Genetic and Functional Analysis of LYN Alleles Associated with Lupus

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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.