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Polymorphisms in the endothelin-1 (EDN1) are associated with asthma in two populations

Genes & Immunity volume 9, pages 23–29 (2008)Cite this article

Abstract

Endothelin-1 (EDN1) has been reported to be implicated in the pathophysiology of asthma. Literature results on the genetic association of EDN1 in asthma are inconsistent. Eleven single nucleotide polymorphisms in EDN1 were genotyped in 342 and 100 families from UK and Norway, respectively. Asthma, bronchial hyperreactivity (BHR) and atopic asthma phenotypes were analyzed for the family-based association. Five single nucleotide polymorphisms (SNPs) were associated with asthma (0.0017⩽P⩽0.0291), five with BHR (0.0026⩽P⩽0.0315) and three with atopic asthma (0.0016⩽P⩽0.041) in the UK population. Three SNPs were associated with asthma (0.0041⩽P⩽0.019), seven with BHR (0.0018⩽P⩽0.041) and two with atopic asthma (0.0123⩽P⩽0.0153) in the Norwegian population. A polymorphism (rs1800541) in the promoter region of EDN1 was replicated in the two populations. A nonsynonymous coding polymorphism (rs5370) resulting in a change of amino acid Asn to Lys at position 198 was also replicated. The results of haplotype-based association analyses strongly supported the ones of single SNP associations. This study demonstrates the significant evidence of association between polymorphisms in EDN1 and asthma.

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References

  1. Busse WW, Lemanske RF . Asthma. New Engl J Med 2001; 344: 350–362.

    Article  CAS  Google Scholar 

  2. Ober C . Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol 2005; 116: 274–278.

    Article  CAS  Google Scholar 

  3. Yanagisawa M, Inoue A, Ishikawa T, Kasuya Y, Kimura S, Kumagaye S et al. Primary structure, synthesis, and biological activity of rat endothelin, an endothelium-derived vasoconstrictor peptide. Proc Natl Acad Sci USA 1988; 85: 6964–6967.

    Article  CAS  Google Scholar 

  4. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Pro Natl Acad Sci USA 1989; 86: 2863–2867.

    Article  CAS  Google Scholar 

  5. Kedzierski RM, Yanagisawa M . Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41: 851–876.

    Article  CAS  Google Scholar 

  6. Hosoda K, Nakao K, Tamura N, Arai H, Ogawa Y, Suga S et al. Organization, structure, chromosomal assignment, and expression of the gene encoding the human endothelin-A receptor. J Biol Chem 1992; 267: 18797–18804.

    CAS  PubMed  Google Scholar 

  7. Arai H, Nakao K, Takaya K, Hosoda K, Ogawa Y, Nakanishi S et al. The human endothelin-B receptor gene. Structural organization and chromosomal assignment. J Biol Chem 1993; 268: 3463–3470.

    CAS  PubMed  Google Scholar 

  8. Hay DW, Goldie RG . Potential pathophysiological role of endothelin-1 in asthma. Drug News Perspect 1998; 11: 411–418.

    Article  CAS  Google Scholar 

  9. Hay DW . Putative mediator role of endothelin-1 in asthma and other lung diseases. Clin Exp Pharmacol Physiol 1999; 26: 168–171.

    Article  CAS  Google Scholar 

  10. Webb DJ, Monge JC, Rabelink TJ, Yanagisawa M . Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci 1998; 19: 5–8.

    Article  Google Scholar 

  11. Mattoli S, Soloperto M, Marini M, Fasoli A . Levels of endothelin in the bronchoalveolar lavage fluid of patients with symptomatic asthma and reversible airflow obstruction. J Allergy Clin Immunol 1991; 88: 376–384.

    Article  CAS  Google Scholar 

  12. Springall DR, Howarth PH, Counihan H, Diukanovic R, Holgate ST, Polak JM . Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet 1991; 337: 697–701.

    Article  CAS  Google Scholar 

  13. Trakada G, Tsourapis S, Marangos M, Spiropoulos K . Arterial and bronchoalveolar lavage fluid endothelin-1 concentration in asthma. Respir Med 2000; 94: 992–996.

    Article  CAS  Google Scholar 

  14. Hay DW, Hubbard W, Undem BJ . Endothelin receptor subtypes in human and guinea-pig pulmonary tissues. Br J Pharmacol 1993; 110: 392–398.

    Article  CAS  Google Scholar 

  15. Goldie RG, Henry PJ, Knott PG, Self GJ, Luttmann MA, Hay DW . Endothelin-1 receptor density, distribution and function in human isolated asthmatic airways. Am J Respir Crit Care Med 1995; 152: 1653–1658.

    Article  CAS  Google Scholar 

  16. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hills M et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 247–250.

    Article  CAS  Google Scholar 

  17. CSGA. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 1997; 15: 389–392.

    Article  Google Scholar 

  18. Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B et al. Genome-wide search for asthma susceptibility loci in a founder population. The collaborative study on the genetics of asthma. Hum Mol Genet 1998; 7: 1393–1398.

