Epistasis analysis links immune cascades and cerebral amyloidosis
Epistasis analysis links immune cascades and cerebral amyloidosis
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DOI：
10.1186/s12974-015-0436-z
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发表时间：
2015-12-01
影响因子：
9.3
通讯作者：
Rosa-Neto, Pedro
中科院分区：
文献类型：
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作者：
Benedet, Andrea L.;Labbe, Aurelie;Rosa-Neto, Pedro
背景资料：有证据表明阿尔茨海默病（AD）的病理生理学，如淀粉样变性和神经变性的神经炎症变化的参与。事实上，全基因组关联研究（GWAS）已经显示了参与神经炎症和AD的基因之间的联系。为了进一步研究编码神经炎性分子的候选遗传变异之间的相互作用是否与脑淀粉样蛋白β（A β）的累积相关，我们对与炎症分子介质相关的基因库进行了上位性分析。[F-18]采用Florbetapir正电子发射断层扫描（PET）成像评估来自ADNI-GO/ADNI-2和ADNI-1的后部174。基于先前在AD患者中进行的研究选择IL-1 β、IL 4、IL 6、IL 6 r、IL 10、IL 12、IL 18、C5和C9基因。使用[F-18] florbetapir标准化摄取值比（SUVR）作为血清A β的定量指标，使用性别、诊断和载脂蛋白E（APOE）作为协变量，在两组免疫相关基因标志物之间进行上位性分析。还进行了基于体素的分析。对结果进行了多重比较检验校正。结果：上位性分析显示了两个显著的单核苷酸多态性（SNP）-SNP交互作用（假发现率（FDR）阈值0.1），这两个交互作用均发生在C9基因（rs 261752）和IL 6 r基因（rs 4240872、rs7514452）之间。在合并样本中，相互作用得到证实（p
Background: Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid beta (A beta) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.Methods: [F-18] Florbetapir positron emission tomography (PET) imaging was employed to assess brain A beta levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1 beta, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [F-18] florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary A beta, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) A beta(1-42)/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.Results: Epistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p