Schupf Nicole, Lee Joseph H, Wei Michelle, Pang Deborah, Chace Constance, Cheng Rong, Zigman Warren B, Tycko Benjamin, Silverman Wayne
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, G.H. Sergievsky Center, New York, NY, USA.
Dement Geriatr Cogn Disord. 2008;25(5):476-82. doi: 10.1159/000126495. Epub 2008 Apr 14.
Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). Two tightly linked polymorphisms (PvuII and XbaI) in the first intron of estrogen receptor 1 (ESR1), the gene for ER-alpha, have been reported to influence estrogen receptor expression and may influence the risk of AD.
We examined the relation of polymorphisms in ESR1 to the risk of AD in women with Down syndrome. The subjects (181 women with DS, 41-78 years of age) were followed at 14- to 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record reviews and neurological examinations was used to classify dementia. Genomic DNA was genotyped for 5 single-nucleotide polymorphisms in the upstream region and the first exon/intron of the ESR1 gene. Their association with dementia risk was evaluated, adjusting for covariates.
Women with at least 1 copy of the C allele at rs2234693 (PvuII) and those homozygous for the C allele at rs2077647 had an almost 3-fold increase in the risk of AD, compared with women without the C allele. The increased risks were independent of the apolipoprotein E genotype.
These findings support a role for estrogen receptor activity in the development of AD in women with Down syndrome.
影响雌激素活性的基因变异可能会影响阿尔茨海默病（AD）的发病风险。据报道，雌激素受体1（ESR1，即ER-α基因）第一内含子中的两个紧密连锁的多态性（PvuII和XbaI）会影响雌激素受体的表达，可能影响AD的发病风险。
我们研究了ESR1基因多态性与唐氏综合征女性患AD风险之间的关系。对受试者（181名年龄在41至78岁之间的唐氏综合征女性）每隔14至18个月进行随访。来自认知评估、照顾者访谈、病历回顾和神经学检查的信息用于痴呆症的分类。对ESR1基因上游区域和第一个外显子/内含子中的5个单核苷酸多态性进行基因组DNA基因分型。在调整协变量后评估它们与痴呆症风险的关联。
与没有C等位基因的女性相比，rs2234693（PvuII）位点至少有1个C等位基因拷贝的女性以及rs2077647位点C等位基因纯合的女性患AD的风险增加了近3倍。风险增加与载脂蛋白E基因型无关。
这些发现支持雌激素受体活性在唐氏综合征女性AD发病过程中起作用。