    Article  CAS  Google Scholar 

  19. Mao XQ, Gao PS, Roberts MH, Enomoto T, Kawai M, Sasaki S et al. Variants of endothelin-1 and its receptors in atopic asthma. Biochem Biophys Res Commun 1999; 262: 259–262.

    Article  CAS  Google Scholar 

  20. Immervoll T, Loesgen S, Dutsch G, Gohlke H, Herbon N, Klugbauer S et al. Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes. Hum Mutat 2001; 18: 327–336.

    Article  CAS  Google Scholar 

  21. Holla LL, Vasku A, Lzakovic V, Znojil V . Variants of endothelin-1 gene in atopic diseases. J Investig Allergol Clin Immunol 2001; 11: 193–198.

    CAS  PubMed  Google Scholar 

  22. Holla LL, Vasku A, Znojil V, Siskova L, Vacha J . Association of 3 gene polymorphisms with atopic diseases. J Allergy Clin Immunol 1999; 103: 702–708.

    Article  CAS  Google Scholar 

  23. Silverman EK, Palmer LJ . Case-control association studies for the genetics of complex respiratory diseases. Am J Respir Cell Mol Biol 2000; 22: 645–648.

    Article  CAS  Google Scholar 

  24. Pare G, Serre D, Brisson D, Anand SS, Montpetit A, Tremblay G et al. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol. Am J Hum Genet 2007; 80: 673–682.

    Article  CAS  Google Scholar 

  25. Tiret L, Poirier O, Hallet V, McDonagh TA, Morrison C, McMurray JJ et al. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 1999; 33: 1169–1174.

    Article  CAS  Google Scholar 

  26. Smith PJ, Zhang C, Wang J, Chew SL, Zhang MQ, Krainer AR . An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. Hum Mol Genet 2006; 15: 2490–2508.

    Article  CAS  Google Scholar 

  27. Ober C, Hoffjan S . Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006; 7: 95–100.

    Article  CAS  Google Scholar 

  28. Zhu G, Vestbo J, Lenney W, Silverman M, Whyte M, Helms P et al. Association of PTGDR gene polymorphisms with asthma in two Caucasian populations. Genes Immun 2007; 8: 398–403.

    Article  CAS  Google Scholar 

  29. Pillai SG, Cousens DJ, Barnes AA, Buckley PT, Chiano MN, Hosking LK et al. A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma. Pharmacogenetics 2004; 14: 627–633.

    Article  CAS  Google Scholar 

  30. Pillai SG, Chiano MN, White NJ, Speer M, Barnes KC, Carlsen K et al. A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p. Eur J Hum Genet 2006; 14: 307–316.

    Article  CAS  Google Scholar 

  31. Roses AD, Burns DK, Chissoe S, Middleton L, St Jean P . Disease-specific target selection: a critical first step down the right road. Drug Discov Today 2005; 10: 177–189.

    Article  Google Scholar 

  32. Wigginton JE, Cutler DJ, Abecasis GR . A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  Google Scholar 

  33. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  Google Scholar 

  34. Horvath S, Xu X, Laird NM . The Family based association test method: strategies for studying general genotype-phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  Google Scholar 

  35. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM . Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004; 26: 61–69.

    Article  Google Scholar 

  36. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  37. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the sample management and custom genotyping groups in GlaxoSmithKline. This work was supported by GlaxoSmithKline.

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Authors and Affiliations

  1. Medical Genetics, GlaxoSmithKline, Research Triangle Park, NC, USA

    G Zhu & S G Pillai

  2. Ullevaal University Hospital, Oslo, Norway

    K Carlsen & K-H Carlsen

  3. Academic Department of Pediatrics, Directorate of Child Health, North Staffordshire Hospital, Stoke on Trent, UK

    W Lenney

  4. Division of Child Health, University of Leicester, Leicester, UK

    M Silverman

  5. Academic Unit of Respiratory Medicine, University of Sheffield, Sheffield, UK

    M K Whyte

  6. Pharmacogenetics, GlaxoSmithKline, Research Triangle Park, NC, USA

    L Hosking, A D Roses & W H Anderson

  7. Department of Child Health, Royal Aberdeen Children's Hospital, University of Aberdeen, Aberdeen, UK

    P Helms

  8. Center of Excellence in Drug Discovery, GlaxoSmithKline, Upper Merion, PA, USA

    D W Hay

  9. Molecular Discovery Research Informatics, GlaxoSmithKline, Harlow, UK

    M R Barnes

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  1. G Zhu
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  2. K Carlsen
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  4. W Lenney
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  9. A D Roses
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  10. D W Hay
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Corresponding author

Correspondence to S G Pillai.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Zhu, G., Carlsen, K., Carlsen, KH. et al. Polymorphisms in the endothelin-1 (EDN1) are associated with asthma in two populations. Genes Immun 9, 23–29 (2008). https://doi.org/10.1038/sj.gene.6364441

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  • DOI: https://doi.org/10.1038/sj.gene.6364441

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