Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, Faculty of Health Sciences, PO Box 19063, Stellenbosch University, Tygerberg 7505, South Africa.
BMC Infect Dis. 2010 Jun 7;10:154. doi: 10.1186/1471-2334-10-154.
Interferon gamma is a major macrophage-activating cytokine during infection with Mycobacterium tuberculosis, the causative pathogen of tuberculosis, and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 cells, which can best deal with intracellular pathogens such as M. tuberculosis. Based on the hypothesis that genes which regulate interferon gamma may influence tuberculosis susceptibility, we investigated polymorphisms in eight candidate genes.
Fifty-four polymorphisms in eight candidate genes were genotyped in over 800 tuberculosis cases and healthy controls in a population-based case-control association study in a South African population. Genotyping methods used included the SNPlex Genotyping System, capillary electrophoresis of fluorescently labelled PCR products, TaqMan SNP genotyping assays or the amplification mutation refraction system. Single polymorphisms as well as haplotypes of the variants were tested for association with TB using statistical analyses.
A haplotype in interleukin 12B was nominally associated with tuberculosis (p = 0.02), but after permutation testing, done to assess the significance for the entire analysis, this was not globally significant. In addition a novel allele was found for the interleukin 12B D5S2941 microsatellite.
This study highlights the importance of using larger sample sizes when attempting validation of previously reported genetic associations. Initial studies may be false positives or may propose a stronger genetic effect than subsequently found to be the case.
干扰素γ是分枝杆菌（结核分枝杆菌）感染时主要的巨噬细胞激活细胞因子，其作用在动物模型和人类中得到了很好的证实。这种细胞因子由激活的辅助性 T 细胞 1 产生，能够最好地应对结核分枝杆菌等细胞内病原体。基于调节干扰素γ的基因可能影响结核病易感性的假设，我们研究了八个候选基因中的多态性。
在南非人群中进行的一项基于人群的病例对照关联研究中，对 8 个候选基因中的 54 个多态性进行了超过 800 例结核病病例和健康对照的基因分型。使用的基因分型方法包括 SNPlex 基因分型系统、荧光标记 PCR 产物的毛细管电泳、TaqMan SNP 基因分型检测或扩增突变折射系统。使用统计分析方法检测单核苷酸多态性以及变体的单倍型与 TB 的关联。
白细胞介素 12B 的单倍型与结核病呈名义相关（p = 0.02），但经过置换检验，即评估整个分析的显著性的检验，这并不是全局显著的。此外，还发现了白细胞介素 12B D5S2941 微卫星的一个新等位基因。
本研究强调了当试图验证先前报道的遗传关联时，使用更大的样本量的重要性。初始研究可能是假阳性，或者提出的遗传效应比随后发现的要强。
