Association of the PTPN22 R620W polymorphism with increased risk for SLE in the genetically homogeneous population of Crete.

Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.11 to 3.9, p = 0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR = 1.14, 95% CI = 0.65 to 1.9, p = 0.64). Although the PTPN22 1858 T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied.

Intron 4 polymorphism of the endothelial nitric oxide synthase eNOS gene and early microangiopathy in type 1 diabetes.

Nitric oxide (NO) is an endogenous vasodilator involved in inflammatory and autoimmune response, and in the pathophysiology of diabetic vascular disease. Endothelium-derived NO is formed from L-arginine by endothelial NO synthase (eNOS), and earlier studies have provided evidence for altered NO metabolism and impaired endothelial function in diabetes, probably due to polymorphisms in eNOS gene. In the present study we investigated the association of the eNOS gene intron 4 a/b VNTR polymorphism with diabetic microangiopathy in 61 young individuals with type 1 diabetes (T1D), 35 male and 26 female, aged 5.0-29.1 (mean 15.6) years, and followed up for 3.24-11.4 (mean 7.44) years. Ten patients (16.4%) had developed microalbuminuria, three hypertension and two retinopathy. Wild-type b/b homozygosity for eNOS gene intron 4 VNTR was found in 37 (60.7%) and a/b polymorphism in 24 (39.3%). No significant relationship was demonstrated between eNOS gene intron 4 polymorphisms and microalbuminuria, hypertension or retinopathy in these young individuals. Our findings suggest that a/b polymorphism of the intron 4 eNOS gene is not associated with early onset diabetic microangiopathy.

Association of the nitric oxide synthase (eNOS) gene polymorphism with increased risk for both lupus glomerulonephritis and rheumatoid arthritis in a single genetically homogeneous population.

Nitric oxide (NO), a short-lived gaseous free radical, synthesized from L-arginine by NO synthases (NOS), is a potent mediator of biologic responses involved in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Most biological necessary NO is produced by the family of three NOS. To date, several functionally relevant genetic polymorphisms in the eNOS gene have been associated with various vascular, infectious and autoimmune diseases. To our knowledge, no study has explored these polymorphisms for both SLE and RA in the same population. The objective of this study was to investigate the influence of the eNOS gene intron 4 a/b VNTR polymorphism (a 27-base-pair tandem repeat-based polymorphism) on susceptibility to SLE and RA in patients living in the island of Crete, a genetically homogeneous population. A group of 145 healthy subjects and 190 SLE patients were included in this study. Similarly, a second group of 235 healthy controls and 202 RA patients were analysed. In both cases, patients and controls were sex- and age-matched. Herein we report that the presence of a/b genotype of the eNOS gene may act as a risk factor not for the presence of SLE but for the development of glomerulonephritis (OR 2.71, 95% CI: 1.4-5.2), while it may be a susceptibility gene for RA (OR: 2.005, 95% CI: 1.31-3.07). Thus, in our population, the a/b genotype of the eNOS gene represents a severity rather than a susceptibility genotype for SLE.