Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma

Jason D. Christie, Shwu Fan Ma, Richard Aplenc, Mingyao Li, Paul N. Lanken, Chirag V. Shah, Barry Fuchs, Steven M. Albelda, Carlos Flores, Joe GN Garcia

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients. METHODS: We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score ≥16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2-5 single nucleotide polymorphisms were conducted. RESULTS: Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio ≤ 1.87, 95% confidence interval 1.06-3.33; p ≤ 0.022) and Pro147Ser (TT, odds ratio ≤ 2.13, 95% confidence interval 1.14-4.10; p ≤ 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio ≤ 0.42, 95% confidence interval 0.20-0.85; p ≤ 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2-4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008). CONCLUSIONS: Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis.

Original languageEnglish (US)
Pages (from-to)2794-2800
Number of pages7
JournalCritical Care Medicine
Volume36
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

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Myosin-Light-Chain Kinase
Acute Lung Injury
Single Nucleotide Polymorphism
Wounds and Injuries
Genes
Genotype
African Americans
Haplotypes
Sepsis
Injury Severity Score
Odds Ratio
Confidence Intervals
Asthma
Logistic Models
Transendothelial and Transepithelial Migration
APACHE
Capillary Permeability
Protein Isoforms
Leukocytes
Cohort Studies

Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Genetic polymorphisms
  • Haplotypes
  • Myosin light chain kinase

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma. / Christie, Jason D.; Ma, Shwu Fan; Aplenc, Richard; Li, Mingyao; Lanken, Paul N.; Shah, Chirag V.; Fuchs, Barry; Albelda, Steven M.; Flores, Carlos; Garcia, Joe GN.

In: Critical Care Medicine, Vol. 36, No. 10, 10.2008, p. 2794-2800.

Research output: Contribution to journalArticle

Christie, JD, Ma, SF, Aplenc, R, Li, M, Lanken, PN, Shah, CV, Fuchs, B, Albelda, SM, Flores, C & Garcia, JGN 2008, 'Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma', Critical Care Medicine, vol. 36, no. 10, pp. 2794-2800. https://doi.org/10.1097/CCM.0b013e318186b843
Christie, Jason D. ; Ma, Shwu Fan ; Aplenc, Richard ; Li, Mingyao ; Lanken, Paul N. ; Shah, Chirag V. ; Fuchs, Barry ; Albelda, Steven M. ; Flores, Carlos ; Garcia, Joe GN. / Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma. In: Critical Care Medicine. 2008 ; Vol. 36, No. 10. pp. 2794-2800.
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abstract = "BACKGROUND: Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients. METHODS: We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score ≥16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2-5 single nucleotide polymorphisms were conducted. RESULTS: Ninety-one of the 273 subjects (33{\%}) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio ≤ 1.87, 95{\%} confidence interval 1.06-3.33; p ≤ 0.022) and Pro147Ser (TT, odds ratio ≤ 2.13, 95{\%} confidence interval 1.14-4.10; p ≤ 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio ≤ 0.42, 95{\%} confidence interval 0.20-0.85; p ≤ 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2-4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008). CONCLUSIONS: Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis.",
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T1 - Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma

AU - Christie, Jason D.

AU - Ma, Shwu Fan

AU - Aplenc, Richard

AU - Li, Mingyao

AU - Lanken, Paul N.

AU - Shah, Chirag V.

AU - Fuchs, Barry

AU - Albelda, Steven M.

AU - Flores, Carlos

AU - Garcia, Joe GN

PY - 2008/10

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N2 - BACKGROUND: Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients. METHODS: We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score ≥16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2-5 single nucleotide polymorphisms were conducted. RESULTS: Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio ≤ 1.87, 95% confidence interval 1.06-3.33; p ≤ 0.022) and Pro147Ser (TT, odds ratio ≤ 2.13, 95% confidence interval 1.14-4.10; p ≤ 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio ≤ 0.42, 95% confidence interval 0.20-0.85; p ≤ 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2-4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008). CONCLUSIONS: Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis.

AB - BACKGROUND: Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients. METHODS: We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score ≥16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2-5 single nucleotide polymorphisms were conducted. RESULTS: Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio ≤ 1.87, 95% confidence interval 1.06-3.33; p ≤ 0.022) and Pro147Ser (TT, odds ratio ≤ 2.13, 95% confidence interval 1.14-4.10; p ≤ 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio ≤ 0.42, 95% confidence interval 0.20-0.85; p ≤ 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2-4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008). CONCLUSIONS: Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis.

KW - Acute lung injury

KW - Acute respiratory distress syndrome

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KW - Haplotypes

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