Tycko Benjamin, Lee Joseph H, Ciappa Alejandra, Saxena Anjana, Li Chi-Ming, Feng Lin, Arriaga Alex, Stern Yaakov, Lantigua Rafael, Shachter Neil, Mayeux Richard
Department of Pathology, Division of Neuropathology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
Arch Neurol. 2004 Sep;61(9):1434-9. doi: 10.1001/archneur.61.9.1434.
The APOE epsilon4 allele is a genetic risk factor for Alzheimer disease (AD), though the strength of the association varies by ethnic group. Polymorphisms in regulatory sequences of APOE have also been related to AD, but the effects are inconsistent across studies.
We examined the association between AD and variants in 3 APOE promoters and in the promoter of the adjacent APOC1 gene in African American and Caribbean Hispanic individuals. Polymorphisms tested were the -491A/T, -427T/C, and -219G/T (Th1/E47cs) in the APOE promoter and the HpaI variant in the APOC1 promoter. Using standard research criteria for AD, overall odds ratios were computed and repeated stratified by presence or absence of APOE epsilon4.
The APOC1 HpaI+ variant was associated with AD in Caribbean Hispanic individuals, but strong linkage disequilibrium with the APOE epsilon4 allele indicated that this was not an independent effect. No promoter variant in APOE or APOC1 was associated with AD before or after adjusting for age, education, sex, and multiple comparisons. Estimated haplotypes including -219G/T, APOE, and APOC1 differed significantly in Caribbean Hispanic patients and controls but not in African American participants. This effect was primarily owing to the -219G/T-APOE haplotype, but we did not detect significant allele-specific differences in promoter activity comparing reporter constructs containing the APOE -219G and -219 T alleles.
These findings exclude a strong or independent influence of APOE or APOC1 promoter polymorphisms on the variation in APOE-related risk of AD in African American and Caribbean Hispanic individuals.
APOEε4等位基因是阿尔茨海默病（AD）的遗传风险因素，尽管这种关联的强度因种族而异。APOE调控序列的多态性也与AD有关，但各研究结果并不一致。
我们在非裔美国人和加勒比西班牙裔个体中研究了AD与3个APOE启动子及相邻APOC1基因启动子变异之间的关联。检测的多态性包括APOE启动子中的-491A/T、-427T/C和-219G/T（Th1/E47cs）以及APOC1启动子中的HpaI变异。使用AD的标准研究标准，计算总体优势比，并根据是否存在APOEε4进行重复分层分析。
APOC1 HpaI+变异与加勒比西班牙裔个体的AD相关，但与APOEε4等位基因的强连锁不平衡表明这不是独立效应。在调整年龄、教育程度、性别和多重比较前后，APOE或APOC1的启动子变异均与AD无关。在加勒比西班牙裔患者和对照中，包括-219G/T、APOE和APOC1的估计单倍型有显著差异，但在非裔美国参与者中无差异。这种效应主要归因于-219G/T-APOE单倍型，但在比较含有APOE -219G和-219T等位基因的报告基因构建体时，我们未检测到启动子活性的显著等位基因特异性差异。
这些发现排除了APOE或APOC1启动子多态性对非裔美国人和加勒比西班牙裔个体中APOE相关AD风险变异的强烈或独立影响。
