Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Japan.
Int J Mol Med. 2011 Jun;27(6):795-801. doi: 10.3892/ijmm.2011.645. Epub 2011 Mar 8.
Toll-like receptors (TLRs) are important pathogen-associated molecular pattern recognition receptors involved in initiating immune responses. The adaptor protein MyD88 adaptor-like (Mal), involved in signaling downstream of TLRs, plays a crucial role in mediating NF-κB activation. The association of Mal polymorphisms with allergic diseases has not previously been defined. The objective of this study was to detect polymorphisms in the Mal gene and to investigate their association with allergic diseases. Mal gene polymorphisms were genotyped in 310 subjects. The functional effects of Mal variants were analyzed in vitro. One Mal polymorphism, c.303 G>A (Q101Q), was found at a significantly lower frequency in atopic dermatitis patients (p=0.016). Q101Q is in linkage disequilibrium with -103 A>G (rs1893352) and c.539 C>T (S180L) (rs8177374) in the HapMap database. The A allele of -103 A>G showed significantly reduced transcription of Mal compared with the G allele. In addition, three rare variants were identified in this study, c.394 G>A (E132K), c.428 G>A (R143Q) and c.570 G>C (E190D), and were shown to lead to loss-of-function of Mal. It is possible that gene polymorphisms in Mal could affect atopic dermatitis by influencing the innate immune system. We show that Q101Q, which is in linkage disequilibrium with -103 A>G and S180L, may play a protective role against atopic dermatitis. Furthermore, we propose that loss-of-function variants of Mal could predispose individuals to atopic dermatitis or other immunological disorders.
Toll 样受体 (TLRs) 是参与启动免疫反应的重要病原体相关分子模式识别受体。衔接蛋白 MyD88 样 (Mal) 参与 TLR 下游信号转导，在介导 NF-κB 激活中发挥关键作用。Mal 多态性与过敏性疾病的关联尚未得到明确。本研究旨在检测 Mal 基因的多态性，并探讨其与过敏性疾病的关系。对 310 例患者的 Mal 基因多态性进行了基因分型。在体外分析了 Mal 变异体的功能效应。发现一个 Mal 多态性，c.303 G>A (Q101Q)，在特应性皮炎患者中的频率明显降低 (p=0.016)。Q101Q 与 -103 A>G(rs1893352) 和 c.539 C>T(S180L)(rs8177374) 在 HapMap 数据库中呈连锁不平衡。-103 A>G 的 A 等位基因与 G 等位基因相比，Mal 的转录明显减少。此外，本研究还鉴定出三个罕见变异体，c.394 G>A(E132K)、c.428 G>A(R143Q)和 c.570 G>C(E190D)，它们导致 Mal 功能丧失。Mal 基因多态性可能通过影响固有免疫系统而影响特应性皮炎。我们发现与 -103 A>G 和 S180L 连锁不平衡的 Q101Q 可能对特应性皮炎具有保护作用。此外，我们提出 Mal 的失活变异体可能使个体易患特应性皮炎或其他免疫性疾病。
