Yu Lei, Lutz Michael W, Wilson Robert S, Burns Daniel K, Roses Allen D, Saunders Ann M, Yang Jingyun, Gaiteri Chris, De Jager Philip L, Barnes Lisa L, Bennett David A
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America.
PLoS One. 2017 Jul 3;12(7):e0180356. doi: 10.1371/journal.pone.0180356. eCollection 2017.
Patterns of linkage between the ε4 allele of Apolipoprotein E (APOE) and '523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer's disease (AD) is unclear. We compared the APOE ε4-TOMM40 '523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 '523 genotypes were defined by the poly-T repeat length of rs10524523 (short ['523-S]: poly-T ≤ 19, long ['523-L]: 20 ≤ poly-T ≤ 29, and very long ['523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-ε4 carriers and almost all (94.2%) of the ε4 carriers had '523-L. The classification was highly concordant. Each ε4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 '523-L. In African Americans, nearly none (1.1%) of the non-ε4 carriers had '523-L, but only 47.8% of the ε4 carriers had '523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between ε4 and '523-L carriers. Further, both genotypic and allelic data support that among African Americans the ε4-'523-L haplotype had stronger effect on risk of AD dementia than other ε4-'523 haplotypes.
载脂蛋白E（APOE）的ε4等位基因与相邻基因TOMM40中的“523多聚T”等位基因之间的连锁模式在白种人和非裔美国人中有所不同。这种差异对阿尔茨海默病（AD）风险的影响程度尚不清楚。我们比较了老年白种人和非裔美国人之间的APOE ε4 - TOMM40“523单倍型，并研究了它们与AD痴呆症的关系。数据来自三项针对不同参与者的社区队列研究。APOE基因型由rs429358和rs7412的多态性确定。TOMM40“523基因型由rs10524523的多聚T重复长度定义（短['523 - S]：多聚T≤19，长['523 - L]：20≤多聚T≤29，非常长['523 - VL]：多聚T≥30）。Cox比例风险模型检验了单倍型变异对新发AD痴呆症风险的影响。共有1848名白种人和540名非裔美国人参与了这项研究。在白种人中，几乎没有非ε4携带者（0.8%）有“523 - L”，而几乎所有ε4携带者（94.2%）都有“523 - L”。分类高度一致。每个ε4等位基因使AD痴呆症风险加倍，剂量效应明显。对于TOMM40“523 - L”观察到几乎相同的效应大小和效应模式。在非裔美国人中，几乎没有非ε4携带者（1.1%）有“523 - L”，但只有47.8%的ε4携带者有“523 - L”。与白种人相比，一致性较弱。ε4和“523 - L”携带者对新发AD痴呆症的效应模式有明显差异。此外，基因型和等位基因数据均支持，在非裔美国人中，ε4 - “523 - L”单倍型对AD痴呆症风险的影响比其他ε4 - “523”单倍型更强。
