Polymorphism within the Interferon-γ/Receptor complex is associated with pulmonary tuberculosis
Polymorphism within the Interferon-γ/Receptor complex is associated with pulmonary tuberculosis
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DOI：
10.1164/rccm.200601-088oc
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发表时间：
2006-08-01
影响因子：
24.7
通讯作者：
Hill, Adrian V. S.
中科院分区：
文献类型：
--
作者：
Cooke, Graham S.;Campbell, Sarah J.;Hill, Adrian V. S.
基本原理：干扰素-γ（IFN-γ）是结核病研究的核心兴趣。一些单基因突变已被确定在IFN-γ信号通路，易患严重的分枝杆菌疾病，但这些基因内的多态性的相关性，结核病的常见表型tuberculosis.Methods：共1,301人被列入一个大型的，详细的研究西非人口肺结核。我们研究了编码IFN-γ及其受体亚单位的基因与疾病的相关性结果：在IFNG基因内，两个启动子变体显示了新的疾病关联的证据：-1616GG（比值比[OR]，1.49; 95%置信区间[CI]，1.11-2.00; p = 0.008）和+3234 TT（OR，1.40; 95% CI，1.09-1.80; p = 0.009）。+874AA基因型在病例组中的频率并不显著高于对照组（OR，1.16; 95%CI，0.89-1.51; p = 0.25）。此外，还发现IFNGR 1启动子的-56CC基因型与新的疾病相关（OR，0.75; 95%CI，0.57-0.99; p = 0.041）。没有疾病协会被认为与IFNGR 2 locus.Conclusions：这些结果提供了证据的IFNG基因座的遗传变异的重要作用，并提供了详细的了解这种关联的遗传机制。与IFNGR 1相关的疾病是新的，这些发现共同支持了这样的假设，即IFN-γ产生和反应性的遗传决定的变化影响了患结核病的风险。
Rationale: Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear.Methods: A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2).Results: Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus.Conclusions: These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.