Rationale Acute lung injury (ALI) is a life-threatening syndrome with both susceptibility and outcome known to be influenced by genetic factors. Nonmuscle myosin light chain kinase (nmMLCK) encoded by the MYLK gene is a cytoskeleton protein involved in the endothelial cell barrier regulation and in the inflammatory response. We have reported the association of MYLK variants with susceptibility to sepsis-induced ALI in African and European Americans (AJRCMB 2006;34:487). Here we tested the association of MYLK variants in ALI patients from Spain.
Methods DNA samples of 96 controls and 80 patients with severe septics were obtained from a Spanish ICU Network. Using TaqMan assays, we first genotyped 16 SNPs selected from our previous report and assessed individual SNPs and haplotype association by Armitage tests and a sliding-window approach, respectively. A new set of nine tagging SNPs (tSNPs) were further selected from the strongest associated region based on the HapMap and data were similarly analyzed.
Results Significant association was observed with an SNP (p = .027) previously associated with sepsis and ALI in European Americans with exploratory haplotype analysis of the first 16 SNPs identifying the strongest association (p = .01) in the specific region encoding the nmMLCK N-terminus. The additional nine tSNPs selected from this region and the 4 kb region upstream reinforced the association of the 5′ end of the gene (N-terminus) with susceptibility to ALI (permuted p = .027).
Conclusions Our haplotype analyses confirm that MYLK gene variants are associated with ALI in a well-phenotyped replicate population. A fine map genotyping with tSNPs has allowed us to identify a novel region of MYLK associated with ALI, which may be useful to delineate a smaller region for further functional studies of these susceptibility variants.
Funded by Specialized Centers of Clinically Oriented Research P50 HL-073994.