Polymorphisms within the tumor necrosis factor-alpha promoter region in patients with HLA-B27-associated uveitis - Association with susceptibility and clinical manifestations
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.
SourceAvailable from: Cynthia Azeredo Cordeiro
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ABSTRACT: To use high density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients both with and without ankylosing spondylitis (AS). Method We genotyped 1,711 patients with AAU (either primary or with AAU and AS), 2,339 AS patients without AAU, and 10,000 controls on the Illumina Immunochip Infinium microarray. We also used data on AS patients from previous genomewide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by RT-PCR. Results Comparing all AAU cases with HC, strong association was seen over HLA-B corresponding to the HLA-B27 tag SNP rs116488202. Three non-MHC loci IL23R, the intergenic region 2p15 and ERAP1 were associated at genome-wide significance (P < 5x10(-8) ). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye related gene EYS, were also associated at a suggestive level of significance (P < 5x10(-6) ). A number of previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression was found to vary across eye compartments. Conclusion These findings, with both novel AAU specific associations, and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways. © 2014 American College of Rheumatology.09/2014; DOI:10.1002/art.38873
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ABSTRACT: Polymorphisms of the vitamin D metabolism gene CYP27B1 showed associations with multiple autoimmune diseases. The aim of this study was to investigate a possible association between the rs703842 A>G polymorphism of the CYP27B1 gene and HLA-B27-associated uveitis. One hundred fifty-nine patients with HLA-B27-associated uveitis, 138 HLA-B27-negative controls and 100 HLA-B27-positive controls were recruited for this retrospective case-control study. Main outcome parameters were genotype distribution and allelic frequencies determined by polymerase chain reaction. Carriers of the rs703842G allele were found significantly more often in patients with HLA-B27-associated uveitis than in HLA-B27-positive controls (p = 0.03). Between patients and HLA-B27-negative controls no significant difference in the genotype distribution of the rs703842 A>G polymorphism was found (p = 0.97). Our data suggest that the rs703842 A>G polymorphism may play a role in HLA-B27-associated uveitis.PLoS ONE 04/2013; 8(4):e62244. DOI:10.1371/journal.pone.0062244 · 3.53 Impact Factor