Genome-Wide Association Study Implicates Immunogenetic Variation in Chemokine Signaling Pathways in Pediatric Tuberculosis Susceptibility

Introduction Although immune responses to Bacillus Calmette–Guérin (BCG) vaccination and susceptibility to mycobacterial infection vary across individuals, the underlying cellular mechanisms regulating this heterogeneity are poorly understood. We hypothesized that immunogenetic variation among common host variants contributes to susceptibility to pediatric tuberculosis (TB) disease. Methods We used a case-control study with a 12–36-month prospective observation period to examine pediatric TB susceptibility in children 2 mo–5 years with household Mycobacterium tuberculosis exposure in Worcester, South Africa. Low-pass whole-genome sequencing followed by imputation was completed for 212 TB cases and 184 controls. A genome-wide association study (GWAS) was performed to assess the association between genetic variants and pediatric TB susceptibility. Lead genetic variants were evaluated for their effect on BCG-induced innate and adaptive immune responses in 10-week-old South African infants using flow cytometry. Results We identified a genome-wide significant variant, rs4600676 (p = 3.7e-08), associated with increased pediatric TB susceptibility. Genetic variation at this risk locus is associated with differential expression of mitochondrial ribosomal protein MRPS9 (p < 1e-05), suggesting it may regulate cellular metabolism and stress response. We also identified an additional 18 risk loci mapping to 194 genes at a prespecified suggestive significance level (p < 1e-05) associated with pediatric TB susceptibility. MAGMA gene set analysis of these suggestive variants revealed the strongest enrichment for CXCL2 production (p = 4.1e-06) with suggestive variant rs79846470 (p = 1.9e-06) mapping to the CXCR1 and CXCR2 genes via chromatin association. Genetic variation at this locus is associated with increased IL6 production in myeloid dendritic cells following BCG vaccination (p = 0.007). Conclusion We identified a genome-wide significant variant, together with 18 additional loci, associated with increased pediatric susceptibility to mycobacterial disease. These findings highlight innate immune and metabolic pathways as key immunogenetic determinants of antimycobacterial host responses in children. By delineating these pathways, our work underscores the potential to leverage immunogenetic insights in advancing precision diagnostics and mechanism-based immunomodulatory strategies for children with inborn errors of immunity.