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

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. Unmatched, nested case-control study. Academic medical center. 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. 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 (a parts per thousand yen31 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). 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.