Li Yi-Ju, Oliveira Sofia A, Xu Puting, Martin Eden R, Stenger Judith E, Scherzer Clemens R, Hauser Michael A, Scott William K, Small Gary W, Nance Martha A, Watts Ray L, Hubble Jean P, Koller William C, Pahwa Rajesh, Stern Mathew B, Hiner Bradley C, Jankovic Joseph, Goetz Christopher G, Mastaglia Frank, Middleton Lefkos T, Roses Allen D, Saunders Ann M, Schmechel Donald E, Gullans Steven R, Haines Jonathan L, Gilbert John R, Vance Jeffery M, Pericak-Vance Margaret A, Hulette Christine, Welsh-Bohmer Kathleen A
Department of Medicine, Center for Human Genetics, Institute for Genome Science and Policy, Duke University Medical Center, Box 3445, Durham, NC 27710, USA.
Hum Mol Genet. 2003 Dec 15;12(24):3259-67. doi: 10.1093/hmg/ddg357. Epub 2003 Oct 21.
We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.
我们之前报道，控制阿尔茨海默病（AD）和帕金森病（PD）发病年龄的基因座与10号染色体长臂上一个15厘摩的区域存在遗传连锁。鉴于这个初始起始区域中有大量基因，我们应用“基因组收敛”过程来对候选基因进行优先级排序并减少其数量，以便进一步分析。作为我们的第二个收敛因素，我们对从AD患者和对照者获取的海马体进行了基因表达研究。分析显示，其中四个基因[硬脂酰辅酶A去饱和酶；NADH -泛醌氧化还原酶1β亚复合体8；丝氨酸蛋白酶11；以及谷胱甘肽S -转移酶ω-1（GSTO1）]在AD患者和对照者之间的表达存在显著差异，并且定位于10号染色体长臂发病年龄连锁区域，即第一个收敛因素。使用我们AD数据集的2814个样本（1773例AD患者）和PD数据集的1362个样本（635例PD患者），针对AD和PD发病年龄效应的等位基因关联研究显示，其中三个候选基因无关联，但发现GSTO1（P = 0.007）以及位于GSTO1旁边的GSTω类的另一个转录成员GSTO2（P = 0.005）存在显著关联。GSTO1和GSTO2的功能尚不完全清楚，但最近的数据表明，GSTO1可能参与炎症细胞因子白细胞介素-1β的翻译后修饰。鉴于有报道称炎症在这两种神经退行性疾病中可能发挥作用，这一发现颇具启发性。
