Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma

• Published in: Journal of allergy and clinical immunology 2007-05, Vol.119 (5), p.1111-1118
• Main Authors: Gao, Li, MD, PhD, Grant, Audrey V., MS, Rafaels, Nicholas, MS, Stockton-Porter, Maria, MA, Watkins, Tonya, BS, Gao, Peisong, MD, PhD, Chi, Peter, MS, Muñoz, Melba, MD, Watson, Harold, MD, Dunston, Georgia, PhD, Togias, Alkis, MD, Hansel, Nadia, MD, Sevransky, Jonathan, MD, Maloney, James P., MD, Moss, Marc, MD, Shanholtz, Carl, MD, Brower, Roy, MD, Garcia, Joe G.N., MD, Grigoryev, Dmitry N., PhD, Cheadle, Christopher, PhD, Beaty, Terri H., PhD, Mathias, Rasika A., ScD, Barnes, Kathleen C., PhD
• Format: Article
• Language: English
• Subjects: African Americans; African Americans - genetics; African Continental Ancestry Group - genetics; ALI; Allergy and Immunology; Amino acids; asthma; Asthma - genetics; Biological and medical sciences; Caribbean Region; Disease; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Genetic Predisposition to Disease; Genotype & phenotype; haplotype; Haplotypes; Humans; Hypotheses; Immunopathology; Kinases; Male; Medical sciences; Muscular system; MYLK/MLCK; Myosin-Light-Chain Kinase - genetics; Phosphorylation; Polymorphism, Single Nucleotide; Risk Factors; Sepsis; Sepsis - genetics; Smooth muscle; SNPs; total IgE
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2007.03.019

Background Myosin light chain kinase (MYLK) is a multifunctional protein involved in regulation of airway hyperreactivity and other activities relevant to asthma. Objective To determine the role of MYLK gene variants in asthma among African Caribbean and African American populations. Methods We performed association tests between single nucleotide polymorphisms (SNPs) in the MYLK gene and asthma susceptibility and total serum IgE concentrations in 2 independent, family-based populations of African descent. Previously we identified variants/haplotypes in MYLK that confer risk for sepsis and acute lung injury; we compared findings from our asthma populations to findings in the African American sepsis and acute lung injury groups. Results Significant associations between MYLK SNPs and asthma and total serum IgE concentrations were observed in the African Caribbean families: a promoter SNP (rs936170) in the smooth muscle form gave the strongest association ( P = .009). A haplotype including rs936170 corresponding to the actin-binding activity of the nonmuscle and smooth muscle forms was negatively associated with asthma (eg, decreased risk) in both the American ( P = .005) and Caribbean families ( P = .004), and was the same haplotype that conferred risk for severe sepsis ( P = .002). RNA expression studies on PBMCs and rs936170 suggested a significant decrease in MYLK expression among patients with asthma with this variant ( P = .025). Conclusion MYLK polymorphisms may function as a common genetic factor in clinically distinct diseases involving bronchial smooth muscle contraction and inflammation. Clinical implications Genetic variants in MYLK are significantly associated with both asthma and sepsis in populations of African ancestry.