一項(xiàng)新的研究提示一種編碼2型髓樣細(xì)胞（TREM2）觸發(fā)受體的基因變異型參與阿爾茨海默病的病理過(guò)程,。這項(xiàng)研究在線發(fā)表于2012年11月14日的《新英格蘭醫(yī)學(xué)》雜志上,。
TREM2具有腦內(nèi)的抗炎作用,。“TREM2 活性下降可能導(dǎo)致炎癥反應(yīng)增加而造成腦 損傷”該研究的負(fù)責(zé)人Kari Stefansson博士在一份聲明中說(shuō)道,。阿爾茨海默病協(xié)會(huì)首席醫(yī)療官William Thies博士說(shuō),，“這是一項(xiàng)基礎(chǔ)研究的文章,，其真正臨床的重要性恐怕短期內(nèi)尚不明確”,。
少數(shù)已知的AD基因變異型
Stefansson博士及其同事指出,，除了載脂蛋白ε4等位基因以外,，只有少數(shù)幾個(gè)影響晚發(fā)型AD風(fēng)險(xiǎn)的基因變異型也被發(fā)現(xiàn)。這是他們開(kāi)始此項(xiàng)研究的動(dòng)機(jī)之一,。
研究者對(duì)2261例冰島居民的基因組序列進(jìn)行了分析,，確定了一系列可能影響蛋白功能的基因變異型。隨后,，他們調(diào)查了2550例AD患者和無(wú)AD的85歲高齡以上的正常人中這些基因變異型的情況,。
研究者發(fā)現(xiàn)了在編碼TREM2基因中的一種少見(jiàn)的錯(cuò)義突變（rs75932628-T），取代了原有的R47H位點(diǎn),。在冰島居民中有0.63%的等位基因的突變發(fā)生率,，這導(dǎo)致AD的風(fēng)險(xiǎn)明顯增高[OR，2.92,；95%CI,，2.09-4.09],。在對(duì)照患者中該突變的發(fā)生率為0.46%。他們?cè)诿绹?guó),、挪威,、荷蘭、德國(guó)等國(guó)家的病例對(duì)照研究中也發(fā)現(xiàn)了相同的關(guān)聯(lián)性（OR, 2.90; 95% CI, 2.16 - 3.91）,。同時(shí),，發(fā)現(xiàn)攜帶rs75932628-T基因突變的80-100歲無(wú)癡呆的老年人與非攜帶者相比，其認(rèn)知功能更差（P=0.003）,。
誘人的藥物治療靶點(diǎn)
研究人員說(shuō),，“假設(shè)TREM2參與小膠質(zhì)細(xì)胞吞噬淀粉樣蛋白的過(guò)程，那么由于R47H替代所致的TREM2活性下降可能會(huì)使腦內(nèi)毒物清除作用下降而導(dǎo)致腦損傷,。” Stefansson博士認(rèn)為TREM2是一個(gè)“誘人的治療藥物的開(kāi)發(fā)靶點(diǎn)”,。
Thies博士說(shuō)，“對(duì)于炎癥與阿爾茨海默病之間的關(guān)系,，我們已有些許認(rèn)識(shí),，但我們還沒(méi)有真正開(kāi)發(fā)出相關(guān)的靶向藥物。非甾體抗炎在阿爾茨海默病的應(yīng)用中有一段曲折的歷史”,。“這種全基因組序列的研究發(fā)現(xiàn)的與代謝途徑相關(guān)的特殊基因位點(diǎn)為發(fā)現(xiàn)調(diào)節(jié)代謝途徑位點(diǎn)的分子開(kāi)辟了道路,，可能會(huì)帶來(lái)臨床獲益”。
他補(bǔ)充說(shuō),，“應(yīng)該注意到這種突變還是相對(duì)少見(jiàn)的,，因此人們不應(yīng)該去別的地方尋找人群檢測(cè)這種突變，因?yàn)椴⒉皇请S處可見(jiàn),。這種做法并沒(méi)有任何好處”,。（生物谷Bioon.com）
doi: 10.1056/NEJMoa1211103
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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.)
