Genetic and Functional Analysis of LYN Alleles Associated with Lupus

FcyR11b、CD22和CD72是微调免疫功能的重要负性调节分子 通过包括Src家族酪氨酸激酶Lyn在内的细胞内信号通路进行反应。 与这些调控分子有关的基因敲除和转基因动物都具有Lupusljke的特征 自身免疫力。LYN基因敲除小鼠和LYN功能获得转基因小鼠也都发展为狼疮样 自身免疫表型以高反应性B细胞和增加自身抗体产生为特征。 B细胞Lyn蛋白表达、亚细胞定位及翻译后修饰的差异 与对照组相比，狼疮患者的咯血细胞被描述为。然而，没有人类 到目前为止，LYN的遗传关联研究已经存在。因此，LYN仍然是狼疮的有力候选基因 基于函数和候选路径分析。 我们现在已经确定LYN和人类狼疮有很强的遗传关联。我们的目标是林恩 检测22个SNPs的697例病例和604例对照的候选基因关联研究我们确认了 多个SNP具有很强的关联性。峰关联度x~2=10.42，p=0.0012，OR=1.43±95% CL(1.16-1.78)，我们鉴定了一个3标记单倍型CTA，它赋予狼疮风险x2=8.35，p=0.0039， OR=1.34？(95%CI：1.10-1.63)和一个提供狼疮保护的GAG，x2=11.23，p=0.0008， OR=0.69？(95%CI：0.56~0.86)。 这项可行性研究的重点是描述我们发现的基因关联结果 它将人类LYN与SLE的发育联系起来。我们的具体目标是1。)鉴定LYN基因的多态性 物理定位与狼疮的遗传联系，2。)较大狼疮患者LYN基因关联的精细定位 与其他SNP的队列，和3。)探讨LYN关联的潜在遗传机制及其发病风险 系统性红斑狼疮的发生与Lyn蛋白功能差异有关。 了解改变LYN功能并增加发生系统性红斑狼疮风险的遗传多态(S) 或者，保护患者不患狼疮对于了解如何干预狼疮至关重要。 毁灭性的疾病进程。这些研究将有助于确定什么细胞和什么致病机制 LYN基因多态会导致狼疮发病风险增加。其中每个问题都需要 更全面地解决，以便研究人员可以针对那些对狼疮临床最重要的途径。 摘要：这项研究试图识别和描述一个导致SLE风险的基因。识别 这些基因将对了解这种毁灭性和复杂的疾病是如何发展以及 哪些新的分子靶点可以被考虑用于治疗开发。

FcyRllb, CD22, and CD72 are important negative regulatory molecules which fine tune the immune responses through an intracellular signaling pathway which includes the Src-family tyrosine kinase Lyn. Knockout and transgenic animals regarding these regulatory molecules ALL develop features of lupusljke autoimmunity. Both lyn knockout mice and lyn gain-of-function transgenic mice also develop a lupus-like autoimmune phenotype characterized by hyper-responsive B cells and increase autoantibody production. Differences in Lyn protein expression, sub-cellular localization and post-translational modifications in B cells and hematopqetic cells have been described in lupus patients compared to controls. However, no human genetic association studies of LYN exists to date. LYN therefore remains a strong lupus candidate gene based on function and candidate pathway analysis. We have now identified a strong genetic association with LYN and human lupus. We targeted LYN in a candidate gene genetic association study of 697 cases and 604 controls testing 22 SNPs. We identified multiple SNPs with strong associations. The peak association gave a x2=10.42, p=0.0012, OR=1.43 ¿ 95% Cl (1.16-1.78) and we identified a 3-marker haplotype CTA that confers lupus risk x2=8.35, p=0.0039, OR=1.34 ¿ (95% Cl:1.10-1.63) and one GAG that confers protection from lupus x2=11.23, p=0.0008, OR=0.69 ¿ (95% Cl: 0.56-0.86). The focus of this feasibility study is to characterize the genetic association results we have discovered which link human LYN to SLE development. Our specific aims are to 1.) identify polymorphism in LYN that physically map the genetic association with lupus, 2.) fine map the LYN genetic association in a larger lupus cohort with additional SNPs, and 3.) explore the potential genetic mechanisms of LYN association and risk of SLE development for functional differences in Lyn protein associated with risk. Understanding the genetic polymorphism(s) that alter Lyn function and increases risk of developing SLE or alternatively protecting one from developing lupus is crucial to understanding how to intervene in this devastating disease process. These studies will help determine what cells and what pathogenic mechanisms Lyn polymorphism impact that lead to increased risk of developing lupus. Each of these questions need to be more fully addressed so that researchers can target those pathways most clinically important to lupus. Summary: This study seeks to identify and characterize a gene that contributes to SLE risk. Identifying such genes will be important to understanding how this devastating and complex disease develops and also what new molecular targets can be considered for therapeutic development.