Semin Respir Crit Care Med 2007; 28(3): 255-263
DOI: 10.1055/s-2007-981646
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Early Gene-Environment Interactions: Can They Inform Primary Preventive Strategies for Asthma?

Erika von Mutius1 , Peter Neils Le Souëf2
  • 1Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University Munich, Munich, Germany
  • 2Department of Pediatrics, Princess Margaret Hospital for Children, School of Pediatrics and Child Health, University of Western Australia, Perth, WA, Australia
Further Information

Publication History

Publication Date:
22 August 2007 (online)

ABSTRACT

The concept of using gene-environment studies to discover mechanisms of asthma in early life is deceptively simple and attractive. To do so would appear to require a straightforward examination of relationships between a polymorphism and asthma-related phenotypes in young children. However, in reality, the process is far from simple and lack of appreciation of the complexity of this area of research has been one of the reasons for such slow progress.

To understand current knowledge of gene-environment interactions in early life requires insight into environmental factors that have been associated with early-onset asthma. Gaining such insight is difficult because the critical environmental factors that are causally associated with asthma at this stage are still unclear. This article discusses known environmental and epidemiological factors, along with examples of gene-environment interactions, followed by a general discussion of problems with current studies and a description of newer approaches being used to make progress in this complex area.

REFERENCES

  • 1 Morgan W J, Stern D A, Sherrill D L et al.. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence.  Am J Respir Crit Care Med. 2005;  172 1253-1258
  • 2 Martinez F D. Development of wheezing disorders and asthma in preschool children.  Pediatrics. 2002;  109(Suppl 2) 362-367
  • 3 Illi S, von Mutius E, Lau S, Niggemann B, Gruber C, Wahn U. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study.  Lancet. 2006;  368 763-770
  • 4 Martinez F D, Helms P J. Types of asthma and wheezing.  Eur Respir J Suppl. 1998;  27 3s-8s
  • 5 Strachan D P, Cook D G. Health effects of passive smoking, I: Parental smoking and lower respiratory illness in infancy and early childhood.  Thorax. 1997;  52 905-914
  • 6 Weiland S, Weinmayr G, Rzehak P et al.. International variation in the prevalence of asthma in children: the role of atopic sensitisation and economic development.  Eur Respir J Suppl. 2006;  28(Suppl 50) 835s-836s
  • 7 Nicolai T, Pereszlenyiova-Bliznakova L, Illi S, Reinhardt D, von Mutius E. Longitudinal follow-up of the changing gender ratio in asthma from childhood to adulthood: role of delayed manifestation in girls.  Pediatr Allergy Immunol. 2003;  14 280-283
  • 8 Mandhane P J, Greene J M, Cowan J O, Taylor D R, Sears M R. Sex differences in factors associated with childhood- and adolescent-onset wheeze.  Am J Respir Crit Care Med. 2005;  172 45-54
  • 9 Wenzel S E. Asthma: defining of the persistent adult phenotypes.  Lancet. 2006;  368 804-813
  • 10 Sears M R, Burrows B, Flannery E M, Herbison G P, Hewitt C J, Holdaway M D. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children.  N Engl J Med. 1991;  325 1067-1071
  • 11 Palmer L J, Rye P J, Gibson N A, Burton P R, Landau L I, Lesouef P N. Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age.  Am J Respir Crit Care Med. 2001;  163 37-42
  • 12 Latzin P, Kuehni C E, Baldwin D N, Roiha H L, Casaulta C, Frey U. Elevated exhaled nitric oxide in newborns of atopic mothers precedes respiratory symptoms.  Am J Respir Crit Care Med. 2006;  174 1292-1298
  • 13 Langley S J, Goldthorpe S, Custovic A, Woodcock A. Relationship among pulmonary function, bronchial reactivity, and exhaled nitric oxide in a large group of asthmatic patients.  Ann Allergy Asthma Immunol. 2003;  91 398-404
  • 14 Eder W, Ege M J, von Mutius E. The asthma epidemic.  N Engl J Med. 2006;  355 2226-2235
