Objective:

To investigate whether 2 intronic immunity-related GTPase M (IRGM) single-nucleotide polymorphisms (SNPs), rs4958847 and rs72553867, individually or in combination, are associated with tuberculosis (TB) disease and/or TB infection (TBI) in a European population.

Approach:

• Study Design: An unmatched case-control study was conducted at the National Institute of Infectious Diseases L. Spallanzani-IRCCS in Rome, Italy. Enrollment occurred from 2015 through 2020.
• Participants: The analysis included patients with TB disease, individuals with TBI, and TB-free controls, all residing in Italy at enrollment. TB disease was defined by microbiological confirmation or clinical diagnosis based on radiological and clinical criteria and response to anti-TB treatment; TBI and TB-free status were defined using QuantiFERON-TB Gold Plus testing and other clinical criteria.
• SNP Analysis: Genomic DNA extracted from peripheral blood mononuclear cells was analyzed for IRGM rs72553867 and rs4958847 using real-time polymerase chain reaction–based allele-specific TaqMan assays. Logistic regression evaluated associations of individual SNPs and rs4958847-rs72553867 diplotypes with TB outcomes.

Key Findings:

• Of 709 enrolled participants, 644 with complete data were included: 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.
• In diplotype analysis, 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).
• The GG-AC diplotype was also associated with higher odds in the combined TB disease/TBI group compared with TB-free controls in unadjusted analysis (OR, 2.06; 95% CI, 1.01-4.20; P = .047), but it was not significantly associated in the TB disease vs TBI or TBI vs TB-free comparisons.

Interpretation:

Although neither IRGM variant showed an individual association with TB outcomes, the GG-AC diplotype showed a potentially relevant association with TB disease. The authors suggest that combined haplotypic information may capture susceptibility that is not evident from single-variant analyses and that IRGM effects may be population- and disease-specific.

Limitations:

• The cross-sectional design precluded longitudinal assessment.
• Analysis of only 2 SNPs provided limited coverage of the IRGM locus.
• Sample sizes for stratified analyses, particularly within the GG-AC diplotype, limited statistical power.
• IRGM expression was not assessed, so the functional basis of the observed diplotype association could not be determined.

Conclusion:

The 2 individual IRGM SNPs were not associated with TB outcomes, but combined diplotype analysis identified a potential association between the GG-AC diplotype and TB disease in this European population. The authors conclude that further work should include validation in larger independent European populations, broader IRGM sequencing, functional studies, investigation of gene-environment interactions, and longitudinal designs.