TNF-alpha Genetic Variations in Disease

In 1992, Wilson et al. described a single base transition polymorphism (G to A) in the promoter region of the human TNF-alpha gene.1 The effects of this polymorphism on TNF-alpha gene transcription has been studied using reporter gene constructs. The G to A transition polymorphism results in significantly higher transcription of the rare allele, TNF2.2 TNF2 is part of an extended MHC haplotype: HLA-A1-B8-DR3-DQ2.3 This particular MHC haplotype is associated with high TNF-alpha production, autoimmunity and progression of HIV infection.4

Overrepresentation of -308 TNF2
in Disease Populations
Non-Hodgkin's Lymphoma6
Dermatitis Herpretiformis8
Celiac Disease10
Chronic Bronchitis11
Severe Sepsis12
Systemic Lupus Erythematosus15
Meningococcal Infection16

Many studies have demonstrated that the TNF2 allele is overrepresented in diseases where increased TNF-alpha levels are associated with poor prognosis. For example, in humans suffering from malaria, higher levels of TNF are observed in fatal cases of cerebral malaria. Individuals homozygous for the TNF2 allele are seven-fold more likely to die or suffer severe neurological complications due to cerebral malaria.5 Studies have also shown that circulating levels of TNF-alpha are high in patients with malignant lymphomas. Higher plasma levels of TNF-alpha are associated with poor disease outcome. The rare allele, -308 TNF2, is associated with first line treatment failure, shorter progression-free survival and overall survival of patients.6


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