Heijmans Bastiaan T, Slagboom P Eline, Gussekloo Jacobijn, Droog Simone, Lagaay A Margot, Kluft Cornelis, Knook Dick L, Westendorp Rudi G J
Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
Am J Med Genet. 2002 Jan 22;107(3):201-8. doi: 10.1002/ajmg.10142.
The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE epsilon4 allele were associated with a 4.1-fold (95% CI, 2.2-7.7) increased risk of dementia as compared to the epsilon3/epsilon3 genotype in old subjects. Moreover, homozygosity for the -219T allele was found to be associated with a 2.4-fold (95% CI, 1.0-5.8) increased risk independently of epsilon2 and epsilon4; the -491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among epsilon4 carriers (RR, 0.6; 95% CI, 0.4-1.0) or -219T homozygous subjects (RR, 1.1; 95% CI, 0.7-1.7), nor did it decrease among -491T homozygous subjects (RR, 1.4; 95% CI, 0.6-3.1). In conclusion, both the APOE epsilon2/epsilon3/epsilon4 and the -219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age.
常见的载脂蛋白E（APOE）等位基因ε2、ε3和ε4与痴呆症和心血管疾病风险相关。最近，在APOE基因启动子中鉴定出两个功能性变体（-219G/T和-491A/T），这使得能够进一步明确APOE基因座在疾病中的作用。我们使用一个基于人群的队列研究，对648名85岁及以上的受试者（莱顿85岁及以上研究）进行调查，以研究这些APOE基因变体对老年痴呆症和心血管疾病死亡率的影响。与老年受试者中的ε3/ε3基因型相比，含有APOEε4等位基因的基因型与痴呆症风险增加4.1倍（95%置信区间，2.2-7.7）相关。此外，发现-219T等位基因纯合与痴呆症风险增加2.4倍（95%置信区间，1.0-5.8）相关，且独立于ε2和ε4；-491A/T变体与痴呆症无关。在10年的随访期内，ε4携带者（风险比，0.6；95%置信区间，0.4-1.0）或-219T纯合受试者（风险比，1.1；95%置信区间，0.7-1.7）的心血管疾病死亡率未增加，-491T纯合受试者的心血管疾病死亡率也未降低（风险比，1.4；95%置信区间，0.6-3.1）。总之，APOEε2/ε3/ε4和-219G/T变体均被确定为老年痴呆症的风险因素，但不是心血管疾病死亡率的风险因素。我们的结果支持这样的假设，即APOE的异构体和数量可能都会影响痴呆症风险。此外，它们强调APOE基因座的变异对老年痴呆症风险的影响比对心血管疾病风险的影响更大。
