Migita O, Noguchi E, Koga M, Jian Z, Shibasaki M, Migita T, Ito S, Ichikawa K, Matsui A, Arinami T
Department of Medical Genetics, Majors of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan.
Clin Exp Allergy. 2005 Jun;35(6):790-6. doi: 10.1111/j.1365-2222.2005.02265.x.
The tumour necrosis factor (TNF) gene family, which includes TNF, LTA, and LTB, is located consecutively on human chromosome 6p21 region, which has been linked to asthma by several genome-wide screens. (LTA, lymphotoxin-alpha; LTB, lymphotoxin-beta).
The aim of the present study was to determine whether genes on 6q21 are related to development of atopic asthma. Methods We screened for mutations in the coding and promoter regions of genes in the TNF-LTA region, including BAT1, NFKBIL1, LTA, TNF, LTB, AIF, and BAT2, and conducted a transmission disequilibrium test of 41 polymorphisms in 137 families identified through pro-bands with childhood-onset atopic asthma. (BAT1, HLA-B-associated transcript 1; NFKBIL1, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-like 1; AIF, allograft inflammatory factor 1).
Haplotypes of the LTA/TNF linkage disequilibrium block were associated significantly with asthma (global P=0.0097). Transmission patterns of the common haplotypes to asthmatic offspring were predicted by a single-nucleotide polymorphism in the LTA promoter region. The G allele of the LTA-753G/A polymorphism was transmitted preferentially to asthma-affected individuals (P=0.001). Luciferase reporter assays with constructs containing the 5' and 3' flanking regions of the LTA gene showed 30-50% lower transcriptional activity when the -753A allele was present than that of other haplotypes.
Our results suggest that LTA is one of the genes that contributes to susceptibility to atopic asthma, and that the association of the TNF/LTA haplotypes to asthma may be defined by the polymorphism in the LTA promoter region in the Japanese population.
肿瘤坏死因子（TNF）基因家族，包括TNF、LTA和LTB，连续定位于人类6号染色体p21区域，多项全基因组筛查已将该区域与哮喘相关联。（LTA，淋巴毒素-α；LTB，淋巴毒素-β）。
本研究旨在确定6q21上的基因是否与特应性哮喘的发生有关。方法我们筛查了TNF-LTA区域中基因的编码区和启动子区的突变，包括BAT1、NFKBIL1、LTA、TNF、LTB、AIF和BAT2，并对通过儿童期发病的特应性哮喘先证者确定的137个家庭中的41个多态性进行了传递不平衡检验。（BAT1，HLA-B相关转录本1；NFKBIL1，B细胞中κ轻链多肽基因增强子的核因子抑制物样1；AIF，同种异体移植炎症因子1）。
LTA/TNF连锁不平衡区域的单倍型与哮喘显著相关（总体P=0.0097）。常见单倍型向哮喘后代的传递模式由LTA启动子区域的一个单核苷酸多态性预测。LTA-753G/A多态性的G等位基因优先传递给哮喘患者（P=0.001）。用含有LTA基因5'和3'侧翼区域的构建体进行的荧光素酶报告基因分析表明，当存在-753A等位基因时，转录活性比其他单倍型低30%-50%。
我们的结果表明，LTA是导致特应性哮喘易感性的基因之一，在日本人群中，TNF/LTA单倍型与哮喘的关联可能由LTA启动子区域的多态性决定。
