Log in

MYLK polymorphism associated with blood eosinophil level among asthmatic patients in a Korean population

  • Published:
Molecules and Cells

Abstract

The myosin light chain kinase (MYLK) gene encodes both smooth muscle and nonmuscle cell isoforms. Recently, polymorphisms in MYLK have been reported to be associated with several diseases. To examine the genetic effects of polymorphisms on the risk of asthma and related phenotypes, we scrutinized MYLK by re-sequencing/genoty** and statistical analysis in Korean population (n = 1,015). Seventeen common polymorphisms located in or near exons, having pairwise r 2 values less than 0.25, were genotyped. Our statistical analysis did not replicate the associations with the risk of asthma and log-transformed total IgE levels observed among African descendant populations. However, two SNPs in intron 16 (+89872C > G and +92263T >C), which were in tight LD (|D′| = 0.99), revealed significant association with log-transformed blood eosinophil level even after correction multiple testing (P = 0.002/Pcorr= 0.01 and P = 0.002/Pcorr = 0.01, respectively). The log-transformed blood eosinophil levels were higher in individuals bearing the minor alleles for +89872C > G and +92263T > C, than in those bearing other allele. In additional subgroup analysis, the genetic effects of both SNPs were much more apparent among asthmatic patients and atopic asthma patients. Among atopic asthma patients, the log-transformed blood eosinophil levels were proportionally increased by gene-dose dependent manner of in both +89872C > G and +92263T > C (P = 0.0002 and P = 0.00007, respectively). These findings suggest that MYLK polymorphisms might be among the genetic factors underlying differential increases of blood eosinophil levels among asthmatic patients. Further biological and/or functional studies are needed to confirm our results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adachi, T., Stafford, S., Kayaba, H., Chihara, J., and Alam, R. (2003). Myosin light chain kinase mediates eosinophil chemotaxis in a mitogen-activated protein kinase-dependent manner. J. Allergy Clin. Immunol. 111, 113–116.

    Article  PubMed  CAS  Google Scholar 

  • Ammit, A.J., Armour, C.L., and Black, J.L. (2000). Smooth-muscle myosin light-chain kinase content is increased in human sensitized airways. Am. J. Respir. Crit. Care Med. 161, 257–263.

    PubMed  CAS  Google Scholar 

  • Amsellem, S., Briffaut, D., Carrie, A., Rabes, J.P., Girardet, J.P., Fredenrich, A., Moulin, P., Krempf, M., Reznik, Y., Vialettes, B., et al. (2002). Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. Hum. Genet. 111, 501–510.

    Article  PubMed  CAS  Google Scholar 

  • Bochner, B.S., and Busse, W. (2005). Allergy and asthma. J. Allergy Clin. Immunol. 115, 953–959.

    Article  PubMed  Google Scholar 

  • Burrows, B., Martinez, F.D., Halonen, M., Barbee, R.A., and Cline, M.G. (1989). Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med. 320, 271–277.

    PubMed  CAS  Google Scholar 

  • Cardon, L.R., and Bell, J.I. (2001). Association study designs for complex diseases. Nat. Rev. Genet. 2, 91–99.

    Article  PubMed  CAS  Google Scholar 

  • Chae, S.C., Lee, Y.C., Park, Y.R., Shin, J.S., Song, J.H., Oh, G.J., Hong, S.T., Pae, H.O., Choi, B.M., and Chung, H.T. (2004). Analysis of the polymorphisms in eotaxin gene family and their association with asthma, IgE, and eosinophil. Biochem. Biophys. Res. Commun. 320, 131–137.

    Article  PubMed  CAS  Google Scholar 

  • Chen, Y., Rennie, D.C., Lockinger, L.A., and Dosman, J.A. (2005). Gender, environmental tobacco smoke, and pulmonary function in rural children and adolescents: the Humboldt study. J. Agric. Saf. Health 11, 167–173.

    PubMed  CAS  Google Scholar 

  • Cheong, H.S., Shin, H.D., Lee, S.O., Park, B.L., Choi, Y.H., Lim, G.I., Uh, S.T., Kim, Y.H., Lee, J.Y., Lee, J.K., et al. (2006). Polymorphisms in interleukin 8 and its receptors (IL8, IL8RA and IL8RB) and association of common IL8 receptor variants with peripheral blood eosinophil counts. J. Hum. Genet. 51, 781–787.

