IFNGR1, IRF8 genetic polymorphisms modulate the susceptibility of non-tuberculous mycobacteria pulmonary disease and influence the patients' treatment outcomes and immune status.

Objective: To investigate the association of genetic polymorphisms in MB21D1 (Mab-21 domain-containing 1), TMEM173 (Transmembrane Protein 173), IFNB1 (Interferon beta 1), IFNGR1 (Interferon gamma receptor 1), IFNGR2 (Interferon gamma receptor 2), IRF3 (Interferon Regulatory Factor 3), and IRF8 (Interferon Regulatory Factor 8) with susceptibility to non-tuberculous mycobacteria pulmonary disease (NTM-PD) as well as their correlation with the treatment outcomes and immune status of patients.

Methods: Forty-four tagSNPs from the candidate genes were genotyped in a 2-phase cohort study including an initial discovery phase involving 707 NTM-PD patients and 726 healthy controls and a replication phase involving 357 NTM-PD patients and 400 controls. The frequencies and distributions of genotypes were compared between the case and control groups. Treatment success rates, sputum culture conversion rates, imaging characteristics, and peripheral blood immunological indices were compared among patients with different genotypes.

Results: Individuals with the IFNGR1 rs2234711 A/A genotype were more susceptible to MAC-PD compared to those with the G/G genotype (discovery phase OR = 1.752, P.adj = 0.025; replication phase OR = 2.143, P.adj = 0.019). Patients with the rs2234711 A/A genotype exhibited significantly lower treatment success rates and sputum culture conversion rates, along with elevated levels of peripheral blood heparin-binding protein (HBP), erythrocyte sedimentation rate, and interleukin-10, but significantly decreased interleukin-1β levels (all P < 0.05). Individuals with the IRF8 rs2280378 A/A genotype were more susceptible to MAB-PD (discovery phase OR = 2.302, P.adj = 0.014; replication phase OR = 2.465, P.adj = 0.015). Compared to G/G genotype patients, those with the rs2280378 A/A genotype exhibited lower treatment success rates and sputum culture conversion rates, were more likely to develop pulmonary cavities and multiple lung field involvement, and showed elevated levels of peripheral blood HBP and C-reactive protein, along with significantly reduced levels of serum interleukin-12 P70, tumor necrosis factor-α, and CD8 + T lymphocytes (all P < 0.05).

Conclusion: In the Chinese Han population, IFNGR1 genetic polymorphisms are closely associated with MAC-PD susceptibility, while IRF8 genetic polymorphisms are associated with MAB-PD susceptibility. Variants in IFNGR1 and IRF8 significantly affect the immune status and treatment outcomes of MAC-PD and MAB-PD patients, respectively.