Ozeki Takeshi, Furuya Yoko, Nagano Chieko, Matsui Chika, Takayanagi Risa, Yokoyama Haruko, Yamada Yasuhiko
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Mutat Res. 2006 Dec 1;602(1-2):170-4. doi: 10.1016/j.mrfmmm.2006.09.002. Epub 2006 Oct 17.
Tumor necrosis factor (TNF)alpha is increased in patients with Crohn's disease (CD) and considered to play an important role in the inflammation. Infliximab (IFX) is used as a therapeutic agent for CD. Recently, it was reported that homozygosity for a lymphotoxin alpha (LTA) haplotype (LTA 1-1-1-1) may identify subgroups with a poor response to IFX. In the present study, we characterized the linkage of the LTA haplotype with SNPs in the 5'-flanking region of the TNFalpha gene. In subjects who had homozygosity for each LTA haplotype, 6 nucleotide variations, -857C > T, -522C > G, -357A > C, -261C > G, -159G > T and -96G > T, were found in the 5'-flanking region of the TNFalpha gene. As for linking with the allele, only -857T met the LTA haplotype 1-1-1-1. We concluded that the differences in therapeutic effects of IFX among patients with CD may be explained in part by the induction ability of TNFalpha via the -857C > T polymorphism.
肿瘤坏死因子（TNF）α在克罗恩病（CD）患者中升高，并被认为在炎症中起重要作用。英夫利昔单抗（IFX）被用作CD的治疗药物。最近，有报道称淋巴毒素α（LTA）单倍型（LTA 1-1-1-1）的纯合性可能识别出对IFX反应不佳的亚组。在本研究中，我们对LTA单倍型与TNFα基因5'侧翼区域单核苷酸多态性（SNP）的连锁关系进行了特征分析。在每种LTA单倍型纯合的受试者中，在TNFα基因5'侧翼区域发现了6个核苷酸变异位点，即-857C>T、-522C>G、-357A>C、-261C>G、-159G>T和-96G>T。至于与等位基因的连锁关系，只有-857T符合LTA单倍型1-1-1-1。我们得出结论，CD患者中IFX治疗效果的差异可能部分由TNFα通过-857C>T多态性的诱导能力来解释。