    Article  PubMed  CAS  Google Scholar 

  • Dudek, S.M., and Garcia, J.G. (2001). Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487–1500.

    PubMed  CAS  Google Scholar 

  • Flores, C., Ma, S.F., Maresso, K., Ober, C., and Garcia, J.G. (2007). A variant of the myosin light chain kinase gene is associated with severe asthma in African Americans. Genet. Epidemiol. 31, 296–305.

    Article  PubMed  Google Scholar 

  • Gao, L., Grant, A., Halder, I., Brower, R., Sevransky, J., Maloney, J.P., Moss, M., Shanholtz, C., Yates, C.R., Meduri, G.U., et al. (2006). Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am. J. Respir. Cell Mol. Biol. 34, 487–495.

    Article  PubMed  Google Scholar 

  • Gao, L., Grant, A.V., Rafaels, N., Stockton-Porter, M., Watkins, T., Gao, P., Chi, P., Munoz, M., Watson, H., Dunston, G., et al. (2007). Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma. J. Allergy Clin. Immunol. 119, 1111–1118.

    Article  PubMed  CAS  Google Scholar 

  • Garcia, J.G., Davis, H.W., and Patterson, C.E. (1995). Regulation of endothelial cell gap formation and barrier dysfunction: role of myosin light chain phosphorylation. J. Cell Physiol. 163, 510–522.

    Article  PubMed  CAS  Google Scholar 

  • Garcia, J.G., Verin, A.D., Herenyiova, M., and English, D. (1998). Adherent neutrophils activate endothelial myosin light chain kinase: role in transendothelial migration. J. Appl. Physiol. 84, 1817–1821.

    PubMed  CAS  Google Scholar 

  • Gilbert, W. (1978). Why genes in pieces? Nature 271, 501.

    Article  PubMed  CAS  Google Scholar 

  • Gonlugur, U., and Gonlugur, T.E. (2006). Non-allergic eosinophilic inflammation. Immunol. Invest. 35, 29–45.

    Article  PubMed  CAS  Google Scholar 

  • Haagerup, A., Bjerke, T., Schiotz, P.O., Binderup, H.G., Dahl, R., and Kruse, T.A. (2002). Asthma and atopy-a total genome scan for susceptibility genes. Allergy 57, 680–686.

    Article  PubMed  CAS  Google Scholar 

  • Hedrick, P.W. (1987). Gametic disequilibrium measures: proceed with caution. Genetics 117, 331–341.

    PubMed  CAS  Google Scholar 

  • Kamm, K.E., and Stull, J.T. (2001). Dedicated myosin light chain kinases with diverse cellular functions. J. Biol. Chem. 276, 4527–4530.

    Article  PubMed  CAS  Google Scholar 

  • Karjalainen, J., Hulkkonen, J., Nieminen, M.M., Huhtala, H., Aromaa, A., Klaukka, T., and Hurme, M. (2003). Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma. Clin. Exp. Allergy 33, 78–83.

    Article  PubMed  CAS  Google Scholar 

  • King, K., Flinter, F.A., Nihalani, V., and Green, P.M. (2002). Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum. Genet. 111, 548–554.

    Article  PubMed  CAS  Google Scholar 

  • Kurz, T., Altmueller, J., Strauch, K., Ruschendorf, F., Heinzmann, A., Moffatt, M.F., Cookson, W.O., Inacio, F., Nurnberg, P., Stassen, H.H., et al. (2005). A genome-wide screen on the genetics of atopy in a multiethnic European population reveals a major atopy locus on chromosome 3q21.3. Allergy 60, 192–199.

    Article  PubMed  CAS  Google Scholar 

  • Lazar, V., and Garcia, J.G. (1999). A single human myosin light chain kinase gene (MLCK; MYLK). Genomics 57, 256–267.

    Article  PubMed  CAS  Google Scholar 

  • Lee, J.H., Chang, H.S., Kim, J.H., Park, S.M., Lee, Y.M., Uh, S.T., Rhim, T., Chung, I.Y., Kim, Y.H., Park, B.L., et al. (2007). Genetic effect of CCR3 and IL5RA gene polymorphisms on eosinophilia in asthmatic patients. J. Allergy Clin. Immunol. 120, 1110–1117.

    Article  PubMed  CAS  Google Scholar 

  • Lohmueller, K.E., Pearce, C.L., Pike, M., Lander, E.S., and Hirschhorn, J.N. (2003). Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182.

    Article  PubMed  CAS  Google Scholar 

  • Ma, X., Cheng, Z., Kong, H., Wang, Y., Unruh, H., Stephens, N.L., and Laviolette, M. (2002). Changes in biophysical and biochemical properties of single bronchial smooth muscle cells from asthmatic subjects. Am. J. Physiol. Lung Cell Mol. Physiol. 283, L1181–1189.

    PubMed  CAS  Google Scholar 

  • Makridakis, N.M., and Reichardt, J.K. (2001). Multiplex automated primer extension analysis: simultaneous genoty** of several polymorphisms. Biotechniques 31, 1374–1380.

    PubMed  CAS  Google Scholar 

  • Min, W.K., Lim, H., Lee, Y.P., Sung, S.K., Kim, B.D., and Kim, S. (2008). Identification of a third haplotype of the sequence linked to the Restorer-of-fertility (Rf) gene and its implications for male-sterility phenotypes in peppers (Capsicum annuum L.). Mol. Cells 25, 20–29.

    PubMed  CAS  Google Scholar 

  • Namkung, J.H., Lee, J.E., Kim, E., Cho, H.J., Kim, S., Shin, E.S., Cho, E.Y., and Yang, J.M. (2007). IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in Koreans. Allergy 62, 934–942.

    Article  PubMed  CAS  Google Scholar 

  • Nyholt, D.R. (2004). A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet. 74, 765–769.

    Article  PubMed  CAS  Google Scholar 

  • Ober, C. (2005). Perspectives on the past decade of asthma genetics. J. Allergy Clin. Immunol. 116, 274–278.

    Article  PubMed  CAS  Google Scholar 

  • Parker, J.C. (2000). Inhibitors of myosin light chain kinase and phosphodiesterase reduce ventilator-induced lung injury. J. Appl. Physiol. 89, 2241–2248.

    PubMed  CAS  Google Scholar 

  • Petrache, I., Verin, A.D., Crow, M.T., Birukova, A., Liu, F., and Garcia, J.G. (2001). Differential effect of MLC kinase in TNF-alpha-induced endothelial cell apoptosis and barrier dysfunction. Am. J. Physiol. Lung Cell Mol. Physiol. 280, L1168–1178.

    PubMed  CAS  Google Scholar 

  • Schaid, D.J., Rowland, C.M., Tines, D.E., Jacobson, R.M., and Poland, G.A. (2002). Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J. Hum. Genet. 70, 425–434.

    Article  PubMed  Google Scholar 

  • Sublett, J.L. (2005). The environment and risk factors for atopy. Curr. Allergy Asthma Rep. 5, 445–450.

    Article  PubMed  Google Scholar 

  • Tattersfield, A.E., Knox, A.J., Britton, J.R., and Hall, I.P. (2002). Asthma Lancet 360, 1313–1322.

    Article  CAS  Google Scholar 

  • Wainwright, M.S., Rossi, J., Schavocky, J., Crawford, S., Steinhorn, D., Velentza, A.V., Zasadzki, M., Shirinsky, V., Jia, Y., Haiech, J., et al. (2003). Protein kinase involved in lung injury susceptibility: evidence from enzyme isoform genetic knockout and in vivo inhibitor treatment. Proc. Natl. Acad. Sci. USA 100, 6233–6238.

    Article  PubMed  CAS  Google Scholar 

  • Watterson, D.M., Schavocky, J.P., Guo, L., Weiss, C., Chlenski, A., Shirinsky, V.P., Van Eldik, L.J., and Haiech, J. (1999). Analysis of the kinase-related protein gene found at human chromosome 3q21 in a multi-gene cluster: organization, expression, alternative splicing, and polymorphic marker. J. Cell. Biochem. 75, 481–491.

    Article  PubMed  CAS  Google Scholar 

  • Weller, P.F. (1994). Eosinophils: structure and functions. Curr. Opin. Immunol. 6, 85–90.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Choon-Sik Park or Hyoung Doo Shin.

About this article

Cite this article

Lee, S.O., Cheong, H.S., Park, B.L. et al. MYLK polymorphism associated with blood eosinophil level among asthmatic patients in a Korean population. Mol Cells 27, 175–181 (2009). https://doi.org/10.1007/s10059-009-0022-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-009-0022-2

Keywords

Navigation