Clinical Scorecard: Genetic Variants in IRGM Linked to Tuberculosis Susceptibility in a European Cohort

At a Glance

Key Highlights

• Tuberculosis affects more than 10 million people annually and caused approximately 1.25 million deaths in 2023.

• IRGM plays a central role in autophagy initiation and has been investigated as a host genetic factor that may influence TB susceptibility.

• Previous studies have reported population-specific associations between IRGM polymorphisms and TB susceptibility.

• This study evaluated 2 intronic IRGM SNPs, rs4958847 and rs72553867, individually and in combination, in a European population.

• Neither SNP was significantly associated with TB outcomes individually, but the GG-AC diplotype was associated with increased odds of TB disease compared with TB-free controls.

Guideline-Based Recommendations

The study was a genetic case-control analysis rather than a clinical guideline. The following reflects study definitions, diagnostic methods, and research considerations described by the authors.

Diagnosis

• TB disease was defined by microbiological confirmation through molecular testing and/or culture, or by clinical diagnosis based on radiological and clinical criteria and response to anti-TB treatment.

• TBI was identified primarily using the QuantiFERON-TB Gold Plus assay in the absence of clinical or radiological evidence of TB disease.

Management

• Patients with TB disease were enrolled within 7 days of treatment initiation; this was a study enrollment criterion rather than a treatment recommendation.

Monitoring & Follow-up

• Genotyping of rs4958847 and rs72553867 was performed using real-time polymerase chain reaction–based allele-specific TaqMan assays, with quality control including Hardy-Weinberg equilibrium testing and assessment of missing genotype rates.

• Logistic regression was used to evaluate individual SNPs and combined diplotypes across TB disease, TBI, and TB-free comparisons.

Risks

• The study excluded individuals receiving immunosuppressive medications or those with autoimmune diseases, limiting applicability to those populations.

• Population- and disease-specific genetic effects may influence associations between IRGM variants and TB susceptibility.

Patient & Prescribing Data

The analysis included 644 participants: 194 with TB disease, 194 with TBI, and 256 TB-free controls. Most participants had Italian ancestry, with additional representation from Romania and other Eastern European populations.

No prescribing intervention was evaluated. The study focused on genetic associations between IRGM variants and TB outcomes.

Clinical Best Practices

• Interpret individual IRGM SNP findings cautiously because neither rs4958847 nor rs72553867 was significantly associated with TB outcomes when analyzed separately.

• Consider combined haplotypic or diplotype analyses in genetic susceptibility research because multi-variant approaches may capture associations not apparent in single-SNP analyses.

• Further research should validate findings in larger independent European populations and include broader IRGM sequencing, functional studies, gene-environment analyses, and longitudinal designs.

Related Resources & Content

• 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.

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

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

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

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