Genetics of TNF

The TNF-a gene is mapped to the MHC Class III region on the short arm of chromosome 6, between the HLA-B and HLA-DR genes, and is highly polymorphic. Studies suggest that approximately 60% of the variation in TNF-a production is genetically determined (85), and these genes are potential candidates for both susceptibility and severity in RA. At least 14 SNPs have been identified within the TNF-a gene, and functional data exist for some of these polymorphisms (85). Two of the polymorphisms, the — 238GA genotype and the +489GA genotype, may be associated with less erosive disease independent of the shared epitope (85,86). Fabris et al. (87) studied 163 RA patients and divided them into severe disease (active RA despite combination DMARD therapy) and moderate disease (responders to MTX). The — 238AG genotype was absent in the severe RA group, and they concluded that the — 238GG genotype might be associated with a poorer outcome. There was, however, a high proportion of controls with the — 238GG genotype, and so its overall significance remains to be confirmed. Cvetkovic et al. (88) investigated TNF polymorphisms via restriction fragment length polymorphisms (RFLPs) and found that patients with the A1A2 genotype (equivalent to — 308GA genotype) had more severe disease in terms of both disease activity and functional class, although there was no difference between the groups in terms of the number of DMARDs used. Other workers have failed to find an association between disease severity and the presence of this polymorphism (89). One small study aimed to examine the effects of TNF-a polymorphisms on responses to infliximab in Crohn's disease, but the results were contradictory between the cohorts studied (90).

To date, two other studies have examined the effect of polymorphisms in the TNF-a gene on the outcome of infliximab treatment. Mugnier et al. (91) genotyped 59 patients with established RA treated with infliximab and found that patients with the TNFa — 308G/G genotype had a better response to infliximab at 22 weeks than patients carrying at least one copy of the TNFa — 308A/G polymorphism. A second study (92) found a similar association, between the TNFa — 308G/G genotype and a good clinical response to etanercept. In addition a combination of alleles influencing the production of IL-1 receptor antagonist (IL-1Ra) and TGF^1 (A2 allele of the IL-1 receptor antagonist and TGF^1 +915 GSBC) were also associated with a poor response to etanercept. To date, there are no published studies evaluating pharmacogenetic markers on outcome of adali-mumab treatment.

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The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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