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

Abstract

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.

Reactive Intermediates, Inflammation and Epigenetics in Lupus

“…Most of these studies are small cohort studies and await confirmation by larger multi-ethnic cohort studies [58]. A recent study from Greece found an association between NOS3 polymorphisms and lupus nephritis [59]. These genetic studies further support the view that the effects of RNIs and ROIs on disease are significantly affected by the biological setting in which they are produced and the overall production of RNIs compared with ROIs.…”

Influence of Endothelial Nitric Oxide Synthase Gene Intron-4 27bp Repeat Polymorphism on Its Expression in Autoimmune Diseases

“…Conflicting results were reported for the Turkish population in which the 4a and 4aa alleles were shown to be associated with susceptibility to SLE [36]. A single study of the Greece population by Vazgiourakis et al 2007 showed a significant association of the 27 bp VNTR with RA [18]. Previously, a possible relationship between the synthesis of nitric oxide by the eNOS gene and immune dysregulation in the thyroid gland was reported by Varul et al [10].…”

“…Analysis of allelic frequency revealed a significant association of the 4b allele with susceptibility to SLE (p = 0.009) and the 4bb genotype to SLE (p = 0.008) and HT (p = 0.05). As shown in Table 4, this polymorphism (4b/4bb) has been associated with SLE in Colombian populations [28], while three other populations (USA, Korea and Greece) failed to show a significant association [18,29,35]. Conflicting results were reported for the Turkish population in which the 4a and 4aa alleles were shown to be associated with susceptibility to SLE [36].…”

“…However, limited studies have been carried out to explore the role of the 27 bp repeat polymorphism in autoimmune diseases. These include lupus [18], diabetes mellitus [19] and primary biliary cirrhosis [20]. Our previous study revealed a strong association of the 27 bp VNTR of the eNOS gene with Alopecia areata in the Kuwaiti population [21].…”

“…Numerous single nucleotide polymorphisms and variable number tandem repeats (VNTRs) have been reported in the eNOS gene, some of which may affect gene expression, protein synthesis and enzymatic activity, including T-786C, located in the promoter region, Glu298Asp, located in exon 7, and a VNTR of 27 bp in intron 4. It has been hypothesised that the 27 bp repeat in intron 4 of eNOS gene is responsible for the plasma levels of NO and could, therefore, play a significant role in the pathogenesis of autoimmune diseases [18]. However, limited studies have been carried out to explore the role of the 27 bp repeat polymorphism in autoimmune diseases.…”