Joint Effect of MCP-1 Genotype GG and MMP-1 Genotype 2G/2G Increases the Likelihood of Developing Pulmonary Tuberculosis in BCG-Vaccinated Individuals
Joint Effect of MCP-1 Genotype GG and MMP-1 Genotype 2G/2G Increases the Likelihood of Developing Pulmonary Tuberculosis in BCG-Vaccinated Individuals
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DOI：
10.1371/journal.pone.0008881
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发表时间：
2010-01-25
期刊：
影响因子：
3.7
通讯作者：
Flores-Villanueva, Pedro O.
中科院分区：
文献类型：
--
作者：
Ganachari, Malathesha;Ruiz-Morales, Jorge A.;Flores-Villanueva, Pedro O.
我们之前报道过 - 2518 MCP-1 基因型 GG 增加了未接种卡介苗的墨西哥人和韩国人患结核病 (TB) 的可能性。在此，我们测试了以下假设：该基因型单独或与 1607 MMP-1 功能多态性一起，会增加接种 BCG 的个体患结核病的可能性。我们对墨西哥和秘鲁接种卡介苗的个体进行了基于人群的病例对照研究，其中包括来自墨西哥的 193 名结核病病例和 243 名健康结核菌素阳性对照，以及来自秘鲁的 701 名结核病病例和 796 名对照。我们还对相关双基因座基因型携带者的淋巴结进行了免疫组织化学 (IHC) 分析，并进行了体外研究，以确定这些变异如何增加发生活动性疾病的风险。我们报告，- 2518 MCP-1 基因型 GG 和 - 1607 MMP-1 基因型 2G/2G 之间的联合效应持续使墨西哥人患结核病的几率增加 3.59 倍，秘鲁人患结核病的几率增加 3.9 倍。淋巴结的 IHC 分析表明，双基因座基因型 MCP-1 GG MMP-1 2G/2G 的携带者表达最高水平的 MCP-1 和 MMP-1。这些易感性基因型的携带者患结核病的风险可能会增加，因为他们产生高水平的 MCP-1，与所研究的其他双位点 MCP-1 MMP-1 基因型的携带者相比，这会增强结核分枝杆菌超声抗原对 MMP-1 产生的诱导，达到更高的水平。这一观点得到了体外实验和基于荧光素酶的启动子活性测定的支持。 MMP-1 可能会破坏肉芽肿形成的稳定性，并在感染早期促进组织损伤和疾病进展。我们的研究结果可能会促进针对 MCP-1 和/或 MMP-1 的新的个性化治疗方法的开发。
We previously reported that the - 2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the 1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the - 2518 MCP-1 genotype GG and the - 1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1.