The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou 251221, China.
Medical Laboratory, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, China.
Aging (Albany NY). 2024 May 30;16(11):9470-9484. doi: 10.18632/aging.205878.
Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease, continues to elude complete comprehension of its pathological underpinnings. Recent focus on inflammation in ALS pathogenesis prompts this investigation into the genetic correlation and potential causal relationships between circulating inflammatory proteins and ALS.
Genome-wide association study (GWAS) data encompassing 91 circulating inflammatory protein measures from 14,824 individuals of European ancestry, alongside records from 27,205 ALS cases and 110,881 controls, were employed. Assessment of genetic correlation and overlap utilized LD score regression (LDSC), high-definition likelihood (HDL), and genetic analysis integrating pleiotropy and annotation (GPA) methodologies. Identification of shared genetic loci involved pleiotropy analysis, functional mapping and annotation (FUMA), and co-localization analysis. Finally, Mendelian randomization was applied to probe causal relationships between inflammatory proteins and ALS.
Our investigation revealed significant genetic correlation and overlap between ALS and various inflammatory proteins, including C-C motif chemokine 28, Interleukin-18, C-X-C motif chemokine 1, and Leukemia inhibitory factor receptor (LIFR). Pleiotropy analysis uncovered shared variations at specific genetic loci, some of which bore potential harm. Mendelian randomization analysis suggested that alterations in specific inflammatory protein levels, notably LIFR, could impact ALS risk.
Our findings uncover a genetic correlation between certain circulating inflammatory proteins and ALS, suggesting their possible causal involvement in ALS pathogenesis. Moreover, the identification of LIFR as a crucial protein may yield new insights into ALS pathomechanisms and offer a promising avenue for therapeutic interventions. These discoveries provide novel perspectives for advancing the comprehension of ALS pathophysiology and exploring potential therapeutic avenues.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其病理基础仍未被完全理解。最近，人们对 ALS 发病机制中的炎症的关注促使我们研究循环炎症蛋白与 ALS 之间的遗传相关性和潜在因果关系。
本研究使用了包含来自 14824 名欧洲血统个体的 91 种循环炎症蛋白测量值的全基因组关联研究（GWAS）数据，以及来自 27205 例 ALS 病例和 110881 例对照的记录。采用 LD 得分回归（LDSC）、高清晰度似然（HDL）和整合多效性和注释（GPA）方法评估遗传相关性和重叠。通过多效性分析、功能映射和注释（FUMA）以及共定位分析鉴定共享遗传位点。最后，应用孟德尔随机化研究炎症蛋白与 ALS 之间的因果关系。
我们的研究发现，ALS 与多种炎症蛋白之间存在显著的遗传相关性和重叠，包括 C-C 基序趋化因子 28、白细胞介素 18、C-X-C 基序趋化因子 1 和白血病抑制因子受体（LIFR）。多效性分析揭示了特定遗传位点的共享变异，其中一些具有潜在危害。孟德尔随机化分析表明，特定炎症蛋白水平的改变，特别是 LIFR 的改变，可能会影响 ALS 的风险。
我们的研究结果揭示了某些循环炎症蛋白与 ALS 之间存在遗传相关性，提示它们可能在 ALS 发病机制中起因果作用。此外，LIFR 作为一种关键蛋白的鉴定可能为 ALS 病理机制提供新的见解，并为治疗干预提供有前途的途径。这些发现为深入了解 ALS 病理生理学和探索潜在治疗途径提供了新的视角。
