Genetic and Functional Analysis of LYN Alleles Associated with Lupus

Fc γ RIIb、CD 22和CD 72是重要的负调节分子，其精细调节免疫调节。 通过包括Src家族酪氨酸激酶林恩的细胞内信号传导途径应答。 关于这些调节分子的敲除和转基因动物都发展出lupusljke的特征 自身免疫林恩林恩敲除小鼠和lyn功能获得性转基因小鼠也会出现狼疮样的 以高反应性B细胞为特征自身免疫表型，并增加自身抗体产生。 林恩蛋白在B细胞中的表达、亚细胞定位和翻译后修饰的差异 和造血细胞在狼疮患者与对照组相比的描述。然而，没有人类 迄今为止存在林恩的遗传关联研究。因此，林恩仍然是一个强有力的狼疮候选基因 基于功能和候选途径分析。 我们现在已经确定了林恩和人类狼疮的强烈遗传关联。我们以林恩为目标 对697例病例和604例对照进行了22个SNPs的候选基因遗传关联研究。我们确定 多个SNPs具有很强的关联。峰值相关性得出x2=10.42，p=0.0012，OR=1.43 <$95% CI（1.16-1.78），我们确定了一个3标记单倍型CTA，赋予狼疮风险x2=8.35，p=0.0039， OR=1.34 <$（95% CI：1.10-1.63）和一种GAG可保护免受狼疮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表征我们发现的遗传关联结果 其将人林恩与SLE发展联系起来。我们的具体目标是1）。鉴定林恩中多态性， 物理映射与狼疮的遗传关联，2.）精细绘制大型狼疮中的林恩遗传关联图 具有额外SNP的群组，以及3.）探索林恩相关性的潜在遗传机制和 系统性红斑狼疮发展中林恩蛋白功能差异与风险相关 了解改变林恩功能和增加发生SLE风险的遗传多态性 或者保护一个人不发展成狼疮对于了解如何干预这一疾病至关重要。 毁灭性的疾病过程。这些研究将有助于确定哪些细胞和哪些致病机制 林恩多态性影响导致发展狼疮风险增加。每一个问题都需要 更充分地解决，使研究人员可以针对这些途径最重要的临床狼疮。 摘要：这项研究旨在确定和表征一个基因，有助于SLE的风险。识别 这些基因对于理解这种毁灭性的复杂疾病的发展是很重要的， 哪些新的分子靶点可以考虑用于治疗开发。

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.