Vascular endothelial growth factor (VEGF) is a potent inflammation, vascular permeability, and angiogenic factor. Variations of the VEGF gene are implicated in the pathogenesis of diabetic retinopathy. Previous studies have shown that Brown Norway (BN) rats have higher retinal VEGF levels and more severe retinal vascular leakage than SpragueDawley (SD) rats in response to ischemia and diabetes. To investigate the molecular mechanism of vascular leakage in this animal model, F2 progeny were generated by crossbreeding BN and SD rats. Neonatal rats were exposed to hyperoxia to induce oxygen-induced retinopathy (OIR) models. The F2 rats in response to ischemia have shown a linear distribution of retinal VEGF levels, which is significantly and positively correlated to retinal vascular leakage. We identified a single nucleotide polymorphism (SNP) at upstream stimulating factor-binding site in the VEGF promoter region between BN and SD rats. No differences were found in retinal vascular permeability or VEGF levels between F2 rats with BN, SD, and BN/SD alleles of VEGF SNP. The increased retinal VEGF levels are correlated to ischemia-induced retinal vascular leakage in the OIR rat model. The VEGF mRNA and promoter are not responsible for increased retinal VEGF level and vascular permeability. The up-regulation of VEGF expression activated by a yet to be identified upstream factor or mediator affecting VEGF stability may be associated with a high susceptibility to retinal vascular leakage in BN rats.
PurposeWe have studied gene expression in Epstein-Barr virus transformed B cell lines to define differences between SLE patients and matched controls. We used this design to remove, to the extent possible, environmental influences and the secondary changes in gene expression caused by lupus and found in peripheral blood cells from patients who are ill. In the present study, we have focused on gene expression analysis of cell lines derived from European-American lupus patients who also present evidence of thyroid disease compared to unrelated matched controls.Methods12 European-American SLE patients were selected according to American College of Rheumatology (ACR) criteria for SLE and their contribution to the 5q14 (lupus affected with autoimmune thyroid disease) genetic linkage. 12 controls were matched by age, sex, race, and state of residence. Human genome U133 plus 2.0 arrays (Affymetrix) were used for each subject. Gene expression differences were evaluated for genes with p < .05 for the paired t-test, p < .0001 for the associative t-test, and an apparent ratio of expression of > 2.0 or < 0.5.ResultsThe affecteds from pedigrees linked at 5q14 differently expressed 191 genes when compared to controls (59 up-regulated, 54 down-regulated, 19 only in lupus patients, and 59 only in matched controls). Two of the differentially expressed genes were located in 5q14 intervals. The differentially expressed genes include members of signal transduction pathways, thyroid hormone receptor, small nuclear ribonucleotide proteins and immune response related genes.ConclusionsWe identified genes by differential gene expression analysis of cell lines derived from European-American lupus patients with thyroid disease. Two of these genes come from within the genetic linkage interval identified in other studies of this subset of lupus patients.
Autoimmune disorders share molecular mechanisms and pathways, suggesting that some genetic effects will be selectively concentrated between them. To identify genetic effects potentially shared between SLE and AITD we selected families from the Oklahoma collection of pedigrees multiplex for SLE that contained a member with AITD, either Graves' disease or Hashimoto's thyroiditis.MethodsWe identified a total of 35 pedigrees (25 European-American, 6 Hispanic, 2 Native American and 2 Asian-American) containing at least one SLE patient with autoimmune thyroid disease (AITD). Nineteen pedigrees were used in the initial genome scan while an independent sample of sixteen was used to replicate findings. Phenotypic characterization included a diagnosis of Graves' disease or Hashimoto's thyroiditis by a physician in the medical records with at least two of the following: presence of antimicrosomal antibodies, a consistent thyroid biopsy report, radioiodine ablation therapy, hormone replacement therapy, or the expected abnormalities in the serum levels of TSH.ResultsWe identified a strong, robust, and reproducible linkage effect in chromosome 5 (5q14.3-q15) at D5S1462. The first 19 pedigrees produced a two-point parametric LOD = 4.97, which was later confirmed in the replication sample (LOD = 2.89). All 35 pedigrees together produce LOD = 7.86 under a dominant model with 90% penetrance and a disease allele frequency of 10% (NPL = 0.00003). Multipoint LOD scores and heterogeneity LOD scores (HLOD) were computed using the same models described above. The 35 pedigrees produced LOD (HLOD) = 6.90 at 5q14.3-15 between D5S1725 and D5S1453, a 12 cM interval, with the peak at D5S1462 at 96.64 cM (NPL = 2.31, p = .01, α = 1.00). Fine mapping further confirms the genetic linkage effect and narrows the region likely to contain the gene to ˜ 5 Mb. The SLE pedigrees selected for AITD in affecteds suggest that the gene responsible for the 5q14.3 effect contributes to both of these autoimmune diseases. 5q14.3-15 has already been linked to AITDs in another linkage study.ConclusionThese results suggest that stratifying SLE pedigrees by other autoimmune disorders may facilitate the discovery of genes related to SLE and that 5q14.3-15 harbors a susceptibility gene shared by SLE and AITD.
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