与非裔美国人阿尔茨海默病相关的 ABCA7 移码缺失。
ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.
机构信息
John P. Hussman Institute for Human Genomics (H.N.C., B.W.K., S.R., K.L.H.-N., M.A.K., P.L.W., D.V.B., D.M.D., M.L.C., J.M.V., J.R.G., G.W.B., E.R.M., R.M.C., M.A.P.-V.), Department of Neurology (H.N.C., J.M.V., M.A.P.-V.), Dr. John T. Macdonald Foundation Department of Human Genetics (D.M.D., M.L.C., J.M.V., J.R.G., G.W.B., E.R.M., R.M.C.), Miller School of Medicine, University of Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Department of Pathology and Laboratory Medicine (B.A.D., G.D.S.), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Department of Biology (R.L., G.S.B., M.A.P.-V.), North Carolina A&T State University, Greensboro, NC; Departments of Medicine, Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics (L.A.F.), Boston University, MA; and Department of Epidemiology and Biostatistics (J.L.H.), Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH.
出版信息
Neurol Genet. 2016 May 17;2(3):e79. doi: 10.1212/NXG.0000000000000079. eCollection 2016 Jun.
OBJECTIVE
To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.
METHODS
Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.
RESULTS
A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.
CONCLUSIONS
This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.
目的
确定 ATP 结合盒，亚家族 A（ABC1），成员 7（ABCA7）基因中的一个致病变异（s），该基因是晚期发病阿尔茨海默病（AD）的已知风险因素。
方法
对 40 例携带 AA 风险等位基因（rs115550680）的 AA 病例和 37 例 AA 对照的约 150kb 的 ABCA7 进行定制捕获测序。对在大型 AA 数据集中发现的 ABCA7 缺失（发现 n = 1,068；复制 n = 1,749）和加勒比西班牙裔（CH）AD 家族的全外显子组测序进行关联测试。
结果
在所有 77 名风险基因型携带者中发现了一个 44 个碱基对的缺失（rs142076058），这表明该缺失与风险等位基因高度连锁不平衡。该缺失在一个大型数据集（531 例病例和 527 例对照）中进行了评估，并且在调整年龄、性别和 APOE 状态后，与疾病显著相关（p = 0.0002，优势比 [OR] = 2.13 [95%置信区间（CI）：1.42-3.20]）。一个独立的数据集复制了该关联（447 例病例和 880 例对照，p = 0.0117，OR = 1.65 [95%CI：1.12-2.44]），联合分析增加了显著性（p = 1.414×10（-5），OR = 1.81 [95%CI：1.38-2.37]）。该缺失在 AA 病例（15.2%）和 AA 对照（9.74%）中很常见，但在我们的非西班牙裔白人队列中仅占 0.12%。CH 家系的外显子组测序发现该缺失与疾病在一个大型家系中共同分离。缺失的等位基因产生一个稳定的、可检测的 RNA 链，并预测导致移码突变（p.Arg578Alafs），这可能干扰蛋白功能。
结论
这种常见的 ABCA7 缺失可能代表 AD 中的一种特定于种族的致病性改变。
Zotero 插件