PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.
摘要：
阿尔茨海默病（AD）和额颞叶变性（FTLD）是神经退行性痴呆的最常见形式，具有高度的表型变异性。在这里，我们研究了与免疫系统和炎症相关的遗传变异作为遗传调节剂在AD和相关痴呆中的作用.在散发性AD/FTLD（n=300）和GRN/C9orf72突变携带者（n=80）的患者中，我们对50个属于免疫系统和炎症的基因进行了靶向测序，根据它们在脑区的高表达和对遗传变异的低耐受性进行选择。线性回归分析揭示了两种遗传变异：（i）转铁蛋白（TF）基因中的rs1049296，在散发性AD组中显示与发病年龄显着相关，预测每个SNP等位基因相对于野生型等位基因的疾病发作4年，和（ii）calsyntenin-1（CLSTN1）基因中的rs7550295，这与C9orf72组的发病年龄显着相关，将携带SNP等位基因的患者的疾病发作延迟17年。总之,我们的数据支持遗传变异在铁代谢(TF)和囊泡钙信号/轴突顺行转运(CLSTN1)作为AD和FTLD中的遗传调节剂(由于C9orf72扩增)中的作用.
