TY - JOUR
T1 - Heme Oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome
AU - Sheu, Chau Chyun
AU - Zhai, Rihong
AU - Wang, Zhaoxi
AU - Gong, Michelle N.
AU - Tejera, Paula
AU - Chen, Feng
AU - Su, Li
AU - Thompson, B. Taylor
AU - Christiani, David C.
N1 - Funding Information:
Acknowledgments This study was supported by grants HL60710 and ES00002 from National Institutes of Health, USA. The authors would like to thank Weiling Zhang, Kelly McCoy, Thomas McC-abe, Julia Shin, and Hanae Fujii-Rios for patient recruitment; Andrea Shafer and Starr Sumpter for research support; Maureen Convery for laboratory expertise; Janna Frelich for data management; and the patients and staff of ICUs at Massachusetts General Hospital.
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
KW - Acute respiratory distress syndrome
KW - Genetic susceptibility
KW - Haplotypes
KW - Heme oxygenase-1
KW - Microsatellite polymorphism
KW - Molecular epidemiology
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U2 - 10.1007/s00134-009-1504-6
DO - 10.1007/s00134-009-1504-6
M3 - Article
C2 - 19526221
AN - SCOPUS:67650995464
SN - 0342-4642
VL - 35
SP - 1343
EP - 1351
JO - Intensive Care Medicine
JF - Intensive Care Medicine
IS - 8
ER -