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The bm12 Inducible Model of Systemic Lupus Erythematosus (SLE) in C57BL/6 Mice
Published on: November 1, 2015
Implication of VEGFR2 in systemic lupus erythematosus: a combined genetic and structural biological approach
Vassilis M Vazgiourakis1, Maria I Zervou, Elias Eliopoulos
1Department of Medicine, Medical School of Crete, Heraklion, Greece. vazsg@med.uoc.gr
Insights
VEGFR2 gene variations may impact endothelial function in SLE, but two common SNPs (V297I and Q472H) were not linked to SLE risk in this study. Further research may explore their role in vascular damage.
Area of Science:
- Genetics and Molecular Biology
- Immunology
- Cardiovascular Disease Research
Background:
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) gene polymorphisms are linked to vascular diseases.
- Systemic Lupus Erythematosus (SLE) is associated with premature atherosclerosis, suggesting endothelial dysfunction.
- VEGFR2 influences endothelial integrity, repair, and function, making it a candidate gene for SLE-related vascular complications.
Purpose of the Study:
- To investigate the structural and functional effects of two common VEGFR2 single nucleotide polymorphisms (SNPs), V297I and Q472H, in SLE patients.
- To determine if these VEGFR2 SNPs are associated with an increased risk of developing SLE by affecting endothelial cells.
Main Methods:
- Utilized 3D homology modeling to analyze the V297I and Q472H polymorphisms.
- Genotyped V297I (rs2305948) and Q472H (rs1870377) SNPs using Taqman technology.
- Examined a Greek cohort (250 SLE patients, 241 controls) and replication cohorts of diverse American ethnicities.
Main Results:
- Homology modeling indicated V297I may alter trans-autophosphorylation and cell signaling efficiency.
- The Q472H polymorphism was found to affect homotypic contacts of membrane proximal Ig-like domains.
- No significant allelic or genotypic association was found between either SNP and SLE risk.
Conclusions:
- Structural analysis suggests VEGFR2 SNPs could potentially contribute to SLE pathogenesis via impaired VEGF signaling.
- Neither analyzed SNP was associated with increased susceptibility to SLE in the studied populations.
- These VEGFR2 SNPs may still be relevant to the vascular damage and atherosclerosis observed in SLE patients.
Objectives:
VEGFR2 gene polymorphisms have already been correlated with vascular diseases such as coronary heart disease (CHD) and may influence endothelial integrity, repair and function. In view of the premature atherosclerosis observed in SLE, we sought to clarify the structural/functional consequences of two common single nucleotide polymorphisms (SNPs) of VEGFR2 in SLE and determine whether they are associated with risk of SLE by influencing endothelial cells.
Methods:
Three-dimensional (3D) homology modelling was applied for the localisation of the V297I and the Q472H polymorphisms. Genotyping of the V297I (rs2305948) and Q472H (rs1870377) SNPs was done through Taqman technology in 250 SLE patients and 241 healthy controls from a Greek population (Cretan). The replication sample set for the rs1870377 SNP consisted of 253, 184 and 77 patients with SLE and 301, 118 and 11 ethnically-matched controls of African-American, European-American and Hispanic-American origin, respectively.
Results:
Modelling revealed that the V297I polymorphism may affect the efficiency of trans-autophosphorylation and cell signalling, while Q472H affects homotypic contacts of membrane proximal Ig-like domains. No significant allelic and genotypic association was observed for both the SNPs with risk of SLE.
Conclusions:
Although structural data suggest that both VEGFR2 SNPs may contribute to SLE pathogenesis by impairing VEGF signalling, none of the SNPs analysed was associated with increased susceptibility to SLE. However, they still may be relevant to the vascular damage/atherosclerosis in SLE.
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