Susceptibility to Pulmonary Diseases

"Understanding host genetic susceptibility is crucial for unraveling the pathogenesis of infectious pulmonary diseases and developing personalized clinical strategies. In the first part of this presentation, we focus on severe COVID-19. Through a genome-wide association study (GWAS) in a Japanese cohort, we identified a risk variant at 5q35 (rs60200309-A) near DOCK2, which is associated with severe COVID-19 in patients under 65 years of age. Single-cell RNA sequencing and functional analyses revealed cell-type-specific downregulation of DOCK2 in non-classical monocytes, leading to impaired macrophage recruitment and dysregulated type I interferon responses. Importantly, this risk allele is prevalent in East Asians but rare in Europeans, underscoring the critical need for genetic studies in non-European populations(Namkoong, et al. Nature 2022.). In the second part, we transition to nontuberculous mycobacterial pulmonary disease (NTM-PD). By expanding our genomic investigation to multinational cohorts across Korea, Japan, and Europe, we identified and validated three susceptibility loci (IL1Rs, PDE8B, and PRKCB). Furthermore, Mendelian randomization analysis demonstrated a significant negative causal relationship between body mass index (BMI) and NTM-PD susceptibility(Park, et al. Am J Respir Crit Care Med . 2025). Together, these findings highlight that establishing multinational and multi-ethnic cohorts is indispensable for precision respirology, as it allows us to uncover both population-specific risk variants and globally conserved host mechanisms in respiratory infections."