Two functional variants of IRF5 influence the development of macular edema in patients with non-anterior uveitis.

Objective Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes. Methods Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin. Results A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (PFDR=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and PFDR=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients. Conclusion Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

Background: Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. Methods: 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. Results: The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. Conclusions: We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition

Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition

Abstract Background Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. Methods A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays. Results A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P- value=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. Conclusion Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.The authors thank Sofía Vargas, Sonia Rodríguez and Gema Robledo (from Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, Spain) for their excellent technical assistance, and all the patients and healthy controls for kindly accepting their essential collaboration. Banco Nacional de ADN (University of Salamanca, Spain) and Biobanco Vasco para la Investigación (Fundación Vasca de Innovación e Investigación Sanitarias, Bizkaia, Spain) are thanked for supplying part of the samples.Peer Reviewe

Lack of association between the protein tyrosine phosphatase non-receptor type 22 R263Q and R620W functional genetic variants and endogenous non-anterior uveitis.

Journal Article;OBJECTIVE Endogenous uveitis is a major cause of visual loss mediated by the immune system. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes a lymphoid-specific phosphatase that plays a key role in T-cell receptor (TCR) signaling. Two independent functional missense single nucleotide polymorphisms (SNPs) located within the PTPN22 gene (R263Q and R620W) have been associated with different autoimmune disorders. We aimed to analyze for the first time the influence of these PTPN22 genetic variants on endogenous non-anterior uveitis susceptibility. METHODS We performed a case-control study of 217 patients with endogenous non-anterior uveitis and 718 healthy controls from a Spanish population. The PTPN22 polymorphisms (rs33996649 and rs2476601) were genotyped using TaqMan allelic discrimination assays. The allele, genotype, carriers, and allelic combination frequencies were compared between cases and controls with χ(2) analysis or Fisher's exact test. RESULTS Our results showed no influence of the studied SNPs in the global susceptibility analysis (rs33996649: allelic P- value=0.92, odds ratio=0.97, 95% confidence interval=0.54-1.75; rs2476601: allelic P- value=0.86, odds ratio=1.04, 95% confidence interval=0.68-1.59). Similarly, the allelic combination analysis did not provide additional information. CONCLUSIONS Our results suggest that the studied polymorphisms of the PTPN22 gene do not play an important role in the pathophysiology of endogenous non-anterior uveitis.Ye

A case of acute lumphoblastic leukemia presenting with migratory superficial thrombophlebitis

Venöz tromboemboHzm ve maliyn hastalıklar arasında bir ilişki olduğu yapılan çalışmalarda gösterilmiştir. Maliyniteli olguların %5-10'unda; derin ven trombozu, arteriyel tromboz, gezici tromboflebit, pulmoner emboli ve non-bakteriyel trombotik endokardit gibi tromboembolik olaylar gelişmektedir. Genellikle ileri evre kanserlerde görülen tromboz bazen kansere ait bulgular ortaya çıkmadan ilk bulgu olarak da saptanabilir. Sağ ayak bileği travması sonrası başvuran, ateş ve hiperlökositoz görülerek yatırılan olguda sağ bacak diz üstü iç yan bölgede yüzeyel tromboflebit olduğu saptandı. Hastanın yapılan periferik yaymasında %90 blast formunda lenfositler görüldü. Periferik kandan yapılan immünfenotipleme sonucu Pre B hücreli ALL ile uyumlu bulundu (CD-19 %93.74, CDL5 %98.73,CD-34 %87.58, CD-22 %63.59, CD-10 negatif). Yapılan kemik iliği biyopsisinde pre B hücreli ALL tanısı teyit edildi. Pre B hücreli lösemi tanısı alan hastanın ikinci günde sol bacakta da tromboflebit gelişti. Antitrombin III (%95) ve fibrinojen (3.7g/dL) düzeyleri normal olan, derin ven trombozu saptanmayan olgu nadir görülmesi ve gezici süperfisiyel tromboflebit ile akut lenfoblastik lösemi arasındaki ilişkiyi düşündürmesi açısından sunulmaya uygun bulunmuştur.The relationship between malignant diseases and venous thromboembolism was shown by different studies. In 10% of patients with malignancy thromboembolic events such as deep vein thrombosis, pulmonary emboli and nonthrombotic endocardit may occur. In high grade cancers, usually before the clinical findings, deep vein thrombosis may be diagnosed. The case who was admitted for right ankle trauma was hospitalized with fever and hyperleucocytosis. A peripheral blood examination revealed lymphocytosis with 90% blast cells. The patient was diagnosed as pre B-cell ALL by the immunophenotype (CD-19 %93.74, CD-45 %98.73, CD-34 %87.58, CD-22 %63.59, CD-10 negative). Pre B-cell ALL diagnosis was confirmed with bone marrow biopsy. The patient developed thrombophlebitis in left leg by the second day of the hospitalization. Antithrombin III (95%) and fibrinogen (3.7 g/dL) levels were in normal ranges and there was no evidence for deep vein thrombosis. The case is presented aş_it-,is d mre condition which indicates a possible association between migratory superficial thrombophlebitis and B-cell acute lymhoblastic leukemia

Two Functional Variants of <i>IRF5</i> Influence the Development of Macular Edema in Patients with Non-Anterior Uveitis

<div><p>Objective</p><p>Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated <i>IRF5</i> genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes.</p> <p>Methods</p><p>Three <i>IRF5</i> polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin.</p> <p>Results</p><p>A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (<i>P</i>_<i>FDR</i>=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and <i>P</i>_<i>FDR</i>=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: <i>P</i>=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: <i>P</i>=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both <i>IRF5</i> genetic variants are specifically associated with the lack of macular edema in uveitis patients.</p> <p>Conclusion</p><p>Our results clearly showed for the first time that two functional genetic variants of <i>IRF5</i> may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.</p> </div

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

__Background__ Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. __Methods__ 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with noninfectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. __Results__ The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLAA* 2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA ( p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. __Conclusions__ We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition