Association between variants in the gene encoding myosin light chain kinase (MLCK) and asthma and atopy

Abstract Rationale Asthma is characterized by lower airway smooth muscle contraction. Smooth muscle contractility is regulated by pathways involving the phosphorylation of myosin light chain 20 by myosin light chain kinase (MLCK), an enzyme whose expression has been observed to be augmented in severe asthmatics compared to milder patients. Recently we identified 19 single nucleotide polymorphisms (SNPs) in the NH 2 -terminus of the human endothelial cell MLCK gene, three of which lead to an amino acid change (c.36C>A, c.439T>C, c.797C>T). The present study tested for the presence of linkage disequilibrium (LD) between each of these three MLCK polymorphisms and the asthma phenotype as well as total serum IgE (tIgE) levels in a family-based study of asthma in Barbados. Methods Genomic DNA was extracted from peripheral blood samples of 743 subjects (in 125 pedigrees) and screened for the MLCK SNPs using PCR-based restriction enzyme assays. The Family-Based Association Test was used to assess association in the presence of linkage. Results We found evidence for linkage and disequilibrium to both asthma and an apparent quantitative trait locus (QTL) controlling tIgE levels for all 3 SNPs. When analyzing asthma itself, the heterozygous genotype was more common than expected under the null hypothesis, suggesting this genotype is at higher risk. When tIgE levels were examined, the heterozygotes showed higher tIgE than expected under a co-dominant model ( P ≤0.001). Conclusions These findings suggest a role for variants in the endothelial cell MLCK gene in a sample of multiplex asthmatic families from Barbados.