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

1. 我们建立了一种快速的方法来确定由三个最近描述的SNPs -1031， -863和-857以及两个先前描述的TNFα -308和-238形成的单倍型。利用该系统，我们证明了5种主要的单倍型可以占种群中大部分的TNFα启动子单倍型，并初步将它们命名为TNFA-U01.1、U01.2、U02、U03和U04.2。类风湿关节炎（RA）患者TNFA-U02单型频率升高；然而，这被证明是由HLA-DRB1^*0405的连锁不平衡引起的。一项前瞻性研究通过对早期RA患者的随访研究来研究其与RA严重程度的关系。在入组12个月后，发现携带TNFA-U02单倍型但不携带HLA-DRB1共享表位的患者与关节破坏进展缓慢和对治疗的良好反应相关。检测到TNFA-U03和HLA-DRB1^*0405或0410与克罗恩病的相关性。这种联系是相互独立的。在多肌炎/皮肌炎患者中，与间质性肺炎相关的患者中TNFA-U03单倍型显著升高。轻、重度非脑型和脑型疟疾患者。TNFA-U04单倍型在脑型疟疾中显著升高。与HLA-DRB1^*1501-DQB1^*0602单倍型无关的TNF-857T与嗜睡症相关。系统性红斑狼疮、显微镜下多血管炎和疱疹后神经痛与TNF单倍型无关联。观察到TNF-863A和-857T等位基因与转录因子Oct-1的高结合。

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.