Abstract
BackgroundDysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region.MethodsThe genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed.ResultsA variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, pmeta = 7.02×10−11, OR 1.19, 95%CI 1.13–1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression.ConclusionsThe present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.
Highlights
Systemic lupus erythematosus (SLE) is a multi-organ involved autoimmune disease characterized as overactivation of T cells followed by B cells proliferation and excessive production of autoantibodies leading to the loss of self-tolerance
The present study confirmed the functional role of rs17268364 in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region that increased systemic lupus erythematosus (SLE) susceptibility in the Chinese population
Here we conducted a combined analysis of genetic association study, bioinformatics with validation, and mRNA expression
Summary
Systemic lupus erythematosus (SLE) is a multi-organ involved autoimmune disease characterized as overactivation of T cells followed by B cells proliferation and excessive production of autoantibodies leading to the loss of self-tolerance. T cell activation-related genetic loci, especially the HLA region, had been confirmed associated with SLE susceptibility by genome wide association studies (GWAS) [1]. After T cell activation, inducible T cell co-stimulator (ICOS), is constitutively expressed on naïve T lymphocytes contributing to effective T cell-dependent immune responses. Cytotoxic T lymphocyte-associated protein-4 (CTLA4) is induced and functions as an inhibitory molecule with the activation of T cells. The genetic contribution of CTLA4 and ICOS to SLE susceptibility remains controversial. Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of vari‐ ants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) inter‐ genic region to SLE susceptibility. Our aim is to find a functional variant in this region
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