Gene Expression Profiles of IL17RC+ and IL17RC- THP1 Cells. Homo sapiens

Age related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. While recent studies have demonstrated strong genetic associations of single nucleotide polymorphisms within a number of genes and AMD, other modes of regulation are also likely to play a role in its aetiology. We undertook DNA methylation microarray analysis on monozygotic and dizygotic twins who were discordant for AMD and identified methylated IL17RC promoters as being present only in non-AMD control individuals rather than in AMD patients. We validated this finding of a significantly decreased level of methylation on the IL17RC promoter in AMD siblings as well as in a case control study involving 202 genetically unrelated AMD patients and 96 controls (95% CI, 0.03-0.17, P=3.1x10-8). Further, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and mRNA in peripheral blood as well as in the retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis. Overall design: Affymetrix U133 plus 2.0 GeneChip was used to detect gene expression patterns of IL17RC+ and IL17RC- THP1 cells.

年龄相关性黄斑变性（Age Related Macular Degeneration, AMD）是全球老年人群不可逆失明的首要病因。尽管近期研究已证实多个基因内的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）与AMD存在显著遗传关联，但其他调控模式也可能参与其发病机制。本研究对表型不一致的同卵双生子与异卵双生子（即一对双胞胎中一人患AMD、另一人未患）开展了DNA甲基化芯片分析，发现IL17RC启动子甲基化仅存在于非AMD对照个体中，AMD患者未检测到该修饰。我们在AMD同胞对以及纳入202名无遗传亲缘关系AMD患者与96名对照个体的病例对照研究中，验证了“AMD患者IL17RC启动子甲基化水平显著降低”这一发现（95%置信区间[Confidence Interval, CI]：0.03~0.17，P=3.1×10^-8）。进一步研究表明，AMD患者IL17RC启动子低甲基化可使其外周血、视网膜及脉络膜中的蛋白与mRNA表达水平升高，提示IL17RC的DNA甲基化模式与表达水平或可作为AMD诊断的潜在生物标志物，并可能参与疾病的发病机制。实验整体设计：采用Affymetrix U133 Plus 2.0 基因芯片（GeneChip）检测IL17RC阳性与IL17RC阴性的THP1细胞的基因表达谱。