Abstract
The genome-wide linkage disequilibrium screen for loci associated with genetic difference between allergic and nonallergic asthma was conducted with 763 autosomal STR markers and included 190 asthmatic children. Evidence for association with differences between the two forms of asthma was observed for 36 STR markers. Marker-to-marker synergetic effect and by simulation resampling tests revealed D5S2011, D6S305, and D9S286 were important loci in allergic asthma while D6S1574, D8S1769, and D19S226 were important in nonallergic asthma. Our results show strong genetic evidence that these markers play an important role in defining allergic and nonallergic asthma and provides important candidates of susceptible genes in these two categories of asthma. This study further shows that asthma is, indeed, a heterogeneous group of underlying diseases and, although with similar clinical phenotypes, may have different clinical severities, outcomes, and need more tailor-made management.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Agresti A (2002) Categorical data analysis, 2nd edn. Wiley, Hoboken NJ
Baldini M, Vercelli D, Martinez FD (2002) CD14: an example of gene by environment interaction in allergic disease. Allergy 57:188–192
Bani D (1997) Relaxin: a pleiotropic hormone. Gen Pharmacol 28:13–22
Bentley AM, Menz G, Storz C, Robinson B, Jeffery PK, Durham SR, Kay AB (1992) Identification of T lymphocytes, macrophages, and activated eosinophils in bronchial mucosa in intrinsic asthma. Am Rev Respir Dis 146:500–506
Brown JE, Greenberger PA, Yarnold PR (1995) Soluble serum interleukin 2 receptors in patients with asthma and allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol 74:484–488
Brzustowicz LM, Matseoane D, Wang CH, Kleyn PW, Vitale E, Penchaszadeh GK, Hausmanowa-Petrusewicz I, Gilliam TC (1993) Linkage disequilibrium and haplotype analysis among Polish families with spinal muscular atrophy. Am J Hum Genet Suppl 53:982
Burney PG, Luczynska C, Chinn S, Jarvis D (1994) The European Community Respiratory Health Survey. Eur Respir J 5:954–960
Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG (1989) Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 320:271–277
Candotti F, Notarangelo L, Visconti R, O’Shea J (2002) Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways. J Clin Invest 109:1261–1269
Chanez P, Vignola M, Stenger R, Vic P, Michel FB, Bousquet J (1995) Platelet-derived growth factor in asthma. Allergy 50:878–883
Chapman NH, Wijsman EM (1998) Genome screens using linkage disequilibrium tests: optimal marker characteristics and feasibility. Am J Hum Genet 63:1872–1885
Cheng G, Ueda T, Numao T, Kuroki Y, Nakajima H, Fukushima Y, Motojima S, Fukuda T (2000) Increased levels of surfactant protein A and D in bronchoalveolar lavage fluids in patients with bronchial asthma. Eur Respir J 16:831–835
Condliffe AM, Cadwallader KA, Walker TR, Rintoul RC, Cowburn AS, Chilvers ER (2000) Phosphoinoditide 3-kinase: a critical signaling event in pulmonary cells. Respir Res 1:24–29
Cookson W (1999) The alliance of genes and environment in asthma and allergy. Nature 402(Suppl):B5–B11
Curnock AP, Ward SG (2003) Development and characterisation of tetracycline-regulated phosphoinositide 3-kinase mutants:assessing the role of multiple phosphoinositide 3-kinases in chemokine signalling. J Immunol Methods 273:29–41
D’Ambrosio D, Panina-Bordignon P, Sinigaglia F (2003) Chemokine receptors in inflammation: an overview. J Immunol Methods 273:3–13
Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST (2003) Airway remodeling in asthma: new insights. J Allergy Clin Immunol 111:215–225
Dorward AJ, Colloff MJ, MacKay NS, McSharry C, Thompson NC (1988) Effect of house dust mite avoidance measures on adult atopic asthma. Thorax 43:98–102
Dziembowska M, Fondaneche MC, Vedrenne J, Barbieri G, Wiszniewski W, Picard C, Cant AJ, Steimle V, Charron D, Alca-Loridan C, Fischer A, Lisowska-Grospierre B (2002) Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenetics 53:821–829
Fryer AD, Jacoby DB (1998) Muscarinic receptors and control of airway smooth muscle. Am J Respir Crit Care Med 158(5 Pt 3):S154–S160
Goddard KA, Yu CE, Oshima J, Miki T, Nakura J, Piussan C, Martin GM, Schellenberg GD, Wijsman EM (1996) Towards localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers. Am J Hum Genet 58:1286–1302
Henderson WRJ, Chi EY, Teo JL, Nguyen C, Kahn M (2002) A small molecule inhibitor of redox-requlated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model. J Immunol 169:5294–5299
Holgate ST, Davies DE (2001) Airway inflammation and remodeling in asthma—cause and effect?. Immunologist 8:131–135
Hotta K, Emala CW, Hirshman CA (1999) TNF-alpha upregulates Gialpha and Gqalpha protein expression and function in human airway smooth muscle cells. Am J Physiol 276(3 Pt 1):L405–411
Humbert M, Grant JA, Tabora-Barata L, Durham SR, Pfister R, Menz G, Barkans J, Ying S, Kay AB (1996a) High affinity IgE receptor (FcεRI) bearing cells in bronchial biopsies from atopic and non-atopic asthma. Am J Respir Crit Care Med 153:1931–1937
Humbert M, Durham SR, Ying S, Kimmit P, Barkans J, Assoufi B, Pfister R, Menz G, Robinson DS, Kay AB et al (1996b) IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. Am J Respir Crit Care Med 154:1497–1504
Humbert M, Ying S, Corrigan CJ, Menz G, Pfister J, Meng Q, Van Damme J, Opdenakker G, Durham SR, Kay AB (1997a) Bronchial mucosal expression of the genes encoding chemokines RANTES and MCP-3 in symptomatic atopic and non-atopic asthmatics: relationship to eosinophil-active cytokines IL-5, GM-CSF and IL-3. Am J Resp Cell Mol Biol 16:1–8
Humbert M, Durham SR, Kimmit P, Assoufi B, Pfister R, Menz G, Lay AB, Corrigan CJ (1997b) Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and non-atopic subjects with asthma. J Allergy Clin Immuno 99:657–665
Humbert M, Menz G, Ying S, Corrigan CJ, Robison DS, Durham SR Kay AB (1999) The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol Today 20:528–533
Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S, Menon S, Seymour B, Jackson C, Kung TT, Brieland JK, ZAurawski SM, Chapman RW, Zurawski G, Coffman RL (2002) New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 169:443–453
Inouye T, Tarlo S, Broder I, Corey P, Davies G, Leznoff A, Mintz S, Thomas P (1985) Severity of asthma in skin-test negative, and skin test-positive patients. J Allergy Clin Immunol 75:313–319
Layton GT, Harris SJ, Bland FA, Lee SR, Fearn S, Kaleta J, Wood ML, Bond A, Ward G (2001) Therapeutic effects of cysteine protease inhibition in allergic lung inflammation: inhibition of allergen-specific T lymphocyte migration. Inflamm Res 50:400–408
Lin HH, Stacey M, Hamann J, Gordon S, McKnight AJ (2000) Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97. Genomics 67:188–200
Messier TL, O’Neill JP, Hou SM, Nicklas JA, Finette BA (2003) In vivo transposition mediated by V(D)J recombinase in human T lymphocytes. EMBO J 22:1381–1388
Miyake K (2003) Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2. Int Immunopharmacol 3:119–128
Mohri M, Reinach PS, Kanayama A, Shimizu M, Moskovitz J, Hisatsune T, Miyamoto Y (2002) Suppression of the TNFalpha-induced increase in IL-lalpha expression by hypochlorite in human corneal epithelial cells. Invest Ophthalmol Vis Sci 43:3190–3195
Ott J, Rabinowitz D (1997) The effect of marker heterozygosity on the power to detect linkage disequilibrium. Genetics 147:927–930
Pandolfo M, Sirugo G, Antonelli A, Weitnauer L, Ferretti L, Leone M, Dones I, Cerina A, Fujita R, Hanauer A et al (1990) Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet 47:228–235
Pearce N, Sunyer J, Cheng S, Chinn S, Bjorksten B, Burr M, Keil U, Anderson HR, Burney P (2000) Comparison of asthma prevalence in the ISAAC and the ECRHS. ISAAC steering committee and the European community respiratory health survey. International study of asthma and allergies in childhood. Eur Respir J 16:420–426
Pendurthi UR, Williams JT, Rao LV (1997) Acidic and basic fibroblast growth factors suppress transcriptional activation of tissue factor and other inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol 17:940–946
Rackeman FM (1947) A working classification of asthma. Am J Med 3:601
Romanet-Manent S, Charpin D, Magnan A, Lantaume A, Vervloet D, The EGEA Cooperative Group (2002) Allergic vs nonallergic asthma: what makes the difference? Allergy 57:607–613
Sano K, Yamauchi K, Hoshi H, Honma M, Tamura G, Shirato K (1997) CD44 expression on blood eosinophils is a novel marker of bronchial asthma. Int Arch Allergy Immunol 114(Suppl 1):67–71
Santiago C, Arguelles JM, Fernandez PL, Lopez-Otin C (2001) Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats. J Biol Chem 276:17932–17940
Schluns KS, Lefrancois L (2003) Cytokine control of memory T-cell development and survival. Nat Rev Immunol 3:269–279
Schulze TG, Chen YS, Akula N, Hennessy K, Badner JA, McInnis MG, DePaulo JR, Schumacher J, Cichon S, Propping P, Maier W, Rietschel M, Nothen MM, McMahon FJ (2002) Can long-range microsatellite data be used to predict short-range linkage disequilibrium? Hum Mol Genet 11:1363–1372
Sham PC, Curtis D (1995) Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 59:97–105
Silverman ES, Baron RM, Palmer LJ, Le L, Hallock A, Subramaniam V, Riese RJ, McKenna MD, Gu X, Libermann TA, Tugores A, Haley KJ, Shore S, Drazen JM, Weiss ST (2002) Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. Am J Respir Cell Mol Biol 27:697–704
Smith LJ, Shamsuddin M, Sporn PH, Denenberg M, Anderson J (1997) Reduced superoxide dismutase in lung cells of patients with asthma. Free Radic Biol Med 22:1301–1307
Stacey M, Lin HH, Hilyard KL, Gordon S, McKnight AJ (2001) Human epidermal growth factor (EGF) module-containing mucin-line hormone receptor 3 is a new member of the EGF-TM7 family that recognizes a ligand on human macrophages and activated neutrophils. J Biol Chem 276:18863–18870
Stelnicki EJ, Chin GS, Gittes GK, Longaker MT (1999) Fetal wound repair: where do we go from here? Semin Pediatr Surg 8:124–130
Szklo M, Nieto FJ (2000) Epidemiology: beyond the basics. Aspen Publisher Inc., Gaithersburg, MD
Tao FC, Tolloczko B, Mitchell CA, Powell WS, Martin JG (2000) Inositol (1,4,5)trisphosphate metabolism and enhanced calcium mobilization in airway smooth muscle of hyperresponsive rats. Am J Respir Cell Mol Biol 23:514–520
Tekin D, Sin BA, Mungan D, Misirligil Z, Yavuzer S (2000) The antioxidative defense in asthma. J Asthma 37:59–63
Teran LM (2000) CCL chemokines and asthma. Immunol Today 21:235–242
Toda M, Leung DY, Molet S, Boguniewicz M, Taha R, Christodoulopoulos P, Fukuda T, Elias JA, Hamid QA (2003) Polarized in vivo expression of IL-11 and IL17 between acute and chronic skin lesions. J Allergy Clin Immunol 111:875–881
Votruba M, Moore AT, Bhattacharya SS (1998) Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees. Hum Genet 102:79–86
Wardlaw AJ (2001) Eosinophil trafficking in asthma. Clin Med 1:214–218
Wei XQ, Orchardson M, Gracie JA, Leung BP, Gao BM, Guan H, Niedbala W, Paterson GK, McInnes IB, Liew FY (2001) The Sushi domain of soluble IL-15 receptor α is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. J Immunol 167:277–282
Wijsman EM (1997) Association versus linlage analysis in mental disorders. In: Blum K, Noble EP (eds) Handbook of psychiatric genetics. CRC Press, New York, pp 7–24
Ying S, Humbert M, Barkans J, Corrigan CJ, Pfister R, Menz G, Robinson DS, Larche M, Durham SR, Kay AB (1997) Expression of IL-4 and IL-5 mRNA and protein product by CD+ and CD8+ T cells, eosinophils and mast cells in bronchial biopsies obtained from atopic and non-atopic (intrinsic) asthmatics. J Immunol 158:3539–3544
Ying S, Meng Q, Zeibecoglou K, Robinson DS, Macfarlane A, Humbert M, Kay AB (1999) Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics. J Immuno 163:6321–6329
Acknowledgements
We thank Dr. John Gu for comments on the manuscript, Dr. Ashely Ching-Wei Chang for comments on statistical analysis, Ms. Julia Yu and Ms. Jiayu Huang for data management, and Ms. Brook Teng for administrative support.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, JY., Lin, C.GJ., Bey, M.SJ. et al. Discovery of genetic difference between asthmatic children with high IgE level and normal IgE level by whole genome linkage disequilibrium mapping using 763 autosomal STR markers. J Hum Genet 50, 249–258 (2005). https://doi.org/10.1007/s10038-005-0248-6
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-005-0248-6
Keywords
This article is cited by
-
Cytokine expression in cord blood cells of children of healthy and allergic mothers
Folia Microbiologica (2010)
-
The Polymorphism of IL-17 G-152A was Associated with Childhood Asthma and Bacterial Colonization of the Hypopharynx in Bronchiolitis
Journal of Clinical Immunology (2010)
-
The polymorphisms of protein-tyrosine phosphatase receptor-type delta gene and its association with pediatric asthma in the Taiwanese population
European Journal of Human Genetics (2008)
-
Association of CD14 promoter polymorphisms and soluble CD14 levels in mite allergen sensitization of children in Taiwan
Journal of Human Genetics (2006)