Clinical Report: Genetic Variants in IRGM Linked to Tuberculosis Susceptibility

Overview

This study evaluated whether 2 intronic single-nucleotide polymorphisms (SNPs) in the immunity-related GTPase M (IRGM) gene, rs4958847 and rs72553867, were associated with tuberculosis (TB) disease and/or TB infection (TBI) in a European population, both individually and in combination.

Background

Tuberculosis remains a major global health challenge, affecting more than 10 million people annually and causing approximately 1.25 million deaths in 2023. IRGM plays a central role in autophagy initiation and is also involved in innate immune regulation, making it a biologically plausible host factor in TB susceptibility. Previous studies have reported population-specific and sometimes inconsistent associations between IRGM polymorphisms and TB susceptibility.

Data Highlights

• Of 709 participants enrolled, 644 with complete data were included in the analysis: 194 with TB disease, 194 with TBI, and 256 TB-free controls.

• Neither rs4958847 nor rs72553867 was significantly associated individually with TB disease, TBI, or combined TB outcomes.

• The rs4958847-rs72553867 GG-AC diplotype was associated with increased odds of TB disease compared with TB-free controls, relative to the GG-CC reference diplotype (OR, 2.56; 95% CI, 1.18-5.56; P = .017).

• In the combined TB disease/TBI group versus TB-free controls, the GG-AC diplotype was also associated with higher odds in unadjusted analysis (OR, 2.06; 95% CI, 1.01-4.20; P = .047).

Key Findings

• IRGM SNPs rs4958847 and rs72553867 were evaluated individually and as combined diplotypes for associations with TB outcomes.

• No significant individual SNP associations were detected for rs4958847 or rs72553867 across TB disease, TBI, or combined TB outcomes.

• The GG-AC diplotype showed a potentially relevant association with TB disease compared with TB-free controls.

• Previous studies have shown that associations between IRGM variants and TB susceptibility can vary across populations and disease contexts.

• The authors suggest that combined multi-variant analyses may capture IRGM-related TB susceptibility that is not apparent from single-SNP analyses alone.

Clinical Implications

The findings do not establish a role for clinical genetic testing to identify individuals at high risk for TB. Rather, they suggest that combined IRGM genetic variation may contribute to TB susceptibility in some populations and support further investigation of multi-variant genetic effects, functional mechanisms, and population-specific influences. The authors call for validation in larger independent European populations and for broader IRGM sequencing, functional studies, gene-environment analyses, and longitudinal research.

Conclusion

The study found no significant association between either individual IRGM SNP and TB outcomes, but identified a potential association between the rs4958847-rs72553867 GG-AC diplotype and TB disease in this European population. The findings support further investigation of combined IRGM genetic variation rather than establishing a clinically actionable genetic risk marker.

Related Resources & Content

1. Dashian MA, Shipulin GA, Deviatkin AA. International Journal of Molecular Sciences. 2025 — Genetic Susceptibility to Tuberculosis and the Utility of Polygenic Scores in Population Stratification.

2. Schurz H, Naranbhai V, Yates TA, et al. eLife. 2024 — Multi-Ancestry Meta-Analysis of Host Genetic Susceptibility to Tuberculosis Identifies Shared Genetic Architecture.

3. Singh SB, Davis AS, Taylor GA, Deretic V. Science. 2006 — Human IRGM Induces Autophagy to Eliminate Intracellular Mycobacteria.

4. Xie H, Li C, Zhang M, Zhong N, Chen L. Medicine. 2017 — Association Between IRGM Polymorphisms and Tuberculosis Risk: A Meta-Analysis.

5. Khan IA, Nayak B, Markandey M, et al. PLOS ONE. 2021 — Differential Prevalence of Pathobionts and Host Gene Polymorphisms in Chronic Inflammatory Intestinal Diseases: Crohn’s Disease and Intestinal Tuberculosis.

6. Das D, Singh PP, Desai S, et al. Mitochondrion. 2025 — Outlier Maternal Haplogroups N5 and X2 and Their Potential Role in Elevated Tuberculosis Prevalence Among the Sahariya Tribe.

7. Verma A, Huffman JE, Rodriguez A, et al. Science. 2024 — Diversity and Scale: Genetic Architecture of 2068 Traits in the VA Million Veteran Program.