Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.Toll样受体（Toll-like receptors, TLRs）参与抵御慢性阻塞性肺疾病（Chronic Obstructive Pulmonary Disease, COPD）患者常见的细菌感染。本研究针对Toll样受体2（TLR2）与Toll样受体4（TLR4）的全部标签单核苷酸多态性（tagging SNPs），分析其与中重度COPD患者的一秒用力呼气容积（FEV1）、痰炎症细胞水平及其随时间变化的关联。研究共纳入110例COPD患者，对9个TLR2单核苷酸多态性位点及17个TLR4单核苷酸多态性位点完成基因分型。采用线性回归开展痰诱导样本中单核苷酸多态性与肺功能、炎症细胞水平的横断面分析，采用线性混合效应模型进行纵向关联分析。结果显示，TLR2上的2个单核苷酸多态性位点（rs1898830与rs11938228）与较低的FEV1水平、FEV1加速下降及更高的痰炎症细胞数量显著相关。未观察到TLR4位点与FEV1水平存在关联。17个TLR4单核苷酸多态性位点中有11个与FEV1下降相关，其中rs12377632与rs10759931还与基线时更高的痰炎症细胞数量及随时间的升高显著相关。本研究为首项纵向研究，证实TLR2与TLR4的标签单核苷酸多态性与COPD患者的肺功能水平、肺功能下降幅度及痰诱导样本中的炎症细胞数量相关，提示TLRs在COPD的严重程度与疾病进展中发挥潜在作用。