Jarka Plskova

Cytokine polymorphism in noninfectious uveitis.

PURPOSE Noninfectious uveitis is a sight-threatening immune-mediated intraocular inflammatory disorder. The inheritance of uveitis in multiplex families and its association with known monogenic and polygenic immunologic disorders suggests that common genetic variants underlie susceptibility to uveitis as well as to other immunologic disorders. TNFA and IL10 are strong candidate genes, given the influence of these cytokines on inflammation, immune tolerance, and apoptosis. METHODS The role of 12 polymorphisms spanning the TNFA and IL10 genomic regions was investigated in 192 uveitis patients and 92 population control subjects from four regional centers in the United Kingdom and Republic of Ireland. RESULTS The results demonstrate that uveitis is associated with three haplotype-tagging SNPs (htSNPs) in the IL10 gene: htSNP2 (rs6703630), htSNP5 (rs2222202), and htSNP6 (rs3024490). IL10htSNP2AG/htSNP5TC was the most significantly associated haplotype (P = 0.00085), whereas the LTA+252AA/TNFhtSNP2GG haplotype was protective (P = 0.00031). Furthermore, subgroup analysis showed that the frequency of the TNFd4 allele was higher in patients with nonremitting ocular disease and/or those requiring higher levels of maintenance immunosuppression. Although these associations lost significance after Bonferroni correction, they infer a relationship that may be validated by a larger study. CONCLUSIONS Since these variants are implicated in the susceptibility and severity of several immunologic disorders, the results support the hypothesis that common genetic determinants influence shared mechanisms of autoimmunity.

Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF Loci

PURPOSE The white-dot syndromes are a heterogenous group of chorioretinal disorders that have many common clinical features. Whether these disorders represent distinct clinical entities or different manifestations of the same disease warrants further interrogation. Two white-dot syndromes were investigated, with closely overlapping phenotypes--multifocal choroiditis with panuveitis (MFCPU) and punctate inner choroidopathy (PIC)--for differences in clinical course and genotype frequency at IL10 and TNF loci, known to be associated with noninfectious uveitis. METHODS Twelve polymorphisms were genotyped, spanning the TNFA and IL10 genomic regions, in 61 patients with MFCPU or PIC and 92 population controls from the United Kingdom and Republic of Ireland. RESULTS There were clear differences in clinical course between patients with MFCPU and PIC which had prognostic significance. However, both patient groups demonstrated similar associations with the IL10 haplotype, IL10htSNP2(-2849)AX/htSNP5(+434)TC and negative associations with the TNF haplotype, LTA+252A/TNFhtSNP1(-308)G/TNFhtSNP2(-238)G/TNFhtSNP3(+488)A/TNFd3. CONCLUSIONS Despite clear differences in clinical course and outcome, MFCPU and PIC may still represent two manifestations of the same disease, given their similar genetic associations with IL10 and TNF loci, which are known to be associated with noninfectious uveitis and autoimmunity, in general. Definitive proof will necessitate genomewide sequence analysis. However, the data also support the notion that epigenetic factors have a strong effect on clinical phenotype.