  • 15 Arlian L G, Platts-Mills T A. The biology of dust mites and the remediation of mite allergens in allergic disease.  J Allergy Clin Immunol. 2001;  107(Suppl 3) S406-S413
  • 16 Lau S, Illi S, Sommerfeld C et al.. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group.  Lancet. 2000;  356 1392-1397
  • 17 Woodcock A, Lowe L A, Murray C S et al.. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years.  Am J Respir Crit Care Med. 2004;  170 433-439 , Epub 2004 May 13
  • 18 Simpson A, Custovic A. Allergen avoidance in the primary prevention of asthma.  Curr Opin Allergy Clin Immunol. 2004;  4 45-51
  • 19 Kramer U, Heinrich J, Wjst M, Wichmann H E. Age of entry to day nursery and allergy in later childhood.  Lancet. 1999;  353 450-454
  • 20 Ball T M, Castro-Rodriguez J A, Griffith K A, Holberg C J, Martinez F D, Wright A L. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood.  N Engl J Med. 2000;  343 538-543
  • 21 Riedler J, Braun-Fahrlander C, Eder W et al.. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey.  Lancet. 2001;  358 1129-1133
  • 22 Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.  Genes Immun. 2006;  7 95-100
  • 23 Sheehan D, Meade G, Foley V M, Dowd C A. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily.  Biochem J. 2001;  360(Pt 1) 1-16
  • 24 Alexandrov K, Cascorbi I, Rojas M, Bouvier G, Kriek E, Bartsch H. CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation.  Carcinogenesis. 2002;  23 1969-1977
  • 25 Lee Y L, Lin Y C, Lee Y C, Wang J Y, Hsiue T R, Guo Y L. Glutathione S-transferase P1 gene polymorphism and air pollution as interactive risk factors for childhood asthma.  Clin Exp Allergy. 2004;  34 1707-1713
  • 26 Kabesch M, Hoefler C, Carr D, Leupold W, Weiland S K, von Mutius E. Glutathione S transferase deficiency and passive smoking increase childhood asthma.  Thorax. 2004;  59 569-573
  • 27 Cook D G, Strachan D P, Carey I M. Health effects of passive smoking, IX: Parental smoking and spirometric indices in children.  Thorax. 1998;  53 884-893
  • 28 Schmitz G, Orso E. CD14 signalling in lipid rafts: new ligands and co-receptors.  Curr Opin Lipidol. 2002;  13 513-521
  • 29 Baldini M, Lohman I C, Halonen M, Erickson R P, Holt P G, Martinez F DA. Polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.  Am J Respir Cell Mol Biol. 1999;  20 976-983
  • 30 Leynaert B, Guilloud-Bataille M, Soussan D et al.. Association between farm exposure and atopy, according to the CD14 C-159T polymorphism.  J Allergy Clin Immunol. 2006;  118 658-665
  • 31 Martinez F D. Gene-environment interactions in asthma: with apologies to William of Ockham.  Proc Am Thorac Soc.. 2007;  4 26-31
  • 32 Ober C, Tsalenko A, Willadsen S et al.. Genome-wide screen for atopy susceptibility alleles in the Hutterites.  Clin Exp Allergy. 1999;  29(Suppl 4) 11-15
  • 33 Vercelli D. Learning from discrepancies: CD14 polymorphisms, atopy and the endotoxin switch.  Clin Exp Allergy. 2003;  33 153-155
  • 34 Simpson A, John S L, Jury F et al.. Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment.  Am J Respir Crit Care Med. 2006;  174 386-392
  • 35 Eder W, Klimecki W, Yu L et al.. Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments.  J Allergy Clin Immunol. 2005;  116 601-607
  • 36 O'Donnell A R, Toelle B G, Marks G B et al.. Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years.  Am J Respir Crit Care Med. 2004;  169 615-622 , Epub 2003 Nov 14
  • 37 Eder W, Klimecki W, Yu L et al.. Toll-like receptor 2 as a major gene for asthma in children of European farmers.  J Allergy Clin Immunol. 2004;  113 482-488
  • 38 Eder W, Klimecki W, Yu L et al.. Association between exposure to farming, allergies and genetic variation in CARD4/NOD1.  Allergy. 2006;  61 1117-1124
  • 39 Hoffjan S, Nicolae D, Ostrovnaya I et al.. Gene-environment interaction effects on the development of immune responses in the 1st year of life.  Am J Hum Genet. 2005;  76 696-704
  • 40 Kurz T, Ober C. The role of environmental tobacco smoke in genetic susceptibility to asthma.  Curr Opin Allergy Clin Immunol. 2004;  4 335-339
  • 41 Meyers D A. Approaches to genetic studies of asthma.  Am J Respir Crit Care Med. 1994;  150(5 Pt 2) S91-S93
