Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.
Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.
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DOI：
10.1038/mp.2009.10
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发表时间：
2009-11
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
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阿尔茨海默病（AD）常见形式的唯一公认的遗传决定因素是载脂蛋白E基因（APOE）的ε4等位基因。为了确定新的候选基因，我们最近使用AD病例和对照的脑组织对染色体感兴趣区域中的2，741个基因进行了转录组学分析。从82个差异表达的基因中，在两个独立的发现子样本（n=945）中对1，156个多态性进行基因分型。17个基因表现出至少一种与AD风险相关的多态性，并在多次检测校正后，我们保留了IL-33基因。我们首次证实，与对照组相比，AD病例的脑中IL-33表达降低。进一步的遗传分析使我们在该基因中选择了3个多态性，我们在3个独立的病例对照研究中进行了分析。这些多态性和由此产生的保护性单倍型与非APOE ε4携带者的AD风险系统相关。使用一项大型前瞻性研究，当一起分析流行和事件AD病例或单独分析事件AD病例时，也检测到这些关联。这些多态性也与非APOE ε4 AD患者脑内淀粉样血管病（CAA）较少相关。免疫组织化学实验最终表明，IL-33的表达始终局限于脑中的血管毛细血管。此外，细胞模型中IL-33过表达导致Aβ40肽（主要CAA组分）分泌的特异性减少。总之，我们的数据表明，IL-33基因的遗传变异可能与AD风险的降低有关，可能在调节CAA的形成。
The only recognised genetic determinant of the common forms of Alzheimer’s disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2,741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1,156 polymorphisms were genotyped in two independent discovery sub-samples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk and following correction for multiple testing, we retained the IL-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select 3 polymorphisms within this gene, which we analysed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE ε4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE ε4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the Aβ40 peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.
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