Microglia 基因改變(PLCG2/ ABI3/ TREM2) 與 阿茲海默症 風險高度相關

阿茲海默症致病原因 找到2關鍵基因 2017年07月20日 【大紀元訊】據中央社報導，英國卡地夫大學的科學家分析成千上萬DNA樣本後發現，兩個新基因與罹患阿茲海默症有關，此兩基因會影響免疫系統，原本被視為保護者，但卻可能助長失智。倫敦「每日郵報」報導，這項突破性研究發現的2個新基因，原本被視為保護者，因為它們是腦部免疫系統的一環。但英國卡地夫大學（Cardiff University）科學家揭露，它們也能為神經退化性疾病創造沃土。攸關重要的是，科學家也表示，存在鎖定這些基因的明確方法，能阻止這些基因引發危險活動。共同資助這項研究的英國阿茲海默症學會（Alzheimer's Society）研發主任布朗（Doug Brown）博士說，「超過6成失智者罹患阿茲海默症，但我們迄今尚未充分理解其複雜致病原因。發現阿滋海默症的這兩個新危險基因，是令人振奮進展，有助於深化我們對病患大腦病變的理解。」布朗又說：「這些基因強化了腦部特定細胞微膠細胞（microglia）的重要角色，微膠細胞負責清除包括受損細胞和蛋白質等廢棄物。」布朗指出，這類發現有助指引研究人員，聚焦於何處致力尋找嶄新有效療法。研究報告刊登於「自然遺傳學」（Nature Genetics）期刊。

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease Nature Genetics (2017) doi:10.1038/ng.3916; Received 01 July 2016 Accepted 16 June 2017 Published online 17 July 2017. We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.