一项新的研究提示一种编码2型髓样细胞(TREM2)触发受体的基因变异型参与阿尔茨海默病的病理过程。这项研究在线发表于2012年11月14日的《新英格兰医学》杂志上。
TREM2具有脑内的抗炎作用。“TREM2 活性下降可能导致炎症反应增加而造成脑 损伤”该研究的负责人Kari Stefansson博士在一份声明中说道。阿尔茨海默病协会首席医疗官William Thies博士说,“这是一项基础研究的文章,其真正临床的重要性恐怕短期内尚不明确”。
少数已知的AD基因变异型
Stefansson博士及其同事指出,除了载脂蛋白ε4等位基因以外,只有少数几个影响晚发型AD风险的基因变异型也被发现。这是他们开始此项研究的动机之一。
研究者对2261例冰岛居民的基因组序列进行了分析,确定了一系列可能影响蛋白功能的基因变异型。随后,他们调查了2550例AD患者和无AD的85岁高龄以上的正常人中这些基因变异型的情况。
研究者发现了在编码TREM2基因中的一种少见的错义突变(rs75932628-T),取代了原有的R47H位点。在冰岛居民中有0.63%的等位基因的突变发生率,这导致AD的风险明显增高[OR,2.92;95%CI,2.09-4.09]。在对照患者中该突变的发生率为0.46%。他们在美国、挪威、荷兰、德国等国家的病例对照研究中也发现了相同的关联性(OR, 2.90; 95% CI, 2.16 - 3.91)。同时,发现携带rs75932628-T基因突变的80-100岁无痴呆的老年人与非携带者相比,其认知功能更差(P=0.003)。
诱人的药物治疗靶点
研究人员说,“假设TREM2参与小胶质细胞吞噬淀粉样蛋白的过程,那么由于R47H替代所致的TREM2活性下降可能会使脑内毒物清除作用下降而导致脑损伤。” Stefansson博士认为TREM2是一个“诱人的治疗药物的开发靶点”。
Thies博士说,“对于炎症与阿尔茨海默病之间的关系,我们已有些许认识,但我们还没有真正开发出相关的靶向药物。非甾体抗炎在阿尔茨海默病的应用中有一段曲折的历史”。“这种全基因组序列的研究发现的与代谢途径相关的特殊基因位点为发现调节代谢途径位点的分子开辟了道路,可能会带来临床获益”。
他补充说,“应该注意到这种突变还是相对少见的,因此人们不应该去别的地方寻找人群检测这种突变,因为并不是随处可见。这种做法并没有任何好处”。(生物谷Bioon.com)
doi: 10.1056/NEJMoa1211103
PMC:
PMID:
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Thorlakur Jonsson, Hreinn Stefansson,Stacy Steinberg, Ingileif Jonsdottir, Palmi V. Jonsson,, Jon Snaedal, Sigurbjorn Bjornsson, Johanna Huttenlocher,Allan I. Levey, James J. Lah, Dan Rujescu, Harald Hampel, Ina Giegling, Ole A. Andreassen, Knut Engedal, Ingun Ulstein, Srdjan Djurovic, Carla Ibrahim-Verbaas, Albert Hofman, M. Arfan Ikram, Cornelia M van Duijn, Unnur Thorsteinsdottir, Augustine Kong and Kari Stefansson
Background Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10?10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10?12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). Conclusions Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.)