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

Christie, Jason D. MD, MS; Ma, Shwu-Fan PhD; Aplenc, Richard MD, MS; Li, Mingyao PhD; Lanken, Paul N. MD; Shah, Chirag V. MD; Fuchs, Barry MD; Albelda, Steven M. MD; Flores, Carlos PhD; Garcia, Joe G. N. MD

doi: 10.1097/CCM.0b013e318186b843
Clinical Investigations
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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.

From the Division of Pulmonary, Allergy, and Critical Care Medicine (JDC, PNL, CVS, BF, SMA), Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Biostatistics and Epidemiology (JDC, RA, ML, CVS), University of Pennsylvania School of Medicine, Philadelphia, PA; Section of Pulmonary and Critical Care Medicine (S-FM, CF, JGNG), Department of Medicine, University of Chicago School of Medicine, Chicago, IL; and Division of Oncology (RA), Children’s Hospital of Philadelphia, Philadelphia, PA.

Supported in part by P50HL60290 (JDC), HL079063 (JDC), and HL58064 (JGNG).

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: jchristi@cceb.med.upenn.edu

© 2008 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins