This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2005-0404OCv1 34/4/487    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gao, L. Articles by Garcia, J. G. N. Search for Related Content PubMed PubMed Citation Articles by Gao, L. Articles by Garcia, J. G. N.

Novel Polymorphisms in the Myosin Light Chain Kinase Gene Confer Risk for Acute Lung Injury

Division of Pulmonary and Critical Care Medicine and the Center for Translational Respiratory Medicine, Bayview Medical Center Genetic and Genomic Research Facility, Department of Epidemiology, The Genetic Resources Core Facility, Johns Hopkins University, and University of Maryland School of Medicine, Baltimore, Maryland; Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Pulmonary and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia; University of Tennessee, Memphis, Tennessee; and Department of Anthropology, Penn State University, State College, Pennsylvania

Correspondence and requests for reprints should be addressed to Joe G. N. Garcia, M.D., Chairman, Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637. E-mail: jgarcia{at}medicine.bsd.uchicago.edu

The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon–intron boundaries, and 2 kb of 5' UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P < 0.001), with an additional SNP associated with the ALI phenotype (P = 0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P = 0.002) and with ALI (P = 0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P < 0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5' of the MYLK gene in both European and African Americans and an additional 3' region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI.

Key Words: MYLK/MLCK • genetic association • SNP • ALI • sepsis

This article has been cited by other articles:

				L. Gao and K. C. Barnes Recent advances in genetic predisposition to clinical acute lung injury Am J Physiol Lung Cell Mol Physiol, May 1, 2009; 296(5): L713 - L725. [Abstract] [Full Text] [PDF]

				M. M. Wurfel, A. C. Gordon, T. D. Holden, F. Radella, J. Strout, O. Kajikawa, J. T. Ruzinski, G. Rona, R. A. Black, S. Stratton, et al. Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 710 - 720. [Abstract] [Full Text] [PDF]

				R. Kamp, X. Sun, and J. G. N. Garcia Making Genomics Functional: Deciphering the Genetics of Acute Lung Injury Proceedings of the ATS, April 15, 2008; 5(3): 348 - 353. [Abstract] [Full Text] [PDF]

				A. L. Lagan, D. D. Melley, T. W. Evans, and G. J. Quinlan Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L161 - L174. [Abstract] [Full Text] [PDF]

				S. A. Nonas, L. M. Vinasco, S. F. Ma, J. R. Jacobson, A. A. Desai, S. M. Dudek, C. Flores, P. M. Hassoun, L. Sam, S. Q. Ye, et al. Use of consomic rats for genomic insights into ventilator-associated lung injury Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L292 - L302. [Abstract] [Full Text] [PDF]

				N. J. Meyer and J. G. N. Garcia Wading into the Genomic Pool to Unravel Acute Lung Injury Genetics Proceedings of the ATS, January 1, 2007; 4(1): 69 - 76. [Abstract] [Full Text] [PDF]

				J. G. N. Garcia and L. Moreno Vinasco Genomic insights into acute inflammatory lung injury Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1113 - L1117. [Abstract] [Full Text] [PDF]