ABSTRACT
PURPOSE: Idiopathic intermediate uveitis (IIU) is a potentially sight-threatening inflammatory disorder with well-defined anatomic diagnostic criteria. It is often associated with multiple sclerosis, and both conditions are linked to HLA-DRB1*15. Previously, we have shown that non-infectious uveitis (NIU) is associated with interleukin 10 (IL10) polymorphisms, IL10-2849A (rs6703630), IL10+434T (rs2222202), and IL10+504G (rs3024490), while a LTA+252AA/TNFA-238GG haplotype (rs909253/rs361525) is protective. In this study, we determined whether patients with IIU have a similar genetic profile as patients with NIU or multiple sclerosis. METHODS: Twelve polymorphisms were genotyped, spanning the tumor necrosis factor (TNF) and IL10 genomic regions, in 44 patients with IIU and 92 population controls from the UK and the Republic of Ireland. RESULTS: IIU was strongly associated with the TNFA-308A and TNFA-238A polymorphisms. We found the combination of TNFA-308 and -238 loci was more strongly associated with IIU than any other loci across the major histocompatibility complex, including HLA-DRB1. CONCLUSIONS: TNF polymorphisms, associated with increased TNF production, are highly associated with IIU. These results offer the potential to ascribe therapeutic response and risk (i.e., the influence of HLA-DRB1*15 status and TNFR1 polymorphism) to anti-TNF therapy in IIU.
Subject(s)
Polymorphism, Genetic , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/genetics , Uveitis, Intermediate/etiology , Uveitis, Intermediate/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , HLA-DRB1 Chains/genetics , Haplotypes , Humans , Interleukin-10/genetics , Male , Middle Aged , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Receptors, Tumor Necrosis Factor, Type I/genetics , Risk Factors , Uveitis, Intermediate/immunology , Young AdultABSTRACT
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.
Subject(s)
Choroiditis/genetics , Haplotypes/genetics , Interleukin-10/genetics , Panuveitis/genetics , Tumor Necrosis Factor-alpha/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Choroiditis/diagnosis , Female , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class II/genetics , Humans , Male , Middle Aged , Panuveitis/diagnosis , Polymerase Chain Reaction , Polymorphism, Single Nucleotide/genetics , Visual Acuity/physiology , Young AdultABSTRACT
The cytokines tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LTalpha) are known to play key roles in B-cell growth, differentiation and maturation. Genetic polymorphism within regulatory regions of these cytokine genes can alter expression levels and may be important in development of lymphoid malignancy. This study investigates a number of single nucleotide polymorphisms (SNPs) and microsatellite variants present within these genes in a large cohort of non-Hodgkin lymphoma (NHL) cases including 211 cases of follicular lymphoma (FL) and 281 cases of diffuse large B-cell lymphoma (DLBCL), and 478 unaffected controls. The study investigated whether particular alleles at these loci, or their combination across the TNF region in the form of haplotypes, may act as markers for predisposition and development of NHL. The study provided evidence for an influence of the TNF region in the susceptibility to NHL, whereby the loci -863, -857, TNFe and TNFd categorised five haplotype groups over which risk of both FL and DLBCL varied significantly. Prediction of disease risk was improved by the addition of loci to the haplotype, demonstrating the importance of considering the haplotype-specific context of the loci in genetic risk assessment.
Subject(s)
Genetic Predisposition to Disease , Haplotypes , Lymphoma, Non-Hodgkin/genetics , Tumor Necrosis Factor-alpha/genetics , Adult , Aged , Case-Control Studies , Female , Genotype , Heteroduplex Analysis/methods , Humans , Linkage Disequilibrium , Lymphotoxin-alpha/genetics , Male , Microsatellite Repeats , Middle Aged , Polymorphism, Single NucleotideABSTRACT
OBJECTIVE: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. METHODS: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. RESULTS: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. CONCLUSION: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.
