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.


METHODS
Unmatched, nested case-control study.


METHODS
Academic medical center.


METHODS
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.


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 (> or = 31 repeats). We found that longer (GT)n repeats were associated with reduced ARDS risk (Ptrend = 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 (Ptrend = 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.
Sheu
Chau-Chyun
CC
Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Zhai
Rihong
R
Wang
Zhaoxi
Z
Gong
Michelle N
MN
Tejera
Paula
P
Chen
Feng
F
Su
Li
L
Thompson
B Taylor
BT
Christiani
David C
DC
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003422:Critical Care; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D051547:Heme Oxygenase-1 / Q000097:blood / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D017720:Molecular Epidemiology; D011110:Polymorphism, Genetic / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000235:genetics* / Q000503:physiopathology; D012307:Risk Factors
C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1