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

Abstract

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 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 1014 Caucasians who did not.Measurements and results-We genotyped the (GT)n polymorphism and three tagging single nucleotide polymorphisms (tSNPs) in 1451 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.

Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1

“…Individual susceptibility varies greatly (i.e., patients presenting with the same severity score can have markedly different clinical outcomes) (13). For this reason, studies have begun to investigate the role of genetics in determining survival during acute lung injury (14)(15)(16)(17). However, because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to case-control studies that evaluate candidate genes associations.…”

Haem oxygenase-1 polymorphism and ARDS, friend and foe?

“…However, evidence suggests HO-1 might function within a tight physiological range, under-expression and over-expression being deleterious and associated with increased mortality in critically ill patients [13]. In the current study, expression of long repeats was associated with protection from ARDS [10]. This fits within the model of HMOX1 expression as others have shown long repeats to equate to lower expression of HMOX1, which in turn would imply less release of potentially reactive iron during haem catabolism [12].…”

“…Further, the assignment of (GT)n repeat lengths into grouped alleles has previously been arbitrary and has been determined mainly through biological reasoning [7]. However, the current authors have employed a mathematical model with sensitivity analysis to assign best-fit allele-grouping criteria for the development of ARDS [10]. This highlights the necessity of investigating (GT)n repeat function.…”

“…The paper by Sheu et al [10] in this edition of the journal furthers our knowledge of this complex area by investigating the hypothesis that polymorphisms in HMOX1 could influence susceptibility to ARDS. Employing an unmatched case-controlled design nested within a prospective cohort of at-risk patients and minimising population stratification by limiting the study to Caucasians, the authors found a trend for longer HMOX1 (GT)n repeats to be associated with a reduced risk of developing ARDS.…”

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

“…Individual susceptibility varies greatly, with patients presenting with the same severity score having markedly different clinical outcomes (6). For this reason, studies have begun to investigate the role of genetics in determining survival during ALI (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”