A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.
A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.
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DOI：
10.3233/jad-160524
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发表时间：
2017
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影响因子：
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通讯作者：
van der Brug M
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作者：
Haddick PC;Larson JL;Rathore N;Bhangale TR;Phung QT;Srinivasan K;Hansen DV;Lill JR;Alzheimer’s Disease Genetic Consortium (ADGC), Alzheimer’s Disease Neuroimaging Initiative (ADNI);Pericak-Vance MA;Haines J;Farrer LA;Kauwe JS;Schellenberg GD;Cruchaga C;Goate AM;Behrens TW;Watts RJ;Graham RR;Kaminker JS;van der Brug M
IL-6R中常见的p.D358A变异(Rs2228145)与多种疾病的风险以及外周和中枢神经系统(CNS)中可溶性IL-6R水平的升高有关。在这里，我们发现p.D358A等位基因导致膜结合的IL-6R蛋白分解增加，并证明带有A358的IL-6R多肽更容易被ADAM10和ADAM17切割。在原代星形胶质细胞和小胶质细胞中发现了IL-6反应基因，在迟发性阿尔茨海默病患者的中枢神经系统中IL-6基因信号以IL6R等位基因依赖的方式增加。我们进行了一项筛查，以确定与载脂蛋白Eε4携带者的AD发病年龄相关的变异。在5个数据集中，p.D358A的Meta P=3×10−4，优势比(OR)=1.395%可信区间(CI)1.12-1.48。我们的研究表明，IL-6受体的一个共同编码区变异导致神经炎性改变，这可能影响载脂蛋白Eε4携带者AD的发病年龄。
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer’s disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of AD onset in APOE ε4 carriers. Across 5 datasets, p.D358A had a meta P=3×10−4 and an odds ratio (OR) = 1.3, 95% confidence interval (CI) 1.12 – 1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset in AD in APOE ε4 carriers.