Fehsel Karin, Schikowski Tamara, Jänner Michaela, Hüls Anke, Voussoughi Mohammed, Schulte Thomas, Vierkötter Andrea, Teichert Tom, Herder Christian, Sugiri Dorothea, Krämer Ursula, Luckhaus Christian
Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University Düsseldorf, Bergische Landstrasse 2, 40629, Düsseldorf, Germany.
IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
J Neural Transm (Vienna). 2016 Dec;123(12):1369-1379. doi: 10.1007/s00702-016-1620-8. Epub 2016 Sep 14.
Genetic and environmental risk factors contribute to the pathogenesis of Alzheimer's dementia. Besides known genetic risk factors like the apolipoprotein (APO) Eε4 allele, single nuclear polymorphisms (SNPs) of the estrogen receptors (ESRs) are candidate genetic risk factors, while air pollution represents an environmental risk factor for dementia. Effects of these risk factors and their interaction were investigated in the SALIA cohort of 834 non-demented elderly women. Cognitive function was assessed by the CERAD-plus test battery. Air pollution was estimated by land use regression (LUR) models. Genotyping was carried out for nine ESR1 and ESR2 SNPs and two ApoE SNPs. Carriers of minor ESR2 alleles showed significantly reduced cognitive performance in the CERAD total score with most pronounced deficits in semantic memory (rs1256062, rs10144225, and rs2274705) and executive function (rs1256062). The minor allele effects of ESR2 were stronger in carriers of APOEε4 for the cognitive domain 'executive function' (p value of interaction 0.023 for rs1256062). The investigated ESR1 SNPs were not associated with cognition. Furthermore, we found a significant gene-environment interaction between the ESR2 SNP rs1256062 and air pollution on cognition. Carriers of two major alleles of rs1256062 were more susceptible for an air pollution-induced decrease in performance of 'figure copying' than carriers of minor alleles (p value of interaction, e.g., 0.031 for PM). In conclusion, ESR2 but not ESR1 minor alleles were associated with lower cognitive performance in elderly women with an indication of a gene-gene interaction with APOEε4. We also found indications for gene-environment interactions of ESR2 with traffic-related air pollution exposure on cognitive performance.
遗传和环境风险因素促成了阿尔茨海默病性痴呆的发病机制。除了载脂蛋白（APO）Eε4等位基因等已知的遗传风险因素外，雌激素受体（ESR）的单核苷酸多态性（SNP）是候选遗传风险因素，而空气污染是痴呆的环境风险因素。在834名未患痴呆的老年女性组成的SALIA队列中研究了这些风险因素及其相互作用的影响。通过CERAD-plus测试组合评估认知功能。通过土地利用回归（LUR）模型估算空气污染。对9个ESR1和ESR2 SNP以及2个载脂蛋白E SNP进行基因分型。ESR2次要等位基因的携带者在CERAD总分中的认知表现显著降低，在语义记忆（rs1256062、rs10144225和rs2274705）和执行功能（rs1256062）方面缺陷最为明显。对于认知领域“执行功能”，ESR2的次要等位基因效应在APOEε4携带者中更强（rs1256062的相互作用p值为0.023）。所研究的ESR1 SNP与认知无关。此外，我们发现ESR2 SNP rs1256062与空气污染在认知方面存在显著的基因-环境相互作用。rs1256062两个主要等位基因的携带者比次要等位基因的携带者更容易受到空气污染导致的“图形临摹”表现下降的影响（相互作用p值，例如PM为0.031）。总之，ESR2而非ESR1的次要等位基因与老年女性较低的认知表现相关，表明与APOEε4存在基因-基因相互作用。我们还发现了ESR2与交通相关空气污染暴露在认知表现方面存在基因-环境相互作用的迹象。
