Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

MYLK Polymorphism Associated with Blood Eosinophil Level among Asthmatic Patients in a Korean Population

  • Lee, Soo Ok (Department of Genetic Epidemiology, SNP Genetics, Inc.) ;
  • Cheong, Hyun Sub (Department of Genetic Epidemiology, SNP Genetics, Inc.) ;
  • Park, Byung Lae (Department of Genetic Epidemiology, SNP Genetics, Inc.) ;
  • Bae, Joon Seol (Department of Life Science, Sogang University) ;
  • Sim, Won Chul (Department of Life Science, Sogang University) ;
  • Chun, Ji-Yong (Department of Life Science, Sogang University) ;
  • Isbat, Mohammad (Department of Life Science, Sogang University) ;
  • Uh, Soo-Taek (Asthma Genome Research Group (Soonchunhyang University Bucheon, Seoul, and Chunan Hospitals), Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital) ;
  • Kim, Yong Hooun (Asthma Genome Research Group (Soonchunhyang University Bucheon, Seoul, and Chunan Hospitals), Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital) ;
  • Jang, An-Soo (Asthma Genome Research Group (Soonchunhyang University Bucheon, Seoul, and Chunan Hospitals), Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital) ;
  • Park, Choon-Sik (Asthma Genome Research Group (Soonchunhyang University Bucheon, Seoul, and Chunan Hospitals), Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital) ;
  • Shin, Hyoung Doo (Department of Genetic Epidemiology, SNP Genetics, Inc.)
  • Received : 2008.08.22
  • Accepted : 2008.11.25
  • Published : 2009.02.28
⟨ Previous Next ⟩

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/genotyping 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 ($P=0.002/P^{corr}=0.01$ and $P=0.002/P^{corr}=0.01$, 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.

Keywords

Acknowledgement

Supported by : Ministry of Health and Welfare, Korean Ministry of Education and Human Resources Development

References

  1. 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 https://doi.org/10.1067/mai.2003.27
  2. 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 https://doi.org/10.1164/ajrccm.161.1.9901005
  3. 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 https://doi.org/10.1007/s00439-002-0813-4
  4. Bochner, B.S., and Busse, W. (2005). Allergy and asthma. J. Allergy Clin. Immunol. 115, 953-959 https://doi.org/10.1016/j.jaci.2005.02.032
  5. 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 https://doi.org/10.1056/NEJM198902023200502
  6. Cardon, L.R., and Bell, J.I. (2001). Association study designs for complex diseases. Nat. Rev. Genet. 2, 91-99 https://doi.org/10.1038/35052543
  7. 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 https://doi.org/10.1016/j.bbrc.2004.05.136
  8. 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 https://doi.org/10.13031/2013.18183
  9. 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 https://doi.org/10.1007/s10038-006-0021-5
  10. Dudek, S.M., and Garcia, J.G. (2001). Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487-1500 https://doi.org/10.1152/jappl.2001.91.4.1487
  11. 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 https://doi.org/10.1002/gepi.20210
  12. 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 https://doi.org/10.1165/rcmb.2005-0404OC
  13. 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 https://doi.org/10.1016/j.jaci.2007.03.019
  14. 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 https://doi.org/10.1002/jcp.1041630311
  15. 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 https://doi.org/10.1152/jappl.1998.84.5.1817
  16. Gilbert, W. (1978). Why genes in pieces? Nature 271, 501 https://doi.org/10.1038/271501a0
  17. Gonlugur, U., and Gonlugur, T.E. (2006). Non-allergic eosinophilic inflammation. Immunol. Invest. 35, 29-45
  18. 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 https://doi.org/10.1034/j.1398-9995.2002.23523.x
  19. Hedrick, P.W. (1987). Gametic disequilibrium measures: proceed with caution. Genetics 117, 331-341
  20. Kamm, K.E., and Stull, J.T. (2001). Dedicated myosin light chain kinases with diverse cellular functions. J. Biol. Chem. 276, 4527-4530 https://doi.org/10.1074/jbc.R000028200
  21. 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 22, 78-83
  22. 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 https://doi.org/10.1007/s00439-002-0830-3
  23. 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 https://doi.org/10.1111/j.1398-9995.2005.00646.x
  24. Lazar, V., and Garcia, J.G. (1999). A single human myosin light chain kinase gene (MLCK; MYLK). Genomics 57, 256-267 https://doi.org/10.1006/geno.1999.5774
  25. 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 https://doi.org/10.1016/j.jaci.2007.08.041
  26. 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 https://doi.org/10.1038/ng1071
  27. 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 https://doi.org/10.1152/ajplung.00389.2001
  28. Makridakis, N.M., and Reichardt, J.K. (2001). Multiplex automated primer extension analysis: simultaneous genotyping of several polymorphisms. Biotechniques 31, 1374-1380
  29. 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 malesterility phenotypes in peppers (Capsicum annuum, L.). Mol. Cells 25, 20-29
  30. 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 https://doi.org/10.1111/j.1398-9995.2007.01445.x
  31. 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 https://doi.org/10.1086/383251
  32. Ober, C. (2005). Perspectives on the past decade of asthma genetics. J. Allergy Clin. Immunol. 116, 274-278 https://doi.org/10.1016/j.jaci.2005.04.039
  33. Parker, J.C. (2000). Inhibitors of myosin light chain kinase and phosphodiesterase reduce ventilator-induced lung injury. J. Appl. Physiol. 89, 2241-2248 https://doi.org/10.1152/jappl.2000.89.6.2241
  34. Petrache, I., Verin, A.D., Crow, M.T., Birukova, A., Liu, F., and Garcia, J.G. (2001). Differential effect of MLC kinase in TNF-alphainduced endothelial cell apoptosis and barrier dysfunction. Am. J. Physiol. Lung Cell Mol. Physiol. 280, L1168-1178 https://doi.org/10.1152/ajplung.2001.280.6.L1168
  35. 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 https://doi.org/10.1086/338688
  36. Sublett, J.L. (2005). The environment and risk factors for atopy. Curr. Allergy Asthma Rep. 5, 445-450 https://doi.org/10.1007/s11882-005-0024-x
  37. Tattersfield, A.E., Knox, A.J., Britton, J.R., and Hall, I.P. (2002). Asthma Lancet 360, 1313-1322 https://doi.org/10.1016/S0140-6736(02)11312-2
  38. 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 https://doi.org/10.1073/pnas.1031595100
  39. 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 https://doi.org/10.1002/(SICI)1097-4644(19991201)75:3<481::AID-JCB12>3.0.CO;2-5
  40. Weller, P.F. (1994). Eosinophils: structure and functions. Curr. Opin. Immunol. 6, 85-90

Cited by

  1. The Search for Genetic Variants and Epigenetics Related to Asthma vol.3, pp.4, 2009, https://doi.org/10.4168/aair.2011.3.4.236
  2. Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome vol.21, pp.13, 2009, https://doi.org/10.1093/hmg/dds135
  3. An intronic MYLK variant associated with inflammatory lung disease regulates promoter activity of the smooth muscle myosin light chain kinase isoform vol.90, pp.3, 2009, https://doi.org/10.1007/s00109-011-0820-9
  4. Myosin light chain kinase MYLK1: Anatomy, interactions, functions, and regulation vol.81, pp.13, 2009, https://doi.org/10.1134/s000629791613006x