Cruchaga Carlos, Graff Caroline, Chiang Huei-Hsin, Wang Jun, Hinrichs Anthony L, Spiegel Noah, Bertelsen Sarah, Mayo Kevin, Norton Joanne B, Morris John C, Goate Alison
Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
Arch Neurol. 2011 May;68(5):581-6. doi: 10.1001/archneurol.2010.350. Epub 2011 Jan 10.
To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association.
Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model.
Alzheimer's Disease Research Center. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals.
Age at onset and GRN plasma levels.
The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.
The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.
检测rs1990622（跨膜蛋白106B，TMEM106B）是否与颗粒蛋白（GRN）突变携带者的发病年龄（AAO）相关，以及是否与突变携带者和健康老年人的血浆GRN水平相关。在最近一项全基因组关联研究中，rs1990622（TMEM106B）被确定为伴TAR DNA结合蛋白包涵体的额颞叶痴呆（FTLD - TDP）的一个风险因素。
对GRN突变携带者的rs1990622进行基因分型，并使用Kaplan - Meier法和Cox比例风险模型检测其与AAO的相关性。
阿尔茨海默病研究中心。研究对象 我们分析了来自之前报道的4个FTLD - TDP家系（HDDD1、FD1、HDDD2和卡罗林斯卡家系）的50名受影响和未受影响的GRN突变携带者。还测量了73名健康老年人的GRN血浆水平。
发病年龄和GRN血浆水平。
rs1990622的风险等位基因与AAO平均降低13年相关（P = 9.9×10⁻⁷），并且与健康老年人（P = 4×10⁻⁴）和GRN突变携带者（P = 0.0027）较低的血浆GRN水平相关。对HapMap数据库的分析确定了一个与rs1990622处于完全连锁不平衡状态的非同义单核苷酸多态性rs3173615（T185S）。
rs1990622与AAO的相关性部分解释了GRN突变携带者中疾病AAO的广泛差异。我们推测rs1990622或处于连锁不平衡状态的另一个变体可能以类似于阿尔茨海默病中载脂蛋白E（APOE）的方式起作用，增加普通人群的疾病风险并改变突变携带者的AAO。我们的结果还表明，TMEM106B中的基因变异可能通过调节GRN的分泌水平影响FTLD - TDP的风险。
