Implication of VEGFR2 in systemic lupus erythematosus: a combined genetic and structural biological approach.

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.

The genetics and molecular pathogenesis of systemic lupus erythematosus (SLE) in populations of different ancestry.

Systemic lupus erythematosus (SLE; OMIM 152700) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and a multi-system involvement commonly affecting the skin, renal, musculoskeletal, and hematopoetic systems clinical manifestations involving. Disease features range from mild manifestations, such as rash or arthritis, to life-threatening end-organ manifestations, such as glomerulonephritis or thrombosis, and it is difficult to predict which manifestations will affect a given patient. SLE is caused by interactions between susceptibility genes and environmental factors resulting in an irreversible loss of immunologic self-tolerance. Incidence is highest in women during the reproductive years; however, people of all ages, genders, and ancestral backgrounds are susceptible. A striking 9:1 female to male differential appears in incidence, which remains largely unexplained. However, people of both sexes and all ages and ethnic backgrounds are susceptible. Distinct differences regarding the pathogenesis of SLE between patients of different ancestral backgrounds have been observed so far, including differences in specific clinical manifestations, disease-susceptibility genetic variants and IFN levels. Genome-wide association studies (GWAS) have attempted to elucidate partially the complex genetic architecture of SLE and to point out the existing differences in risk variants across different continental populations, considering that some alleles have not been found in all ancestral backgrounds. Levels of circulating IFN-α is a heritable risk factor in SLE with causal role in pathogenesis, they differ between SLE patients from different ancestral backgrounds and this information could be important as therapeutics is developed to target this pathway. This review highlights some recent findings referred to the multilevel differences appearing in SLE patients from different ancestral backgrounds and further understanding of this knowledge may permit the development of personalized treatments based on patients' ancestry.