Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis

Abstract

The objective of this study was to investigate TNF promoter region polymorphisms for association with susceptibility to ankylosing spondylitis (AS). The TNF −238 and −308 polymorphisms were genotyped in 306 English AS cases and 204 ethnically matched healthy B27-positive controls, and 96 southern German AS cases, 58 B27-positive and 251 B27-negative ethnically matched controls. Additionally, the TNF −376 polymorphism was genotyped in the southern German cases and controls. In the southern German AS patients a significant reduction in TNF −308.2 alleles was seen, compared with B27 positive controls (odds ratio 0.4, P = 0.03, 95% confidence interval 0.2-0.9), but no difference in allele frequencies was observed at TNF −238. Significant association between AS and both TNF −238 and TNF −308 was excluded in the English cases. These results confirm previous observations in the southern German population of association between TNF promoter region polymorphisms and AS, but the lack of association in the English population suggests that these polymorphisms themselves are unlikely to be directly involved. More likely, a second, non-HLA-B, MHC locus is involved in susceptibility to AS in these two populations. Genes and Immunity (2000) 1, 418-422.

No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia

“…Statistical comparison of these two control groups unraveled a significantly higher frequency of the A allele in the German group. Former studies have confirmed the differences in the TNF2 allele frequency between ethnic groups: Milicic et al (Milicic et al 2000) described a significant reduction in TNF2 alleles only in patients suffering from ankylosing spondylitis recruited in Southern Germany, but not in those recruited in the UK. Another study showed that the TNF2 allele was significantly correlated with self-reported childhood asthma in the UK, but not in a South Asian population (Winchester et al 2000).…”

Is there a future for TNF promoter polymorphisms?

“…In a recent study 63 examining 141 HLA B27 þ AS patients, a significant decrease was seen in the frequency of both the À308 A and À238 A alleles in the B27 þ patients in comparison with B27 þ and B27À control groups, and the authors estimated a relative risk of 0.3 for these alleles in B27 þ patients. This study was followed by a joint German/UK study 64 in which the role of these alleles in the two populations was considered. While an analysis of 96 south German AS patients also found a significantly reduced frequency of the À308 A allele, neither the À238 A allele in the German population nor either allele in a UK population was significantly associated with AS.…”

“…Comparisons of findings between ethnic groups may not be appropriate due to population-specific masking of gene variant effects (epistasis) or geneenvironment interactions in one population. A case in point may be the study of Milicic et al 64 Disease heterogeneity among patient groups may also lead to difficulties in the comparison of studies and their reproducibility, exacerbated by the inclusion of small groups of patients.…”

Cytokines and Chemokines in Uveitis - Is there a Correlation with Clinical Phenotype?

“…157,158 Peptides from HLA-B27 have sequence homology with peptides from enterobacteria 159 and Chlamydia 160 with the latter also documented to possibly reactivate autoreactive cytotoxic T cells with specificity for HLA-B27. TNF-α, 161 TGF-β 162 and IL-1 163 polymorphisms have also been confirmed as possible candidate genes for susceptibility to ankylosing spondylitis. A recent study of patients with HLA-B27-associated anterior uveitis identified an association between HLA-B27 and the alleles TNF-1031 and TNF-308, 96 strongly suggesting linkage disequilibrium between HLA-B27 and TNF-308.…”