Published ahead of print on January 6, 2006, doi:10.1165/rcmb.2005-0404OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 4, April 2006, 487-495 A more recent version of this article appeared on April 1, 2006
Submitted on October 28, 2005 Novel Polymorphisms in the Myosin Light Chain Kinase Gene Confer Risk for Acute Lung InjuryLi Gao1,1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Center for Translational Respiratory Medicine, Baltimore, MD, USA, 2 Johns Hopkins University, Bayview Medical Center Genetic and Genomic Research Facility, Baltimore, MD, USA, 3 Department of Anthropology, Penn State University, State College, State College, PA, USA, 4 Medical College of Wisconsin, Milwaukee, WI, USA, 5 Emory University School of Medicine, Atlanta, GA, USA, 6 University of Maryland School of Medicine, Baltimore, MD, USA, 7 University of Tennessee, Memphis, TN, USA, 8 Johns Hopkins University, The Genetic Resources Core Facility, Baltimore, MD, USA, 9 Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA * To whom correspondence should be addressed. 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 non-muscle 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 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, sepsis-associated ALI or healthy controls and a sample population of 158 African American subjects with sepsis and ALI. Significant single locus associations in EAs were observed between 4 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 EA subjects) was observed in African Americans (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 a 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.
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