Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
Sci Rep. 2017 Oct 9;7(1):12800. doi: 10.1038/s41598-017-13017-8.
There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-γ production after stimulation with live BCG (Bacillus Calmette-Guérin), and a second locus on chromosome region 3q affecting IFN-γ production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-γ production induced by BCG (IFNγ-ESAT6). High-density genotyping and imputation identified ~100,000 variants within each linkage region, which we tested for association with the corresponding IFN-γ phenotype in families from a tuberculosis household contact study in France. Significant associations were replicated in a South African familial sample. The most convincing association observed was that between the IFNγ-ESAT6 phenotype and rs9828868 on chromosome 3q (p = 9.8 × 10 in the French sample). This variant made a significant contribution to the linkage signal (p < 0.001), and a trend towards the same association was observed in the South African sample. This variant was reported to be an eQTL of the ZXDC gene, biologically linked to monocyte IL-12 production through CCL2/MCP1. The identification of rs9828868 as a genetic driver of IFNγ production in response to mycobacterial antigens provides new insights into human anti-tuberculosis immunity.
个体对结核分枝杆菌感染的反应存在较大差异。在先前的连锁分析中，我们在染色体 8q 区域发现了一个主要的基因座，该基因座控制着活卡介苗（BCG）刺激后 IFN-γ 的产生，在考虑到 BCG 诱导的 IFN-γ 产生（IFNγ-ESAT6）后，在染色体 3q 区域发现了另一个基因座，该基因座影响 ESAT-6 早期分泌抗原靶（ESAT-6）触发的 IFN-γ 的产生。高密度基因分型和推测在每个连锁区域内鉴定了约 100,000 个变体，我们在法国结核病家庭接触研究中的家庭中测试了这些变体与相应 IFN-γ 表型的关联。在南非的家族样本中复制了显著的关联。观察到的最令人信服的关联是 IFNγ-ESAT6 表型与染色体 3q 上的 rs9828868 之间的关联（法国样本中的 p=9.8×10）。该变体对连锁信号有显著贡献（p<0.001），在南非样本中也观察到了相同的关联趋势。该变体被报道为 ZXDC 基因的 eQTL，通过 CCL2/MCP1 与单核细胞 IL-12 产生具有生物学联系。鉴定 rs9828868 作为对结核分枝杆菌抗原产生 IFNγ 的遗传驱动因素，为人类抗结核免疫提供了新的见解。
