Durán Anyelo, Rebolledo-Jaramillo Boris, Olguin Valeria, Rojas-Herrera Marcelo, Las Heras Macarena, Calderón Juan F, Zanlungo Silvana, Priestman David A, Platt Frances M, Klein Andrés D
Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.
Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Biochem Biophys Rep. 2021 Aug 18;28:101105. doi: 10.1016/j.bbrep.2021.101105. eCollection 2021 Dec.
The acid β-glucocerebrosidase (GCase) enzyme cleaves glucosylceramide into glucose and ceramide. Loss of function variants in the gene encoding for GCase can lead to Gaucher disease and Parkinson's disease. Therapeutic strategies aimed at increasing GCase activity by targeting a modulating factor are attractive and poorly explored. To identify genetic modifiers, we measured hepatic GCase activity in 27 inbred mouse strains. A genome-wide association study (GWAS) using GCase activity as a trait identified several candidate modifier genes, including and (p=2.1x10), and (p=2.1x10). Bayesian integration of the gene mapping with transcriptomics was used to build integrative networks. The analysis uncovered additional candidate GCase regulators, highlighting modules of the acute phase response (p=1.01x10), acute inflammatory response (p=1.01x10), fatty acid beta-oxidation (p=7.43x10), among others. Our study revealed previously unknown candidate modulators of GCase activity, which may facilitate the design of therapies for diseases with GCase dysfunction.
酸性β-葡萄糖脑苷脂酶（GCase）可将葡萄糖神经酰胺裂解为葡萄糖和神经酰胺。编码GCase的基因功能缺失变异可导致戈谢病和帕金森病。通过靶向调节因子来提高GCase活性的治疗策略很有吸引力，但研究较少。为了鉴定基因修饰因子，我们在27个近交系小鼠品系中测量了肝脏GCase活性。一项以GCase活性为性状的全基因组关联研究（GWAS）鉴定出了几个候选修饰基因，包括（此处原文缺失具体基因名）（p = 2.1×10），以及（此处原文缺失具体基因名）（p = 2.1×10）。将基因定位与转录组学进行贝叶斯整合，以构建整合网络。该分析发现了其他候选GCase调节因子，突出了急性期反应模块（p = 1.01×10）、急性炎症反应模块（p = 1.01×10）、脂肪酸β-氧化模块（p = 7.43×10）等。我们的研究揭示了此前未知的GCase活性候选调节因子，这可能有助于设计针对GCase功能障碍疾病的治疗方法。