  • 42 Hall I P. Genetics and pulmonary medicine, VIII: Asthma.  Thorax. 1999;  54 65-69
  • 43 Lyon H, Lange C, Lake S et al.. IL10 gene polymorphisms are associated with asthma phenotypes in children.  Genet Epidemiol. 2004;  26 155-165
  • 44 Hirota T, Suzuki Y, Hasegawa K et al.. Functional haplotypes of IL-12B are associated with childhood atopic asthma.  J Allergy Clin Immunol. 2005;  116 789-795
  • 45 Dolan C M, Fraher K E, Bleecker E R et al.. Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.  Ann Allergy Asthma Immunol. 2004;  92 32-39
  • 46 Khoo S K, Zhang G, Backer V et al.. Associations of a novel IL4RA polymorphism, Ala57Thr, in Greenlander Inuit.  J Allergy Clin Immunol. 2006;  118 627-634
  • 47 Busse W W, Rosenwasser L J. Mechanisms of asthma.  J Allergy Clin Immunol. 2003;  111(Suppl 3) S799-S804
  • 48 Stick S M, Turner D J, LeSouef P N. Lung function and bronchial challenges in infants: repeatability of histamine and comparison with methacholine challenges.  Pediatr Pulmonol. 1993;  16 177-183
  • 49 Stein R T, Martinez F D. Asthma phenotypes in childhood: lessons from an epidemiological approach.  Paediatr Respir Rev. 2004;  5 155-161
  • 50 Robertson C F, Roberts M F, Kappers J H. Asthma prevalence in Melbourne schoolchildren: have we reached the peak?.  Med J Aust. 2004;  180 273-276
  • 51 Paramesh H. Epidemiology of asthma in India.  Indian J Pediatr. 2002;  69 309-312
  • 52 Le Souef P N, Goldblatt J, Lynch N R. Evolutionary adaptation of inflammatory immune responses in human beings.  Lancet. 2000;  356 242-244
  • 53 Martin A C, Laing I A, Khoo S K et al.. Acute asthma in children: relationships among CD14 and CC16 genotypes, plasma levels, and severity.  Am J Respir Crit Care Med. 2006;  173 617-622
  • 54 Heaton T, Rowe J, Turner S et al.. An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children.  Lancet. 2005;  365 142-149
  • 55 Halapi E, Hakonarson H. Recent development in genomic and proteomic research for asthma.  Curr Opin Pulm Med. 2004;  10 22-30
  • 56 Hansel N N, Hilmer S C, Georas S N et al.. Oligonucleotide-microarray analysis of peripheral-blood lymphocytes in severe asthma.  J Lab Clin Med. 2005;  145 263-274
  • 57 Laprise C, Sladek R, Ponton A, Bernier M C, Hudson T J, Laviolette M. Functional classes of bronchial mucosa genes that are differentially expressed in asthma.  BMC Genomics. 2004;  5 21
  • 58 Wark P A, Johnston S L, Bucchieri F et al.. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.  J Exp Med. 2005;  201 937-947
  • 59 Friedlander S L, Busse W W. The role of rhinovirus in asthma exacerbations.  J Allergy Clin Immunol. 2005;  116 267-273
  • 60 Contoli M, Message S D, Laza-Stanca V et al.. Role of deficient type III interferon-lambda production in asthma exacerbations.  Nat Med. 2006;  12 1023-1026
  • 61 Papadopoulos N G, Stanciu L A, Papi A, Holgate S T, Johnston S L. A defective type 1 response to rhinovirus in atopic asthma.  Thorax. 2002;  57 328-332
  • 62 Yang I A, Fong K M, Holgate S T, Holloway J W. The role of Toll-like receptors and related receptors of the innate immune system in asthma.  Curr Opin Allergy Clin Immunol. 2006;  6 23-28
  • 63 McLean C J, Khoo S-K, Zhang G et al.. Innate immune system polymorphisms and acute asthma in children [abstract].  Am J Respir Crit Care Med. 2007;  4
  • 64 Wiertsema S P, Baynam G, Khoo S K et al.. Impact of genetic variants in IL-4, IL-4 RA and IL-13 on the anti-pneumococcal antibody response.  Vaccine. 2007;  25 306-313
  • 65 Wiertsema S P, Khoo S K, Baynam G et al.. Association of CD14 promoter polymorphism with otitis media and pneumococcal vaccine responses.  Clin Vaccine Immunol. 2006;  13 892-897
  • 66 Baynam G S, Khoo S-K, Rowe J et al.. Parental smoking impairs vaccine responses in children with atopic genotypes.  J Allergy Clin Immunol. 2007;  119 366-374

Erika von MutiusM.D. 

Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University Munich

Lindwurmstr. 4, D 80337 Munich, Germany

Email: Erika.Von.Mutius@med.uni-muenchen.de

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