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.

Specific association of IL17A genetic variants with panuveitis.

BACKGROUND/AIMS: A pathogenic role of Th17 cells in uveitis has become clear in recent years. Therefore, in the present study, we aimed to evaluate the possible influence of the IL17A locus on susceptibility to non-anterior uveitis and its main clinical subgroups. METHODS: Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), selected by tagging, were genotyped using TaqMan assays in 353 Spanish patients with non-anterior uveitis and 1851 ethnically matched controls. RESULTS: The case/control analysis yielded a consistent association between two of the analysed genetic variants, rs8193036 and rs2275913, and the presence of panuveitis under a dominant model (pFDR=2.86E-03, OR=2.26, 95% CI 1.42 to 3.59 and pFDR=0.033, OR=1.83, 95% CI 1.13 to 2.97, respectively). Subsequently, a specific association of both polymorphisms with the diffuse form of the disease was evident in the subphenotype analysis when considering this same genetic model (panuveitis vs posterior and intermediate uveitis: rs8193036, p=0.020; rs2275913, p=0.038). Independent effects of rs8193036 and rs2275913 were observed by conditional regression analysis. CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with panuveitis. Our data agree with the elevated levels of this cytokine that are found in patients with uveitis, supporting a crucial role of Th17 cells in this pathology. SUBTITLE: Our results clearly evidenced the role of IL17A as a novel genetic risk factor for panuveitis, thus suggesting the implication of Th17 cells in the extensive inflammation of the uveal tract that occurs in this subtype of uveitis.

Oral flavonoids, chromocarb diethylamine salt and cyaninosides chloride, to eliminate lipoperoxidation postvitrectomy.

This study was undertaken to determine the concentration of malondialdehyde, an end product of lipoperoxidation, in lens and retinal tissue postvitrectomy associated with oral administration of antioxidant flavonoids cyaninosides chloride and chromocarb diethylamine salt or N -acetylcysteine. Fifty adult pigmented rabbits were divided into five groups: (1) controls (normal eyes, malondialdehyde concentration in lens and retina); (2) vitrectomy with BSS Plus (malondialdehyde level measured 2hr after vitrectomy); (3) vitrectomy with BSS Plus and pretreatment with oral cyaninosides chloride 100mg kg day(-1)for 3 weeks (malondialdehyde level measured 2hr after surgery); (4) vitrectomy with BSS Plus and pretreatment with oral chromocarb diethylamine salt 100 mg kg day(-1)for 3 weeks (malondialdehyde level measured 2hr after surgery); and (5) vitrectomy with BSS Plus and pretreatment with oral N -acetylcysteine 200 mg kg day(-1)for 3 weeks (malondialdehyde level measured 2hr after surgery). Lens and retina samples were used to determine malondialdehyde levels using ion-pairing high performance liquid chromatography. Statistical analysis was done using analysis of variance (P<0.05). The content of malondialdehyde in the normal lens was 0.036 +/- 0.017 microg g(-1); in the vitrectomized groups the malondialdehyde concentrations were as follows: (2) 0.027 +/- 0.013 microg g(-1); (3) under detection limit (detection limit=1.75x e-3 microg g(-1)); (4) under detection limit; and (5) 0.020 +/- 0.006 microg g(-1). The results showed that the malondialdehyde concentration in the normal retina was 1.160 +/- 0.361 microg g(-1), while in the vitrectomized groups with or without pretreatment (cyaninosides chloride, chromocarb diethylamine salt, and N -acetylcysteine) the malondialdehyde levels were 2.091 +/- 0.982 microg g(-1), 0.069 +/- 0.024 microg g(-1), 0.082 +/- 0.027 microg g(-1), and 0.215 +/- 0.134 microg/g(-1), respectively, all significantly different from the normal eyes (P<0.05). Vitrectomy induced increased malondialdehyde levels in the retina. Oral flavonoids are an effective protective therapy for surgically induced lipoperoxidation, especially in the retina.