Effect of multiple genetic polymorphisms on antigen presentation and susceptibility to Mycobacterium tuberculosis infection
Effect of multiple genetic polymorphisms on antigen presentation and susceptibility to Mycobacterium tuberculosis infection
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DOI：
10.1128/iai.01677-07
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发表时间：
2008-07-01
影响因子：
3.1
通讯作者：
Kirschner, Denise E.
中科院分区：
文献类型：
--
作者：
Chang, Stewart T.;Linderman, Jennifer J.;Kirschner, Denise E.
与抗原呈递相关的几种分子，包括γ干扰素（IFN-γ）和主要组织相容性复合物（MHC），由多态性基因编码。当在流行病学研究中单独考虑某些多态性时，发现一些多态性会影响对结核病（TB）的易感性，但多个多态性如何相互作用以确定个体对结核病的易感性仍然是一个悬而未决的问题。我们假设某些基因的多态性可能抵消或增强其他基因多态性的影响。例如，IFN-γ表达的增加可以抵消特定MHC变体对结核分枝杆菌肽的弱结合，从而建立与另一种结合更强的MHC变体相同的T细胞反应。为了检验这一假设，我们基于遗传多态性的已知影响的实验数据和存在多种多态性时的模拟时间过程，开发了抗原呈递的数学模型。我们发现不同基因的多态性可以在相同程度上影响抗原呈递，因此可以相互补偿。此外，我们还定义了这种关系存在的条件。例如，仅在高于某个表达阈值时，模型中增加的 IFN-γ 表达才能补偿肽-MHC 亲和力的降低。低于这个阈值，与肽-MHC 亲和力的变化相比，IFN-γ 表达的变化是无效的。多态性表现出这种关系的发现可以解释流行病学文献中的差异，其中一些多态性与结核病易感性的相关性不一致。此外，该模型允许按效应对多态性进行排序，为设计关联研究提供了新工具。
Several molecules related to antigen presentation, including gamma interferon (IFN-gamma) and the major histocompatibility complex (MHC), are encoded by polymorphic genes. Some polymorphisms were found to affect susceptibility to tuberculosis (TB) when they were considered singly in epidemiological studies, but how multiple polymorphisms interact to determine susceptibility to TB in an individual remains an open question. We hypothesized that polymorphisms in some genes may counteract or intensify the effects of polymorphisms in other genes. For example, an increase in IFN-gamma expression may counteract the weak binding that a particular MHC variant displays for a peptide from Mycobacterium tuberculosis to establish the same T-cell response as another, more strongly binding MHC variant. To test this hypothesis, we developed a mathematical model of antigen presentation based on experimental data for the known effects of genetic polymorphisms and simulated time courses when multiple polymorphisms were present. We found that polymorphisms in different genes could affect antigen presentation to the same extent and therefore compensate for each other. Furthermore, we defined the conditions under which such relationships could exist. For example, increased IFN-gamma expression compensated for decreased peptide-MHC affinity in the model only above a certain threshold of expression. Below this threshold, changes in IFN-gamma expression were ineffectual compared to changes in peptide-MHC affinity. The finding that polymorphisms exhibit such relationships could explain discrepancies in the epidemiological literature, where some polymorphisms have been inconsistently associated with susceptibility to TB. Furthermore, the model allows polymorphisms to be ranked by effect, providing a new tool for designing association studies.