Ivie Joshua J, Dill-McFarland Kimberly A, Simmons Jason D, Peterson Glenna J, Benchek Penelope H, Mayanja-Kizza Harriet, Veith Lily E, Agata Moeko, Ha Dang Tm, Nghia Ho Dt, Boom W Henry, Stein Catherine M, Khor Chiea C, Thwaites Guy E, Hai Hoang T, Thuong Nguyen Tt, Chang Xuling, Dunstan Sarah J, Hawn Thomas R
Department of Global Health and.
Department of Medicine, University of Washington, Seattle, Washington, USA.
J Clin Invest. 2025 May 22;135(14). doi: 10.1172/JCI179822. eCollection 2025 Jul 15.
Immune and clinical outcomes to Mycobacterium tuberculosis (Mtb) infection vary greatly between individuals, yet the underlying genetic and cellular mechanisms driving this heterogeneity remain poorly understood. We performed a cellular genome-wide association study to identify genetic variants associated with Mtb-induced monocyte transcriptional expression of IL1B, IL6, TNF, and IFNB1 via RNA-Seq in a Ugandan cohort. Significantly associated variants were assessed for transferability in an independent Seattle cohort, further validated in vitro, and assessed for clinical phenotype associations. We identified 77 loci suggestively associated with Mtb-induced cytokine expression in monocytes in Uganda. SNPs associated with Mtb-induced TNF were enriched within α-linolenic acid metabolism pathway genes, which was validated in vitro using PLA2 inhibitors. Four loci maintained significant associations in Seattle. We validated a cytokine effect with siRNA knockdown for two of these loci, which mapped to the genes SLIT3 and SLC1A1. Furthermore, exogenous treatment of macrophages with SLIT3 enhanced Mtb intracellular replication. Finally, SLC1A1 and SLIT3 variants were associated with susceptibility to tuberculous meningitis and subsequent survival, respectively, in a Vietnamese cohort. In summary, we identified multiple variants and pathways associated with Mtb-induced cytokine transcriptional responses that were validated in vitro and were associated with clinical tuberculosis susceptibility.
个体对结核分枝杆菌（Mtb）感染的免疫和临床结果差异很大，但导致这种异质性的潜在遗传和细胞机制仍知之甚少。我们进行了一项细胞全基因组关联研究，以在乌干达队列中通过RNA测序确定与Mtb诱导的单核细胞IL1B、IL6、TNF和IFNB1转录表达相关的遗传变异。对显著相关变异在独立的西雅图队列中进行可转移性评估，在体外进一步验证，并评估其与临床表型的关联。我们在乌干达鉴定出77个与Mtb诱导的单核细胞细胞因子表达有提示性关联的位点。与Mtb诱导的TNF相关的单核苷酸多态性（SNP）在α-亚麻酸代谢途径基因中富集，这在体外使用磷脂酶A2抑制剂得到验证。四个位点在西雅图保持显著关联。我们对其中两个位点用小干扰RNA（siRNA）敲低验证了细胞因子效应，这两个位点映射到SLIT3和SLC1A1基因。此外，用SLIT3对外源巨噬细胞进行处理可增强Mtb在细胞内的复制。最后，在越南队列中，SLC1A1和SLIT3变异分别与结核性脑膜炎易感性和随后的生存相关。总之，我们鉴定出多个与Mtb诱导的细胞因子转录反应相关联的变异和途径，这些在体外得到验证，并与临床结核病易感性相关。
