Wu Linlin, Hu Yi, Li Dange, Jiang Weili, Xu Biao
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China.
Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China.
BMC Med Genet. 2015 Apr 1;16:19. doi: 10.1186/s12881-015-0166-1.
We investigated whether polymorphisms in the toll-like receptor genes or gene-gene interactions are associated with susceptibility to latent tuberculosis infection (LTBI) or subsequent pulmonary tuberculosis (PTB) in a Chinese population.
Two matched case-control studies were undertaken. Previously reported polymorphisms in the toll-like receptors (TLRs) were compared between 422 healthy controls (HC) and 205 LTBI patients and between 205 LTBI patients and 109 PTB patients, to assess whether these polymorphisms and their interactions are associated with LTBI or PTB. A PCR-based restriction fragment length polymorphism analysis was used to detect genetic polymorphisms in the TLR genes. Nonparametric multifactor dimensionality reduction (MDR) was used to analyze the effects of interactions between complex disease genes and other genes or environmental factors.
Sixteen markers in TLR1, TLR2, TLR4, TLR6, TLR8, TLR9, and TIRAP were detected. In TLR2, the frequencies of the CC genotype (OR = 2.262; 95% CI: 1.433-3.570) and C allele (OR = 1.566; 95% CI: 1.223-1.900) in single-nucleotide polymorphism (SNP) rs3804100 were significantly higher in the LTBI group than in the HC group, whereas the GA genotype of SNP rs5743708 was associated with PTB (OR = 6.087; 95% CI: 1.687-21.968). The frequencies of the GG genotype of SNP rs7873784 in TLR4 (OR = 2.136; 95% CI: 1.312-3.478) and the CC genotype of rs3764879 in TLR8 (OR = 1.982; 95% CI: 1.292-3.042) were also significantly higher in the PTB group than in the HC group. The TC genotype frequency of SNP rs5743836 in TLR9 was significantly higher in the LTBI group than in the HC group (OR = 1.664; 95% CI: 1.201-2.306). An MDR analysis of gene-gene and gene-environment interactions identified three SNPs (rs10759932, rs7873784, and rs10759931) that predicted LTBI with 84% accuracy (p = 0.0004) and three SNPs (rs3804100, rs1898830, and rs10759931) that predicted PTB with 80% accuracy (p = 0.0001).
Our results suggest that genetic variation in TLR2, 4, 8 and 9, implicating TLR-related pathways affecting the innate immunity response, modulate LTBI and PTB susceptibility in Chinese.
我们研究了Toll样受体基因的多态性或基因-基因相互作用是否与中国人群中潜伏性结核感染（LTBI）易感性或随后发生的肺结核（PTB）相关。
进行了两项匹配的病例对照研究。比较了422名健康对照（HC）与205名LTBI患者以及205名LTBI患者与109名PTB患者之间先前报道的Toll样受体（TLR）多态性，以评估这些多态性及其相互作用是否与LTBI或PTB相关。采用基于聚合酶链反应的限制性片段长度多态性分析来检测TLR基因中的遗传多态性。使用非参数多因素降维法（MDR）分析复杂疾病基因与其他基因或环境因素之间相互作用的影响。
在TLR1、TLR2、TLR4、TLR6、TLR8、TLR9和TIRAP中检测到16个标记。在TLR2中，单核苷酸多态性（SNP）rs3804100的CC基因型（OR = 2.262；95%CI：1.433 - 3.570）和C等位基因（OR = 1.566；95%CI：1.223 - 1.900）在LTBI组中的频率显著高于HC组，而SNP rs5743708的GA基因型与PTB相关（OR = 6.087；95%CI：1.687 - 21.968）。TLR4中SNP rs7873784的GG基因型（OR = 2.136；95%CI：1.312 - 3.478）和TLR8中rs3764879的CC基因型（OR = 1.982；95%CI：1.292 - 3.042）在PTB组中的频率也显著高于HC组。TLR9中SNP rs5743836的TC基因型频率在LTBI组中显著高于HC组（OR = 1.664；95%CI：1.201 - 2.306）。基因-基因和基因-环境相互作用的MDR分析确定了三个SNP（rs10759932 rs7873784和rs10759931）以84%的准确率预测LTBI（p = 0.0004）以及三个SNP（rs3804100 rs1898830和rs10759931）以80%的准确率预测PTB（p = 0.0001）。
我们的结果表明，TLR2、4、8和9中的遗传变异，涉及影响先天免疫反应的TLR相关途径，调节中国人对LTBI和PTB的易感性。
