Heme Oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome

Objective: Heme oxygenase-1 (HO-1) acts in cytoprotection against acute lung injury. The polymorphic (GT) _n repeat in the HO-1 gene (HMOX1) promoter regulates HMOX1 expression. We investigated the associations of HMOX1 polymorphisms with acute respiratory distress syndrome (ARDS) risk and plasma HO-1 levels. Design: Unmatched, nested case-control study. Setting: Academic medical center. Patients: Consecutive patients with ARDS risk factors upon ICU admission were prospectively enrolled. Cases were 437 Caucasians who developed ARDS and controls were 1,014 Caucasians who did not. Measurements and results: We genotyped the (GT) _n polymorphism and three tagging single nucleotide polymorphisms (tSNPs) in 1,451 patients, and measured the plasma HO-1 levels in 106 ARDS patients. We clustered the (GT) _n repeats into: S-allele (<24 repeats), M-allele (24-30 repeats) and L-allele (≥31 repeats). We found that longer (GT) _n repeats were associated with reduced ARDS risk (P _trend = 0.004 for both alleles and genotypes), but no individual tSNP was associated with ARDS risk. HMOX1 haplotypes were significantly associated with ARDS risk (global test, P = 0.016), and the haplotype S-TAG was associated with increased ARDS risk (OR, 1.75; 95% CI, 1.15-2.68; P = 0.010). Intermediate-phenotype analysis showed longer (GT) _n repeats were associated with higher plasma HO-1 levels (P _trend = 0.019 for alleles and 0.027 for genotypes). Conclusions: Longer (GT) _n repeats in the HMOX1 promoter are associated with higher plasma HO-1 levels and reduced ARDS risk. The common haplotype S-TAG is associated with increased ARDS risk. Our results suggest that HMOX1 variation may modulate ARDS risk through the promoter microsatellite polymorphism.