Studies on the clinical significance of TNFα upstream promoter region haplotypes.

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1. We established a raipid method to determine haplotypes formed by three recently described SNPs at-1031, -863 and -857, as well as by two previously described SNPs at -308 and -238, of TNFα. Using such a system, we demonstrated that five major haplotypes could account for most of the TNFα promoter haplotypes among the population, and tentatively designated them as TNFA-U01.1, U01.2, U02, U03 and U04.2. Increase in the hapoltype frequency of TNFA-U02 was observed in rheumatoid arthritis (RA); however, that was demonstrated to derive from the linkage disequilibrium with HLA-DRB1^*0405, A prospective study to examine the association with the severity of RA was initiated by a follow-up study of early RA patients. At 12 months after enrollment the patients carrying TNFA-U02 haplotype but not HLA-DRB1 shared epitope were found to be associated with slow progression of joint destruction and good response to treatment Further follow-up considered to be necessary.3. Association of TNFA-U03 and HLA-DRB1^*0405 or 0410 with Crohn's disease was detected. This association was independent from each other. Among patients with polymyositis/dermatoyositis, TNFA-U03 haplotype was significantly increased in those associated with interstitial pneumonitis.4. Among the patients with mild, severe non-cerebral and cerebral malaria. TNFA-U04 haplotype was significantly increased in cerebral malaria.5. Association of TNF-857T, Independent from HLA-DRB1^*1501-DQB1^*0602 haplotype, was observed in narcolepsy.6. No association with TNF haplotype was observed in systemic lupus erythematosus, microscopic polyangiitis and post-herpetic neuralgia.7. Higher binding with the transcription factor Oct-1 was observed for TNF-863A and -857T alleles.