Connect
MJA
MJA

Risk factors and epidemiology

Peter N Le Souëf
Med J Aust 2002; 177 (6): S40. || doi: 10.5694/j.1326-5377.2002.tb04812.x
Published online: 16 September 2002

Abstract

What we know

What we need to know

How important are genetic factors in determining susceptibility to asthma?

The increase in asthma prevalence over the past few decades is likely to be due to increased phenotypic expression of underlying genetic susceptibility to asthma. Strong environmental factors, as yet unidentified, are the most plausible explanation for this increase. Increased genetic penetration of asthma (ie, increased expression of the disease by those who have a genetic predisposition) may help researchers to identify the specific genetic changes that predispose to asthma.

Many regions of the human genome have been reported to show linkage to asthma or associated phenotypic features, but no region has been found to be associated with asthma in every study. Similarly, particular alleles of many candidate genes appear to be linked with asthma, but no allele has been shown to be associated with asthma in every population. These genome screen and candidate gene data suggest that no one allele accounts for more than 10% of the overall susceptibility to asthma.1 Nonetheless, several polymorphisms have produced similar associations in different populations, and the results are biologically plausible and may be important in those populations. At our current state of knowledge, the most important genes implicated in genetic susceptibility to asthma include the genes coding for CD14, β2-adrenoreceptor, tumour necrosis factor alpha (TNF-α), and interleukins IL-4R and IL-12.

Few studies have attempted to define the genes that may be important in predisposing to asthma in early childhood. CD14 is most likely to be important, as it has a critical role in early differentiation of TH1 and TH2 responses. Recent preliminary data suggest that a CD14 promoter allele is associated with asthma-related phenotype from 8 to 12 years of age, making this the first genotype identified as contributing to the development of asthma at a particular age.2

Susceptibility to asthma may be higher among certain racial groups than others.3 The genetic tendency to produce TH2-type inflammatory responses appears to be substantially greater in populations with longstanding ancestry in tropical regions, as evidenced by an increased prevalence of pro-inflammatory alleles in genes with TH2 activity. Europeans have a lesser tendency to produce such responses, and people who have lived in polar regions for tens of thousands of years have the lowest level of TH2-type responses.4 These differences in allele prevalence between populations are the likely reason for race being an important risk factor for asthma in children. For example, asthma is about twice as common in African-Americans as European-Americans when all other factors are controlled for.3 Clearly, this genetic risk factor operates independently of the strong environmental factors that contribute to asthma.

Why is living with animals good for asthma?

Several studies have shown that the presence of a cat in the family has a protective effect on the development of asthma,5 despite cat allergen being a recognised risk factor for provoking asthma symptoms in sensitised individuals. Living in close proximity to farm animals also has a protective effect on the development of asthma in children,6 and this finding has been replicated in several studies from a number of countries. A plausible mechanism may be by lipopolysaccharide stimulation producing a TH1 shift in the balance of TH1 and TH2 responses.

Is good hygiene a risk factor for asthma?

The perception that asthma was less common in developing countries led to the "hygiene hypothesis".6,7 The problem with this hypothesis is that there are many lines of evidence that do not fit.8 The most extensive body of evidence against the hypothesis comes from the ISAAC study,9 in which asthma was found to be unexpectedly prevalent in several countries with a relatively low standard of living. In collaboration with Venezuelan colleagues, we have found high levels of pro-inflammatory alleles, IgE and asthma in people living on Coche Island, in the Caribbean, with endemic parasitic disease and poor socioeconomic conditions.10 Some epidemiological studies have reported associations between increased infection and reduced asthma, but the results are not consistent in all studies.7 There is still too little evidence to conclude that good hygiene itself is an important risk factor for the high levels of asthma in affluent or "westernised" societies. Important, unrecognised factors are likely to be responsible for producing high disease levels.

Can change of diet or breastfeeding decrease asthma?

Several studies have suggested that consumption of fish oil reduces the risk of developing asthma in children.11 This has led to the hypothesis that omega-3 fatty acids may be responsible for these observations, and controlled trials are under way to investigate this possibility. Breastfeeding may also be associated with a change in asthma prevalence, but some studies have shown that it decreases the incidence of asthma in the general population, while others have shown that it increases asthma in the offspring of asthmatic mothers.12

Are physiological characteristics important risk factors for asthma in children?

