Medway Christopher, Combarros Onofre, Cortina-Borja Mario, Butler Helen T, Ibrahim-Verbaas Carla A, de Bruijn Renée F A G, Koudstaal Peter J, van Duijn Cornelia M, Ikram M Arfan, Mateo Ignacio, Sánchez-Juan Pascual, Lehmann Michael G, Heun Reinhard, Kölsch Heike, Deloukas Panos, Hammond Naomi, Coto Eliecer, Alvarez Victoria, Kehoe Patrick G, Barber Rachel, Wilcock Gordon K, Brown Kristelle, Belbin Olivia, Warden Donald R, Smith A David, Morgan Kevin, Lehmann Donald J
Human Genetics Research, Queens Medical Centre, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas(CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), Santander, Spain.
Eur J Hum Genet. 2014 Feb;22(2):216-20. doi: 10.1038/ejhg.2013.116. Epub 2013 Jun 5.
Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.
先前有报道称，白细胞介素-10（IL10）与芳香化酶基因多态性之间的上位性会改变阿尔茨海默病（AD）的风险。然而，尽管芳香化酶变体的主要效应表明其在AD中存在性别特异性效应，但迄今为止，检测这些基因之间性别特异性上位性的能力不足。在此，我们使用了上位性项目中的1757例AD患者和6294例对照的队列。我们重复了先前报道的芳香化酶多态性对女性AD风险的主要效应，例如，rs1065778 GG基因型的疾病调整优势比=1.22（95%置信区间：1.01-1.48，P=0.03）。我们还证实了IL10 rs1800896与芳香化酶（CYP19A1）rs1062033之间存在报道的上位性相互作用，同样仅在女性中：调整后的协同因子=1.94（1.16-3.25，P=0.01）。芳香化酶是雌激素合成中的一种限速酶，在与AD相关的脑区表达，且在疾病过程中下调。IL-10是一种抗炎细胞因子。鉴于雌激素具有神经保护和抗炎活性，并调节小胶质细胞细胞因子的产生，上位性在生物学上是合理的。绝经后女性血清雌激素减少，加上脑内雌激素合成欠佳，可能会导致炎症状态，而炎症状态是AD的一个病理特征。
