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

Chau Chyun Sheu, Rihong Zhai, Zhaoxi Wang, Michelle Ng Gong, Paula Tejera, Feng Chen, Li Su, B. Taylor Thompson, David C. Christiani

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1343-1351
Number of pages9
JournalIntensive Care Medicine
Volume35
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

Fingerprint

Heme Oxygenase-1
Adult Respiratory Distress Syndrome
Microsatellite Repeats
Haplotypes
Alleles
Single Nucleotide Polymorphism
Genotype
Cytoprotection
Acute Lung Injury
Case-Control Studies

Keywords

  • Acute respiratory distress syndrome
  • Genetic susceptibility
  • Haplotypes
  • Heme oxygenase-1
  • Microsatellite polymorphism
  • Molecular epidemiology

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Heme Oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome. / Sheu, Chau Chyun; Zhai, Rihong; Wang, Zhaoxi; Gong, Michelle Ng; Tejera, Paula; Chen, Feng; Su, Li; Thompson, B. Taylor; Christiani, David C.

In: Intensive Care Medicine, Vol. 35, No. 8, 08.2009, p. 1343-1351.

Research output: Contribution to journalArticle

Sheu, Chau Chyun ; Zhai, Rihong ; Wang, Zhaoxi ; Gong, Michelle Ng ; Tejera, Paula ; Chen, Feng ; Su, Li ; Thompson, B. Taylor ; Christiani, David C. / Heme Oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome. In: Intensive Care Medicine. 2009 ; Vol. 35, No. 8. pp. 1343-1351.
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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 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.",
keywords = "Acute respiratory distress syndrome, Genetic susceptibility, Haplotypes, Heme oxygenase-1, Microsatellite polymorphism, Molecular epidemiology",
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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 Ng

AU - Tejera, Paula

AU - Chen, Feng

AU - Su, Li

AU - Thompson, B. Taylor

AU - Christiani, David C.

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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