Neurodegenerative Brain Disease Group, VIB Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, 2610 Antwerpen, Belgium.
Brain. 2011 Mar;134(Pt 3):808-15. doi: 10.1093/brain/awr007.
In a genome-wide association study of frontotemporal lobar degeneration with pathological inclusions of TAR DNA-binding protein, significant association was obtained with three single nucleotide polymorphisms at 7p21.3, in a region encompassing the gene TMEM106B. This study also suggested a potential modifying effect of TMEM106B on disease since the association was strongest in progranulin mutation carriers. Further, the risk effect seemed to correlate with increased TMEM106B expression in patients. In the present study, we sought to replicate these three findings using an independent Flanders-Belgian cohort of primarily clinically diagnosed patients with frontotemporal lobar degeneration (n = 288). We were able to confirm the association with TMEM106B with a P-value of 0.008 for rs1990622, the top marker from the genome-wide association study [odds ratio 0.75 (95% confidence interval 0.61-0.93)]. Further, high-density single nucleotide polymorphism mapping suggested that the association was solely driven by the gene TMEM106B. Homozygous carriers of the TMEM106B protective alleles had a 50% reduced risk of developing frontotemporal lobar degeneration. However, we were unable to detect a modifying effect of the TMEM106B single nucleotide polymorphisms on onset age in progranulin mutation carriers belonging to an extended, clinical and pathological well-documented founder family segregating a progranulin null mutation. Also, we could not observe significant differences in messenger RNA expression between patients and control individuals in lymphoblast cell lines and in brain frontal cortex. In conclusion, we replicated the genetic TMEM106B association in a primarily clinically diagnosed cohort of patients with frontotemporal lobar degeneration from Flanders-Belgium. Additional studies are needed to unravel the molecular role of TMEM106B in disease onset and pathogenesis.
在一项针对 TAR DNA 结合蛋白病理性内含物的额颞叶痴呆的全基因组关联研究中，在包含 TMEM106B 基因的 7p21.3 区域的三个单核苷酸多态性与显著关联。这项研究还表明，TMEM106B 可能对疾病有潜在的修饰作用，因为在颗粒蛋白基因突变携带者中，这种关联最强。此外，风险效应似乎与患者 TMEM106B 表达的增加有关。在本研究中，我们试图使用主要由临床诊断的额颞叶痴呆患者组成的独立的佛兰德-比利时队列来复制这三个发现（n = 288）。我们能够通过 rs1990622 证实与 TMEM106B 的关联，这是全基因组关联研究中的最高标志物 [比值比 0.75（95%置信区间 0.61-0.93）]。此外，高密度单核苷酸多态性图谱表明，这种关联仅由 TMEM106B 基因驱动。TMEM106B 保护性等位基因的纯合子携带者患额颞叶痴呆的风险降低 50%。然而，我们无法在属于一个扩展的、临床和病理记录良好的、携带颗粒蛋白缺失突变的家族的 progranulin 基因突变携带者中检测到 TMEM106B 单核苷酸多态性对发病年龄的修饰作用。此外，我们在淋巴母细胞系和大脑额叶皮质中均未观察到患者和对照个体之间信使 RNA 表达的显著差异。总之，我们在来自佛兰德-比利时的主要由临床诊断的额颞叶痴呆患者队列中复制了 TMEM106B 的遗传关联。需要进一步的研究来阐明 TMEM106B 在疾病发病和发病机制中的分子作用。
