University Hospital of Bonn, Bonn, Germany.
Adv Exp Med Biol. 2013;756:239-45. doi: 10.1007/978-94-007-4549-0_30.
The etiology of inflammatory diseases of the lung like sarcoidosis and chronic obstructive pulmonary disease (COPD) is multifactorial. The main trigger for developing a COPD is tobacco smoking while exogenous factors causing sarcoidosis are unclear. In both diseases there is an underlying genetic susceptibility determining both the onset and the course of the diseases. Toll-like receptor (TLR)-9 plays an important role in innate immunity by recognizing bacterial CpG-DNA motifs. It is unclear whether single nucleotide polymorphisms (SNPs) in TLR-9 are able to alter the course of sarcoidosis or COPD, or raise the susceptibility for developing one of the disorders. We examined two SNPs in the promoter region of the TLR-9 gene (T1486C and T1237C) in 175 COPD patients (59% with a stable course of the disease, 41% with an instable course with more than 3 exacerbations over the last 3 years) and 166 sarcoidosis patients (19% with an acute and 81% with a chronic course of the disease lasting >2 years) comparing each group to 233 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was used for genotyping. The C-allele frequency of T1486C was significantly elevated in COPD patients (p = 0.008). For T1237C there were no significant associations comparing the COPD cohort with the controls. In the sarcoidosis cohort, we could observe a significantly higher prevalence of the C-allele for T1237C in the chronic sarcoidosis cohort in comparison to the control group (p = 0.026). For T1486 there no statistical association was observed. This is the first study showing an association between a SNP (T1486C) in the TLR-9 gene and the onset of COPD. Moreover, we could demonstrate that T1237C is able to alter the course of sarcoidosis as a disease-modifying gene. This study underlines that SNPs in TLR-9 might be involved in acquiring and maintaining lung diseases such as sarcoidosis and COPD.
肺的炎症性疾病（如结节病和慢性阻塞性肺疾病（COPD））的病因是多因素的。COPD 的主要诱因是吸烟，而导致结节病的外源性因素尚不清楚。在这两种疾病中，都存在潜在的遗传易感性，决定了疾病的发病和病程。Toll 样受体（TLR）-9 通过识别细菌 CpG-DNA 基序在天然免疫中发挥重要作用。TLR-9 中的单核苷酸多态性（SNP）是否能够改变结节病或 COPD 的病程，或者增加发生其中一种疾病的易感性，目前尚不清楚。我们检测了 TLR-9 基因启动子区域的两个 SNP（T1486C 和 T1237C），共纳入 175 名 COPD 患者（59%疾病稳定，41%病情不稳定，过去 3 年中发生 3 次以上加重）和 166 名结节病患者（19%急性病程，81%慢性病程>2 年），将每组患者分别与 233 名健康对照者进行比较。采用聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）分析进行基因分型。COPD 患者 T1486C 的 C 等位基因频率显著升高（p=0.008）。对于 T1237C，COPD 组与对照组比较无显著相关性。在结节病组中，我们观察到 T1237C 的 C 等位基因在慢性结节病组中的发生率明显高于对照组（p=0.026）。对于 T1486 则未观察到统计学相关性。这是第一项表明 TLR-9 基因中的 SNP（T1486C）与 COPD 发病相关的研究。此外，我们还证明 T1237C 作为一种疾病修饰基因，能够改变结节病的病程。本研究强调 TLR-9 中的 SNP 可能参与获得和维持肺疾病，如结节病和 COPD。
