Article

Polymorphisms within the Tumor Necrosis Factor–α Promoter Region in Patients with HLA-B27–Associated Uveitis

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Gratz, Styria, Austria
Ophthalmology (Impact Factor: 6.17). 05/2006; 113(4):695-700. DOI: 10.1016/j.ophtha.2006.01.004
Source: PubMed

ABSTRACT The existence of genetic variations in a number of cytokines has been considered to influence susceptibility or relate to disease severity in various autoimmune diseases. Among these, single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF-alpha) promoter at nucleotides -308 and -238 are considered to be protective against inflammation in HLA-B27-positive individuals, whereas the SNP at position -857 has been associated with disease development in anterior uveitis. We investigate a hypothesized association between the TNF-alpha -857 C-to-T, -308 G-to-A, and the TNF-alpha -238 G-to-A SNPs and the presence of HLA-B27-associated uveitis.
Retrospective case-control study.
One hundred fourteen Caucasian patients with HLA-B27-associated uveitis were studied. Mean age of patients was 44.9+/-14 years (range, 16-81), and mean duration of HLA-B27-associated uveitis was 115.6+/-104 months (range, 6 months-51 years). Eighty-six patients (75.4%) suffered from an additional systemic manifestation of the disease. Sixty-three unrelated healthy HLA-B27-positive blood donors and 88 unrelated healthy HLA-B27-negative individuals served as controls.
Genotypes were determined by polymerase chain reaction.
Association of genotypes at positions -857, -308, and -238 of the TNF-alpha gene with disease development.
Frequencies of the TNF-alpha -308GA and TNF-alpha -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative control group, 23% at -308 (P = 0.003), and 7.9% at -238 (P = 0.0003). When compared with healthy HLA-B27-positive controls, a significantly lower frequency of the TNF-alpha -238GA genotype was found among patients (6.3%, P = 0.015). The frequency of the TNF-alpha -308GA genotype was also found to be lower in patients than among HLA-B27-positive control subjects, without, however, reaching statistical significance (6.1%, P = 0.07). No difference in frequencies was seen among the different groups for the SNPs at position -857.
Our data suggest that HLA-B27-positive individuals show a higher susceptibility towards development of an intraocular inflammation in the presence of an A allele at nucleotide -238 and, to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.

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    • "HLA-B27 is a well-recognized susceptibility allele for idiopathic anterior uveitis and linkage disequilibrium between HLA-B27 and other variants within the human MHC known to confound analyses for additional susceptibility loci in this region. Several previous studies investigating the prevalence of TNF polymorphisms in patients with anterior uveitis have suggested genetic associations, but the inconsistent outcomes may be a result of heterogenous patient cohorts with a mixed number of underlying systemic disease associations or incomplete stratification analyses for HLA-B27 in patient and control groups [45-47]. "
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    • "Recent genetic studies endorse such a scenario. Polymorphisms in tumor necrosis factor (TNF; -308A and -238A), which are associated with increased production of the cytokine, are significantly more frequent in HLA-B*27–positive patients [20]. Similarly, HLA-B*27–positive patients with extraocular disease show an association with SNPs in the TNFRSF1A gene (TNFR1) compared to patients with AAU alone [21]. "
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