This analysis of data from a population-based birth cohort has identified significant differences between males and females for factors associated with childhood- and adolescent-onset wheeze. Atopy and airway hyperresponsiveness were associated with childhood wheeze in both sexes. However, although atopy continues to be a risk factor for developing wheeze through adolescence in males, atopy was not a risk factor for adolescent-onset wheeze in females.
The results from this study may clarify contradictory results from previous studies on the influence of atopy on the development of adolescent asthma. An Australian study has previously reported that atopy, defined by skin testing at age 8 through 10, was a risk factor for the development of wheeze in puberty (23
). In contrast, a German study found that atopy at age 10 was not a risk factor for the development of adolescent asthma (22
). Although the proportion of females included in the analysis is similar for both studies (55% females in the Australian study, 48.5% females in the German study; p> 0.05), the prevalence of atopy at baseline was significantly lower in the Australian study than in the German cohort and our cohort (22.3% in the Australian cohort, 45.6% in the German cohort, 44.7% in our cohort; p < 0.001). The lower prevalence of atopy in the Australian study may explain why atopy was a risk factor for adolescent-onset wheeze. Neither the Australian or German studies stratified their analysis to evaluate if atopy was a sex-specific risk for adolescent-onset wheeze. Our analysis found that atopy was a risk factor for adolescent-onset wheeze in males but not in females.
One of the limitations of our study is that several factors associated with childhood-onset wheeze, including atopy and airway responsiveness, were measured near or after age 10. As a result, this study cannot establish whether these factors are causally related. Further studies with more detailed and prospective measurements of childhood atopy and airway responsiveness are needed to understand the relationship between these variables and asthma. The first comprehensive history of childhood wheezing was obtained when the children were age 9 (29
). Those study members with childhood-onset wheeze likely represent children with either persistent or relapsing symptoms, symptoms significant enough to be reported by the mother. Early-childhood wheezing not recalled by the mother had probably been mild and had remitted; otherwise, one would expect these symptoms to be remembered. Therefore, the risk factors for childhood wheeze identified in this study are more likely to apply to children with persistent wheeze, and less to children with transient wheeze.
Paternal and maternal history of asthma and hay fever was obtained from the guardian (usually mother) at age 7 and the study member at 18. Both mother and study member may underreport or confuse symptoms for other family members (e.g., reporting hay fever rather than a diagnosis of asthma). Therefore, we chose to combine asthma and hay fever into a single variable. Despite the potential for recall bias for maternal and paternal atopy by mother and study member, a maternal history of atopy was a risk factor for wheeze for both males and females, consistent with other studies (37
). A paternal history of atopy was a significant predictor of wheeze in females but did not show an age-dependent effect. Previous studies have found that maternal history was a strong risk factor for asthma under age 5, with paternal history being a weak risk factor for early-childhood wheeze and a stronger risk factor for wheeze after age 5 (39
). Both of these studies were analyzed cross-sectionally, without stratification by sex. If we analyze our study in a similar manner, paternal history is a risk factor for adolescent-onset wheeze. When analyzed longitudinally with stratification by sex, maternal and paternal history affects males and females differently.
Although dividing a sample into subgroups decreases the power of the study, subgroup analysis may still be sufficiently powered to see larger effects in at-risk subgroups within a study population (e.g., wheeze in females with a family history of atopy who are breastfed). One danger in stratification is if the subgroups are selected after a preliminary analysis has been completed. Such post hoc stratification may lead to biased results because the authors have prior knowledge of differences within the sample. In this report, all stratification decisions were made before undertaking the analyses.
We have considered several potential explanations for the finding of maternal history as a strong risk factor for wheeze in males and females, and paternal history as a strong risk factor for wheeze in females but a weak risk factor in males. Several of these (maternal–fetal interactions, genomic imprinting) only provide an incomplete explanation. We suggest that asthma might possibly be partly explained as an X-linked recessive disorder in the context of a complex genetic disorder. In short, if asthma is an X-linked recessive disorder, males should have a higher incidence of disease because they only have one copy of the X chromosome, whereas females need an abnormal X chromosome from both parents to manifest disease. However, because of X inactivation, heterozygous females may still develop a milder form of disease. Maternal history would be a strong risk factor because it would affect both sons and daughters. Paternal history would be a risk factor for asthma in females, who receive an X chromosome from their father, but not for males, who do not.
This X-linked recessive disorder hypothesis alone cannot explain the increased incidence of wheeze among adolescent females. However, several studies have suggested that female sex hormones influence asthma (41
). Atopy, measured by skin-prick test, changes during the menstrual cycle (42
). When estrogen levels are high, wheal and flare responses increase (42
). The proliferation of peripheral blood monocytes to pokeweed mitogen is increased in the presence of estrogen, whereas testosterone inhibits this response (45
This analysis of our longitudinal birth cohort study suggests different mechanisms for the development of asthma at different times between males and females. The possibility that asthma may in part be an X-linked recessive disorder, explaining the different effects of maternal and paternal history of atopy, and that the gene products on the X chromosome that cause asthma are subsequently influenced by changes in sex hormones, needs to be further tested in genetic, epidemiologic, and clinical studies (47