Yang I A, Barton S J, Rorke S, Cakebread J A, Keith T P, Clough J B, Holgate S T, Holloway J W
Asthma Genetics Laboratory, Division of Human Genetics and Infection, University of Southampton, Southampton, UK.
Genes Immun. 2004 Jan;5(1):41-5. doi: 10.1038/sj.gene.6364037.
Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with > or = 2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P>0.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n=39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n=279) (P=0.003, t-test). No associations were found with total IgE, FEV(1) % predicted, slope of FEV(1) response to methacholine or asthma severity score (P>0.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.
内毒素暴露可能对哮喘和特应性疾病具有保护作用。Toll样受体4（TLR4）基因中的Asp299Gly多态性会降低对内毒素的反应性。本研究确定了TLR4多态性对哮喘和特应性疾病风险及严重程度的影响。总共对336个有≥2名患病同胞（经医生诊断为哮喘且正在使用药物治疗）的英国白种人家庭以及179名无哮喘或哮喘家族史的白种人进行了基因分型，采用扩增阻滞突变系统聚合酶链反应（ARMS-PCR）。无论是在父母-患病同胞三联体中，还是在病例对照分析中，均未发现TLR4多态性与患哮喘风险之间存在关联（P>0.05）。在首批患病的哮喘同胞中，与Asp/Asp基因型者（均值1.2，标准差1.0，n=279）相比，Asp/Gly或Gly/Gly基因型者的特应性严重程度评分（基于阳性皮肤点刺试验的大小和数量以及特异性IgE）更高（均值1.8，标准差1.1，n=39）（P=0.003，t检验）。未发现与总IgE、预测的第一秒用力呼气容积（FEV(1)）百分比、FEV(1)对乙酰甲胆碱反应的斜率或哮喘严重程度评分存在关联（P>0.05）。本研究证实了先前观察到的TLR4多态性与哮喘之间缺乏关联。相比之下，研究结果表明，遗传决定的对内毒素低反应性可能会增加特应性严重程度。
