Heun Reinhard, Kölsch Heike, Ibrahim-Verbaas Carla A, Combarros Onofre, Aulchenko Yurii S, Breteler Monique, Schuur Maaike, van Duijn Cornelia M, Hammond Naomi, Belbin Olivia, Cortina-Borja Mario, Wilcock Gordon K, Brown Kristelle, Barber Rachel, Kehoe Patrick G, Coto Eliecer, Alvarez Victoria, Lehmann Michael G, Deloukas Panos, Mateo Ignacio, Morgan Kevin, Warden Donald R, Smith A David, Lehmann Donald J
Department of Psychiatry, University of Bonn, Bonn, Germany; 2Department of Psychiatry, Royal Derby Hospital,Uttoxeter Road, Derby DE22 3WQ, UK.
Int J Mol Epidemiol Genet. 2012;3(1):39-47. Epub 2012 Feb 23.
Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1β, IL-6, and IL-10 may interact to increase AD risk.
The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (p<0.05 two-sided).
We observed four significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6.
In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.
神经炎症在散发性阿尔茨海默病（AD）的发病机制中起作用。与炎症相关的基因变异可能是AD风险的候选基因。全基因组关联研究已经确定了相关的新基因和已知基因。它们的综合作用并不能解释100%的风险，基因相互作用可能起作用。我们研究了参与炎症的基因，即过氧化物酶体增殖物激活受体-α（PPAR-α）、白细胞介素（IL）-1α、IL-1β、IL-6和IL-10是否相互作用以增加AD风险。
上位性项目确定影响AD风险的相互作用。对PPARA、IL1A、IL1B、IL6和IL10中的单核苷酸多态性（SNP）进行基因分型。通过以AD为结局拟合逻辑回归模型分析可能的关联，同时控制中心、年龄、性别和载脂蛋白ε4等位基因（APOEε4）的存在。调整后的协同因子来自相互作用项（双侧p<0.05）。
我们观察到PPARA与白细胞介素IL1A、IL1B、IL10中的不同SNP之间存在四种显著的相互作用，可能影响AD风险。PPARA与IL6之间没有显著的相互作用。
除了PPARA L162V多态性与AD风险相关外，我们还观察到PPARA中的SNP与IL1A、IL1B和IL10中的SNP之间存在四种显著的相互作用，影响AD风险。我们证明基因-基因相互作用解释了AD遗传度的一部分，在评估遗传风险时应予以考虑。根据SNP的患病率，需要1450至2950例病例和对照进行必要的重复研究，才能有80%的把握检测到观察到的协同因子。
