Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nat Commun. 2023 Feb 1;14(1):549. doi: 10.1038/s41467-023-36282-w.
The genetics underlying tuberculosis (TB) pathophysiology are poorly understood. Human genome-wide association studies have failed so far to reveal reproducible susceptibility loci, attributed in part to the influence of the underlying Mycobacterium tuberculosis (Mtb) bacterial genotype on the outcome of the infection. Several studies have found associations of human genetic polymorphisms with Mtb phylo-lineages, but studies analysing genome-genome interactions are needed. By implementing a phylogenetic tree-based Mtb-to-human analysis for 714 TB patients from Thailand, we identify eight putative genetic interaction points (P < 5 × 10) including human loci DAP and RIMS3, both linked to the IFNγ cytokine and host immune system, as well as FSTL5, previously associated with susceptibility to TB. Many of the corresponding Mtb markers are lineage specific. The genome-to-genome analysis reveals a complex interactome picture, supports host-pathogen adaptation and co-evolution in TB, and has potential applications to large-scale studies across many TB endemic populations matched for host-pathogen genomic diversity.
结核病（TB）发病机制的遗传学基础知之甚少。全基因组关联研究迄今为止未能揭示可重复的易感基因座，部分原因是潜在的结核分枝杆菌（Mtb）细菌基因型对感染结局的影响。几项研究发现了人类遗传多态性与 Mtb 谱系的关联，但需要分析基因组-基因组相互作用的研究。通过对来自泰国的 714 名结核病患者实施基于系统发育树的 Mtb-人类分析，我们确定了八个假定的遗传相互作用点（P < 5×10），包括与 IFNγ 细胞因子和宿主免疫系统相关的人类基因座 DAP 和 RIMS3，以及先前与结核病易感性相关的 FSTL5。许多相应的 Mtb 标记物是谱系特异性的。全基因组分析揭示了一个复杂的相互作用网络图景，支持结核病中的宿主-病原体适应和共同进化，并有可能应用于针对许多结核病流行人群的宿主-病原体基因组多样性的大规模研究。
