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Functional heterogeneity in the tumor necrosis factor alpha (TNF-alpha) gene may be responsible for the TNF-alpha response in infectious and autoimmune diseases. Recently, the TNF-238 promoter polymorphism was observed as being associated with a more destructive disease in rheumatoid arthritis (RA). To determine the relation between TNF-238 and disease progression, the extent of joint destruction in a cohort of 101 RA patients followed for 12 years was analyzed. Furthermore, we have attempted to link this polymorphism to TNF-alpha gene transcription in monocytes and lymphocytes in vitro.The extent of joint destruction determined on X-rays of hands and feet assessed after 0, 3, 6, and 12 years was compared with TNF-238 genotypes. Functional consequences of TNF-alpha gene polymorphisms using reporter gene constructs were analyzed in cells of the monocyte and lymphocyte lineage by means of transient transfection systems.The rate of joint damage in -238GA patients was lower than that in the -238GG patients, independent of HLA-DR4. Damage after 12 years was 76 +/- 30 for the -238GA versus 126 +/- 13 for the -238GG patients as determined by the van der Heijde's modification of Sharp's method. Furthermore, TNF-238A was found to be in linkage disequilibrium with an additional polymorphism at position -376. Functional assays revealed no significant differences in the level of inducible reporter gene expression between the TNF-238/-376 promoter constructs in the cell types tested.In a prospective study, we show that the TNF-238GG genotype contributes to progression of joint destruction in RA, independent of the presence of HLA-DR4. However, in vitro transfection assays indicate that TNF-238A by itself or in combination with TNF-376A is not likely to be of direct functional relevance for transcriptional activation. Therefore, these polymorphisms may serve as markers for additional polymorphisms in the TNF/LT locus or neighboring genes that may influence disease severity.

Functional Analysis of a Human Tumor Necrosis Factor α (TNF-α) Promoter Polymorphism Related to Joint Damage in Rheumatoid Arthritis