HMOX1 – Heme Oxygenase-1 and Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder characterized by irreversible airflow limitation and progressive inflammation. HMOX1 encodes heme oxygenase-1, an inducible enzyme that catabolizes heme into biliverdin, carbon monoxide, and iron, playing a critical antioxidant role in the lung. Polymorphisms in the HMOX1 promoter, notably the GT-repeat length variant, have been investigated as modifiers of COPD susceptibility.

1. Clinical Validity (Limited)

Multiple family-based and case-control studies have assessed HMOX1 promoter variants in COPD cohorts but lacked consistent replication across designs. The (GT)31 allele was associated with COPD phenotypes in a Boston family study (n = 29 polymorphisms; P = 0.02) (PMID:15817713) and in a Taiwanese cohort (n = 200 patients; P < 0.05) (PMID:25268359). A meta-analysis of 63 publications encompassing 14,733 COPD cases and 50,570 controls confirmed a modest risk increase for the long GT alleles under dominant models (PMID:37817181). However, several studies failed to replicate these associations or survive multiple testing correction (PMID:21902835).

2. Genetic Evidence (Limited)

Inheritance of COPD is polygenic and non-Mendelian. No rare coding variants in HMOX1 have been shown to segregate with COPD in families. Common promoter polymorphisms, particularly the (GT)n repeat length (> 32 repeats), have been associated with disease risk in case-control settings (dominant model OR = 1.91) (PMID:25268359) and meta-analysis (Venice criteria Grade C) (PMID:37817181). No founder or recurrent coding variants have been reported in COPD populations.

3. Functional Evidence (Limited)

Reporter gene assays for HMOX1 promoter constructs carrying the (GT)n and rs2071746 variants demonstrated no consistent difference in inducible expression under oxidative stimuli in alveolar macrophages (PMID:21902835). The functional impact of GT-repeat length on mRNA or protein levels in lung tissue remains inconclusive. No in vivo COPD-relevant animal models or rescue experiments have been reported to date.

4. Conflicting Evidence

Several studies reported nominal associations that did not withstand correction for multiple comparisons (PMID:21902835). Discrepant protective vs. risk effects of long GT repeats have been observed across ethnicities, indicating potential publication bias and heterogeneity.

5. Integration & Conclusion

While HMOX1 promoter polymorphisms have been implicated in oxidative stress responses relevant to COPD pathogenesis, the current genetic and functional data are inconsistent and insufficient for clinical utility. Larger, well-powered replication studies and mechanistic in vivo models are needed.

Key Take-home: HMOX1 promoter GT-repeat polymorphisms may modulate COPD risk via oxidative stress pathways, but evidence remains limited and not yet actionable in diagnostics.

References

• American journal of respiratory cell and molecular biology | 2005 | Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. PMID:15817713
• PloS one | 2014 | Microsatellite polymorphism in the heme oxygenase-1 gene promoter and the risk of atrial fibrillation in Taiwanese. PMID:25268359
• BMC pulmonary medicine | 2023 | Association between the oxidative stress gene polymorphism and chronic obstructive pulmonary disease risk: a meta-analysis. PMID:37817181
• BMC medical genetics | 2011 | Effect of heme oxygenase-1 polymorphisms on lung function and gene expression. PMID:21902835

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