGP1) were identified through targeted proteomic profiling of plasma. The subtyping efficiency of these biomarkers was assessed at both the tissue gene expression and blood protein expression levels. To explore the underlying biology of APA and BHA, significant differential pathways were investigated.
The five-protein panel proved highly effective in distinguishing APA from BHA in both tissue and blood samples. By integrating these five protein biomarkers with aldosterone and renin, our blood-based predictive methods achieved remarkable receiver operating characteristic (ROC) area under the ROC curves of 0.986 (95% CI: 0.963-1.000) for differentiating essential hypertension from PA, and 0.922 (95% CI: 0.846-0.998) for subtyping APA versus BHA. These outcomes surpass the performance of the existing Kobayashi score subtyping system. Furthermore, the study validated differential pathways associated with the pathophysiology of PA, aligning with current scientific knowledge and opening new avenues for advancing PA care.
The new blood-based biomarkers for PA subtyping hold the potential to significantly enhance clinical utility and advance the practice of PA care.
原发性醛固酮增多症（PA）是继发性高血压的一个重要病因，影响约10%的重度高血压患者，即使血压得到控制，也会加剧心血管和脑血管并发症。PA主要分为两种亚型：单侧醛固酮分泌腺瘤（APA）和双侧醛固酮增多症（BHA），每种亚型需要不同的治疗方法。准确的亚型分类对于选择最有效的治疗方法至关重要。本研究的目的是开发新的基于血液的蛋白质组学生物标志物，以区分PA患者的APA和BHA亚型。
通过血浆靶向蛋白质组分析，鉴定了5种亚型差异蛋白质生物标志物候选物（载脂蛋白C3、CD56、嗜铬粒蛋白A、细胞角蛋白5和锌α2糖蛋白1）。在组织基因表达和血液蛋白质表达水平上评估了这些生物标志物的亚型分类效率。为了探索APA和BHA的潜在生物学机制，研究了显著的差异途径。
这五种蛋白质组成的检测组在组织和血液样本中均被证明在区分APA和BHA方面非常有效。通过将这五种蛋白质生物标志物与醛固酮和肾素相结合，我们基于血液的预测方法在区分原发性高血压与PA时，受试者工作特征（ROC）曲线下面积达到了0.986（95%CI：0.963-1.000）；在区分APA与BHA亚型时，ROC曲线下面积为0.922（95%CI：0.846-0.998）。这些结果超过了现有的小林评分亚型分类系统的性能。此外，该研究验证了与PA病理生理学相关的差异途径，与当前科学知识相符，并为推进PA治疗开辟了新途径。
用于PA亚型分类的新型基于血液的生物标志物有可能显著提高临床实用性，并推进PA治疗实践。
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