Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
J Alzheimers Dis. 2020;77(1):401-409. doi: 10.3233/JAD-200415.
Hypometabolism detected by fluorodeoxyglucose F18 positron emission tomography ([18F] FDG PET) is an early neuropathologic changes in Alzheimer's disease (AD) and provides important pathologic staging information.
This study aimed to discover genetic interactions that regulate longitudinal glucose metabolic decline in AD-related brain regions.
A total of 586 non-Hispanic white individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts that met all quality control criteria were included in this study. Genome-wide association study of glucose metabolic decline in regions of interest (ROIs) was performed with linear regression under the additive genetic model.
We identified two novel variants that had a strong association with longitudinal metabolic decline in different ROI. Rs4819351-A in gene 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) demonstrated reduced metabolic decline in right temporal gyrus (p = 3.97×10-8, β= -0.016), while rs13387360-T in gene LOC101928196 demonstrated reduced metabolic decline in left angular gyrus (p = 1.69×10-8, β= -0.027).
Our results suggest two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 as protective loci that modulate glucose metabolic decline. These two genes should be further investigated as potential therapeutic target for neurodegeneration diseases.
氟代脱氧葡萄糖 F18 正电子发射断层扫描 ([18F] FDG PET) 检测到的低代谢是阿尔茨海默病 (AD) 的早期神经病理学变化，并提供了重要的病理分期信息。
本研究旨在发现调节 AD 相关脑区葡萄糖代谢纵向下降的遗传相互作用。
本研究纳入了符合所有质量控制标准的来自阿尔茨海默病神经影像学倡议 (ADNI) 1/GO/2 队列的 586 名非西班牙裔白人个体。采用加性遗传模型下的线性回归对感兴趣区域 (ROI) 中葡萄糖代谢下降的全基因组关联研究进行了分析。
我们发现了两个与不同 ROI 纵向代谢下降具有强关联的新变体。AGPAT3 基因中的 rs4819351-A 显示右侧颞叶代谢下降减少（p=3.97×10-8，β=-0.016），而 LOC101928196 基因中的 rs13387360-T 显示左侧角回代谢下降减少（p=1.69×10-8，β=-0.027）。
我们的结果表明，AGPAT3 和 LOC101928196 基因中的两个全基因组显著 SNP(rs4819351, rs13387360) 作为保护性基因座，调节葡萄糖代谢下降。这两个基因应该作为神经退行性疾病的潜在治疗靶点进一步研究。