Longitudinal studies beginning in infancy have identified physiological factors that predispose to asthma in early life. In the Tucson study,13 maximal flow at functional residual capacity (V'maxFRC) was obtained in 125 infants at a variable age after birth. A low V'maxFRC value was found to be a risk factor for wheeze in the first three years of life, but not thereafter. In our longitudinal study,14 V'maxFRC was measured in 253 infants at one month of age and reassessed at six and 12 years of age. We found that early infant lung function and airway responsiveness both correlated with physiological status and clinical outcome at six years of age. In preliminary analyses of the 192 infants reassessed at 12 years of age, we have found that significant associations remain between the assessments at one month and at 12 years. We have also noted that the lung function of children diagnosed with bronchiolitis in infancy was just as abnormal before they had bronchiolitis as it was at the 12-year follow-up, suggesting that the low lung function found after bronchiolitis in other studies was pre-existing and not related to infection. These studies establish underlying physiology as a risk factor for asthma throughout childhood.

Why are viruses the most important precipitant of acute asthma?

Viral respiratory infections are the most common triggers of acute, severe asthma attacks in people with both non-atopic and atopic asthma, but how viral infections precipitate acute asthma remains unclear.15 Protection from viral infection is mainly via TH1 pathways, yet children susceptible to asthma have a TH2 skew. Understanding the relative balance of TH1 and TH2 activity at both the genetic and cellular levels in response to respiratory viral infections may well be fundamental to understanding how control of inflammation is lost and acute asthma develops.

  • Peter N Le Souëf1

  • Department of Paediatrics, University of Western Australia, Crawley, WA.


Correspondence: plesouef@cyllene.uwa.edu.au

  • 1. Sandford AJ, Pare PD. The genetics of asthma. The important questions. Am J Respir Crit Care Med 2000; 161: s202-s206.
  • 2. O'Donnell AR, Toelle B, Marks G. A polymorphism in the CD14 gene is associated with childhood onset atopy [abstract]. Am J Respir Crit Care Med 2002; 165: A659.
  • 3. Le Souëf PN, Goldblatt J, Lynch NR. Evolutionary adaptation of inflammatory immune responses in humans. Lancet 2000; 356: 242-244.
  • 4. Candelaria PV, Laing IA, Khoo SK, et al. The prevalence of proinflammatory immune alleles in several climatically adapted populations [abstract]. Am J Respir Crit Care Med 2002; 165: A808.
  • 5. Platts-Mills T, Vaughan J, Squillace S, et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001; 357: 752-756.
  • 6. Von Mutius E. The increase in asthma can be ascribed to cleanliness. Am J Respir Crit Care Med 2001; 164: 1106-1107.
  • 7. Martinez FD. The coming-of-age of the hygiene hypothesis. Respir Res 2001; 2: 129-132.
  • 8. Platts-Mills T, Woodfolk JA, Sporik RB. The increase in asthma cannot be ascribed to cleanliness. Am J Respir Crit Care Med 2001; 164: 1107-1109.
  • 9. International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998; 351: 1225-1232.
  • 10. Ramsay CE, Hayden CM, Tiller KJ, et al. Association of polymorphisms in the beta-2-adrenoreceptor gene with higher levels of parasitic infection. Hum Genet 1999; 104: 269-274.
  • 11. Hodge L, Salome CM, Peat JK, et al. Consumption of oily fish and childhood asthma risk. Med J Aust 1996; 164: 137-140.
  • 12. Oberle D, Von Kries F, Von Mutius E. Asthma and breast feeding. Thorax 2001; 56: 896.
  • 13. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995; 332: 133-138.
  • 14. Palmer LJ, Rye PJ, Gibson NA, et al. 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.
  • 15. Tuffaha A, Gern JE, Lemanske RF Jr. The role of respiratory viruses in acute and chronic asthma. Clin Chest Med 2000; 21: 289-300.

Author

remove_circle_outline Delete Author
add_circle_outline Add Author

Comment
Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Online responses are no longer available. Please refer to our instructions for authors page for more information.