Polymorphisms within the Tumor Necrosis Factor–α Promoter Region in Patients with HLA-B27–Associated Uveitis: Association with Susceptibility and Clinical Manifestations
Received 18 April 2005; accepted 3 January 2006.
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 α (TNF-α) 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-α -857 C-to-T, -308 G-to-A, and the TNF-α -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-α gene with disease development.
Results
Frequencies of the TNF-α -308GA and TNF-α -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-α -238GA genotype was found among patients (6.3%, P = 0.015). The frequency of the TNF-α -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-α gene promoter.
1Department of Ophthalmology, Medical University of Graz, Graz, Austria
2Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
3Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria
4Department of Internal Medicine, Medical University of Graz, Graz, Austria
Correspondence to Dr Yosuf El-Shabrawi, Department of Ophthalmology, Medical University of Graz, Auenbruggerplatz 4, A-8036 Graz, Austria
ABSTRACT