Common genetic determinants of dynamic human in vivo immune response to Mycobacterium tuberculosis
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
We investigated host-genetic TB susceptibility by expression quantitative trait loci (eQTL) analysis of the tuberculin skin test (TST) as a standardised challenge model of human in vivo TB immunology. Paired genotyping with 415 RNA-sequencing profiles from day 2 and day 7 TST biopsies in 267 individuals with latent or active TB identified cis-eQTLs affecting 1,719 response genes. The strongest signal mapped to ERAP2 , and colocalisation analysis linked reduced ERAP2 expression to increased TB risk in GWAS data. Heritability was greatest in HLA class II antigen presentation and T-cell activation pathways. HLA-DR haplotypes associated with subsequent expansion of Mtb-reactive T cells, linking host genotype to antigen-specific immunity. Trans-eQTLs also identified a proliferative programme centred on NCAPD3 , implicating genetically regulated cell-cycle control as an antigen-independent determinant of T-cell immunity. These findings provide a functional framework for interpreting TB susceptibility loci and identification of candidate biomarkers for TB risk stratification and vaccine development.
