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The bm12 Inducible Model of Systemic Lupus Erythematosus (SLE) in C57BL/6 Mice
Published on: November 1, 2015
A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40
Vassilios M Vazgiourakis1, Maria I Zervou, Christianna Choulaki
1Laboratory of Molecular Medicine and Human Genetics, Department of Medicine, University of Crete, Heraklion, Greece.
Insights
The CD40 rs4810485 single nucleotide polymorphism (SNP) is linked to a reduced risk of systemic lupus erythematosus (SLE). This SNP is associated with lower CD40 expression in immune cells, potentially impacting disease regulation.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Systemic lupus erythematosus (SLE) pathogenesis involves CD40L-CD40 interactions.
- CD40 is a known rheumatoid arthritis susceptibility gene, but its role in SLE was unclear.
Purpose of the Study:
- To investigate the association between the CD40 rs4810485 single nucleotide polymorphism (SNP) and SLE risk.
- To assess the impact of this SNP on CD40 expression levels.
Main Methods:
- Genotyping of the CD40 rs4810485 SNP in Greek and Turkish cohorts.
- Analysis of CD40 mRNA and protein expression in peripheral blood mononuclear cells using qPCR and flow cytometry.
Main Results:
- The minor allele T of rs4810485 was significantly under-represented in SLE patients from both cohorts.
- Meta-analysis confirmed the protective association of the T allele against SLE (OR=0.63, p=2x10(-8)).
- rs4810485 genotypes (G/T, T/T) correlated with reduced CD40 expression in monocytes and B cells.
Conclusions:
- CD40 rs4810485 is a novel susceptibility locus for SLE in Greek and Turkish populations.
- The minor allele T confers protection against SLE and is associated with decreased CD40 expression.
- This finding suggests a role for CD40 in regulating aberrant immune responses in SLE.
Background:
In systemic lupus erythematosus (SLE) sustained CD40L expression by T cells and platelets activates a variety of cells via its receptor CD40 contributing to disease pathogenesis. Although CD40 has recently been identified in genome-wide association study as a novel rheumatoid arthritis susceptibility gene such an association has not been documented for SLE.
Objective:
To investigate whether the rs4810485 CD40 single nucleotide polymorphism (SNP) is associated with increased risk for SLE and its impact on CD40 expression.
Materials And Methods:
The primary sample set consisted of 351 patients with SLE and 670 matched healthy controls of Greek origin. 158 patients with SLE and 155 controls from Turkey were used as a replication sample. Genotyping of rs4810485 was performed by restriction fragment length polymorphism and the Sequenom MassArray technology. The expression of CD40 mRNA and protein was assessed in unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells by quantitative real time PCR and flow cytometry, respectively.
Results:
The minor allele T of CD40 rs4810485 SNP was significantly under-represented in Greek patients with SLE compared with healthy controls (OR=0.65, 95% CI 0.54 to 0.79). The association was replicated in the Turkish cohort (OR=0.57, 95% CI 0.41 to 0.80; meta-analysis of 509 patients with SLE and 825 healthy controls: OR=0.63, 95% CI 0.53 to 0.74, p = 2×10(-8)). In both cases and controls, the rs4810485 G/T and T/T genotypes were associated with significantly reduced CD40 mRNA and protein expression in peripheral blood CD14+ monocytes and CD19+ B cells compared with G/G genotype, both under basal conditions and following stimulation.
Conclusions:
CD40 has been identified as a new susceptibility locus in Greek and Turkish patients with SLE. The rs4810485 minor allele T is under-represented in SLE and correlates with reduced CD40 expression in peripheral blood monocytes and B cells, with potential implications for the regulation of aberrant immune responses in the disease.
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