Demographic profile of the study population*.

Rheumatic heart disease (RHD) continues to affect developing countries with low income due to the lack of resources and effective diagnostic techniques. Understanding the genetic basis common to both the diseases and that of progression from its prequel disease state, Acute Rheumatic Fever (ARF), would aid in developing predictive biomarkers and improving patient care. To gain system-wide molecular insights into possible causes for progression, in this pilot study, we collected blood transcriptomes from ARF (5) and RHD (5) patients. Using an integrated transcriptome and network analysis approach, we identified a subnetwork comprising the most significantly differentially expressed genes and most perturbed pathways in RHD compared to ARF. For example, the chemokine signaling pathway was seen to be upregulated, while tryptophan metabolism was found to be downregulated in RHD. The subnetworks of variation between the two conditions provide unbiased molecular-level insights into the host processes that may be linked with the progression of ARF to RHD, which has the potential to inform future diagnostics and therapeutic strategies. We also found a significantly raised neutrophil/lymphocyte ratio in both ARF and RHD cohorts. Activated neutrophils and inhibited Natural Killer cell gene signatures reflected the drivers of the inflammatory process typical to both disease conditions.

风湿性心脏病（Rheumatic heart disease, RHD）仍因资源匮乏与有效诊断技术缺失，持续困扰低收入发展中国家。明确该病与其前驱疾病急性风湿热（Acute Rheumatic Fever, ARF）共有的遗传基础，以及疾病从ARF进展为RHD的分子机制，将有助于开发预测性生物标志物并改善患者诊疗水平。为系统性解析疾病进展的潜在分子诱因，本预实验研究收集了5例ARF患者与5例RHD患者的血液转录组（blood transcriptomes）样本。通过整合转录组与网络分析策略，本研究鉴定出相较于ARF，RHD中显著差异表达基因构成的子网，以及扰动最为显著的通路。例如，趋化因子信号通路（chemokine signaling pathway）在RHD中呈上调表达，而色氨酸代谢（tryptophan metabolism）则呈下调表达。上述两种疾病状态间的差异子网，为阐释ARF进展为RHD相关的宿主生物学过程提供了无偏倚的分子层面视角，有望为未来的诊断与治疗策略提供参考依据。本研究同时发现，ARF与RHD队列中的中性粒细胞/淋巴细胞比值（neutrophil/lymphocyte ratio）均显著升高。活化的中性粒细胞与受抑的自然杀伤（Natural Killer, NK）细胞基因特征，反映了两种疾病共有的典型炎症过程驱动因素。