Polymorphisms within the tumor necrosis factor-alpha promoter region in patients with HLA-B27-associated uveitis: association with susceptibility and clinical manifestations.

PURPOSE: 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.

DESIGN: Retrospective case-control study.

PARTICIPANTS: 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.

METHODS: Genotypes were determined by polymerase chain reaction.

MAIN OUTCOME PARAMETERS: Association of genotypes at positions -857, -308, and -238 of the TNF-alpha gene with disease development.

RESULTS: 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.

CONCLUSION: 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.