Lee Joseph H, Cheng Rong, Schupf Nicole, Manly Jennifer, Lantigua Rafael, Stern Yaakov, Rogaeva Ekaterina, Wakutani Yosuke, Farrer Lindsay, St George-Hyslop Peter, Mayeux Richard
Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Arch Neurol. 2007 Apr;64(4):501-6. doi: 10.1001/archneur.64.4.501.
To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population.
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older.
Northern Manhattan, NY.
There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%).
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods, which included apolipoprotein E genotype as a covariate.
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5' region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3' region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3' region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 (P = .035), which was significantly associated with AD in the North European white individuals in our previous report.
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
在一个城市多民族社区人群中，通过一系列单核苷酸多态性（SNP）研究阿尔茨海默病（AD）与SORL1基因变异等位基因之间的关联。
我们在一项针对65岁及以上医疗保险受益人的基于人群的衰老与痴呆前瞻性研究中采用巢式病例对照分析。
纽约曼哈顿北部。
有296例可能患有AD的患者和428名健康老年对照。参与者为非裔美国人（34%）、加勒比西班牙裔（51%）或非西班牙裔白人（15%）。
我们对先前报告中检测的SORL1基因的所有29个SNP进行基因分型。我们使用标准病例对照方法评估等位基因与AD的关联，其中包括将载脂蛋白E基因型作为协变量。
在这个前瞻性收集的基于社区的队列中，几个个体SNP和SNP单倍型与AD显著相关，证实了先前报道的SORL1与AD的正相关。5'区域附近的单核苷酸多态性12与非裔美国人和西班牙裔个体的AD相关。3'区域的两个SNP也分别与非裔美国人（SNP 26）和非西班牙裔白人（SNP 20）个体的AD相关。3'区域的一个单倍型与西班牙裔个体的AD相关。然而，非裔美国人和白人个体中有几种不同的单倍型与AD相关，包括SNP 23至25处的TTC单倍型（P = 0.035），在我们先前的报告中该单倍型与北欧白人个体的AD显著相关。
本研究证实了SORL1基因变异与AD之间的关联。虽然这些数据集中观察到的关联与先前报告的重叠，但新的SNP和单倍型关联的发现表明SORL1可能存在广泛的等位基因异质性。因此，需要对SORL1基因的广泛区域进行功能性致病变异的仔细检查。
