Risk factors and epidemiology

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.

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.

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.

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

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.

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.