{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:00:50Z","timestamp":1761742850214},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2006,9,28]],"date-time":"2006-09-28T00:00:00Z","timestamp":1159401600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2006,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Shear stress is the main physiologic stimulus for the expression of <jats:italic>NOS3<\/jats:italic>, the gene for human endothelial nitric oxide synthase. Interestingly, a promoter variant of the <jats:italic>NOS3<\/jats:italic> gene, the <jats:sup>\u2013786<\/jats:sup>C variant, is insensitive to shear stress, and individuals homozygous for this single\u2010nucleotide polymorphism (SNP) have an increased risk of developing coronary artery disease. The cytokine interleukin\u201010 (IL\u201010) is also capable of up\u2010regulating endothelial NOS3 expression through binding of the transcription factor STAT\u20103 to a nearby promoter sequence. The aim of this study was to explore the possibility that the <jats:sup>\u2013786<\/jats:sup>C variant of the <jats:italic>NOS3<\/jats:italic> gene is also insensitive to IL\u201010 and that individuals with the <jats:sup>\u2013786<\/jats:sup>C\/C genotype are more prone to developing rheumatoid arthritis (RA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Endothelial cells were isolated from human umbilical cord veins, clonally expanded, and analyzed for NOS3 and IL\u201012 expression by real\u2010time quantitative reverse transcription\u2013polymerase chain reaction and enzyme\u2010linked immunosorbent assay. Umbilical cord arteries and blood samples from RA patients were genotyped for the <jats:sup>\u2013786<\/jats:sup>C\/T SNP of the <jats:italic>NOS3<\/jats:italic>gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In contrast to cells of other genotypes, endothelial cells of the <jats:sup>\u2013786<\/jats:sup>C\/C genotype did not reveal an increase in NOS3 expression upon exposure to IL\u201010, and the cytokine failed to suppress IL\u201012 expression upon stimulation of CD40. Preincubation of these cells with a 16\u2010mer C\u2010type decoy oligonucleotide fully reconstituted the defective IL\u201010\u2013induced suppression of IL\u201012 synthesis. The frequency of the <jats:sup>\u2013786<\/jats:sup>C\/C genotype was significantly higher in the 596 RA patients than in the general population (19.1% versus 12.1%; <jats:italic>P<\/jats:italic> &lt; 0.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Individuals with the <jats:sup>\u2013786<\/jats:sup>C\/C genotype have an increased risk of developing RA. This may be explained by the IL\u201010 insensitivity of the C\u2010type <jats:italic>NOS3<\/jats:italic> gene promoter and the resulting failure to subdue CD40\u2010mediated proinflammatory gene expression.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.22147","type":"journal-article","created":{"date-parts":[[2006,9,28]],"date-time":"2006-09-28T16:29:34Z","timestamp":1159460974000},"page":"3144-3151","source":"Crossref","is-referenced-by-count":19,"title":["The <sup>\u2013786<\/sup>C\/T single\u2010nucleotide polymorphism in the promoter of the gene for endothelial nitric oxide synthase: Insensitivity to physiologic stimuli as a risk factor for rheumatoid 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