生物谷報(bào)道:阿耳茨海默氏癥Alzheimer’s disease是老年人中最常見的記憶、思考障礙的疾病,,又稱老年癡呆癥。這種漸行性的神經(jīng)紊亂疾病大約影響著5百萬的美國人,,而且據(jù)估計(jì),,到2050年這個(gè)數(shù)據(jù)將增長到3倍。
刊登在6月7日的Neuron雜志上的一篇文章指出,,研究著發(fā)現(xiàn)了新的阿爾茨海默氏癥的致病基因,。該研究是在之前的研究基礎(chǔ)上,將患有和未患有阿爾茨海默氏癥的人的遺傳標(biāo)記作比較,,比較患病人群與未患病人群的基因差異,,科學(xué)家們識(shí)別出了一個(gè)共同的關(guān)鍵性基因,。該基因可以增加人患阿爾茨海默氏癥的風(fēng)險(xiǎn)。研究表明GAB2通過與其他基因協(xié)作,,包括APOE4,,可以改變個(gè)體的患病風(fēng)險(xiǎn)。這將對(duì)預(yù)防和治療阿爾茨海默氏癥相關(guān)研究有重要的指導(dǎo)作用,。
原始出處:
Neuron, Vol 54, 713-720, 07 June 2007
Report
GAB2 Alleles Modify Alzheimer's Risk in APOE 4 Carriers
Eric M. Reiman,1,2,3,17,18, Jennifer A. Webster,1,17,18 Amanda J. Myers,4,5,18 John Hardy,5,6 Travis Dunckley,1,17 Victoria L. Zismann,1,17 Keta D. Joshipura,1,17 John V. Pearson,1,17 Diane Hu-Lince,1,17 Matthew J. Huentelman,1,17 David W. Craig,1,17 Keith D. Coon,1,7,17 Winnie S. Liang,1,17 RiLee H. Herbert,1,17 Thomas Beach,8,17 Kristen C. Rohrer,5 Alice S. Zhao,5 Doris Leung,5 Leslie Bryden,5 Lauren Marlowe,5 Mona Kaleem,5 Diego Mastroeni,8 Andrew Grover,8,17 Christopher B. Heward,9 Rivka Ravid,10 Joseph Rogers,8,17 Michael L. Hutton,11 Stacey Melquist,11 Ron C. Petersen,12 Gene E. Alexander,13,17 Richard J. Caselli,14,17 Walter Kukull,16 Andreas Papassotiropoulos,1,15 and Dietrich A. Stephan1,2,17,
1 Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
2 Banner Alzheimer's Institute, Phoenix, AZ 85006, USA
3 Department of Psychiatry, University of Arizona, Tucson, AZ 85724, USA
4 Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
5 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, 20892, USA
6 Reta Lila Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N, 3BG, England
7 Division of Thoracic Oncology Research, St. Joseph's Hospital, Phoenix, AZ 85013, USA
8 Sun Health Research Institute, Sun City, AZ 85351, USA
9 Kronos Science Laboratory, Phoenix, AZ 85016, USA
10 Netherlands Institute for Neurosciences, Dutch Royal Academy of Arts and Sciences, Meibergdreef 47 AB Amsterdam, The Netherlands
11 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
12 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
13 Department of Psychology, Arizona State University, Tempe, AZ 85281, USA
14 Department of Neurology, Mayo Clinic, Scottsdale, AZ 85259, USA
15 Division of Molecular Psychology and Life Sciences Training Facility, Biozentrum, University of Basel, Switzerland
16 National Alzheimer's Coordinating Center, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195, USA
17 Arizona Alzheimer's Consortium, Phoenix AZ 85006, USA
Corresponding author
Eric M. Reiman
[email protected]
Corresponding author
Dietrich A. Stephan
[email protected]
Summary
The apolipoprotein E (APOE) 4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In 4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10−11) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with APOE 4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE 4 carriers and influences Alzheimer's neuropathology.