Applications of the First-Generation Epigenetic Clocks to Asthma and Allergic Disease Research
The asthma phenotype, and in particular, allergic asthma, presents a test case for the utility of the epigenetic clock in studying prenatal and childhood traits and exposures over the lifespan. Asthma often begins in the early years and may be transient. The clinical presentation is heterogeneous, especially in early childhood, making timely diagnosis difficult19. Wheeze in young children may resolve without intervention or may persist and transition into asthma. In addition, there is an unexplained switch in the sex-specific prevalence of asthma between childhood and adolescence25. According to the atopic march theory78, asthma and allergic diseases begin in infancy, with the first presenting symptoms being eczema/atopic dermatitis, progressing to infant food allergies, then asthma and allergic rhinitis. The atopic march is thought to be initiated by environmental exposures, and it has been proposed that the impact of environmental exposures may be reflected in DNAm, explaining the heterogeneity of asthma19,20.
Genetic variants have been shown to account for ~61-75% of susceptibility to asthma79,80. Numerous genome-wide association studies have demonstrated associations between the HLA region and asthma and allergic disease. The remaining ~25-40% of the risk is thought to be due to environmental factors. Epigenome Wide Association Studies (EWAS) have repeatedly implicated DNAm in both childhood and adult asthma5,81,82.
One exposure of particular interest is viral infection, which may have either a punitive or protective effect, depending upon the age when infected and viral subtype. Infection may skew the immune response towards the Th2 pattern observed in allergy50,83,84. For example, infection with the respiratory syncytial virus (RSV) in infancy is associated with increased risk for asthma, and this effect appears to be mediated through changes in DNAm83-85. Differential methylation at three CpG sites, mapped to airway and immune response genes, can separate (with area under the curve (AUC) =1) children who will develop recurrent wheeze and asthma subsequent to an RSV infection from those who recover normally85.
The few available studies show a positive association between allergy and asthma and EAA19,20. Peng et al. found that EEAA was linked to asthma and allergic disease (i.e. atopy, food allergy) in Project Viva – a longitudinal birth cohort which included 408 mother-child pairs with blood DNAm data at mid-childhood (mean age: 7.8 years, range: 6.7-10.2 years)19. Epigenetic age as predicted by the pan-tissue Horvath clock and IEAA have also been associated with allergic disease19: the Peng study found a 1.21 increase in the odds of developing atopic disease and food allergy and 1.16 increase in the odds for asthma at mid-childhood for every one year increase in EA19. These results were independently replicated. A study examining DNAm of nasal epithelium cells of 547 Project Viva participants (mean age=12.9, range:11.9-15.3 years) showed increased EAA in children with asthma (0.74 years) and allergic asthma (1.30 years)20.
The epigenetic clock may provide a greater understanding of the sex-specific asthma prevalence between childhood and adulthood25,86. It is believed that hormonal fluctuations during puberty, menstruation, pregnancy and menopause are associated with asthma pathogenesis, exacerbations and disease severity25(Fig.1B&C ). Sex hormones are key to determining immune response87; thus, an epigenetic clock that captures early development and puberty may be crucial to understanding the relationship between EAA and asthma (Fig. 1C ). EAA has been shown to be affected by biological sex with males having higher acceleration rates compared to females77. This pattern is seen at mid-childhood (~year 7) with persistence into adolescence (~year 17) and adulthood61.
A study by Patel et al. identified 13 CpG sites with sex-specific methylation that were associated with the acquisition of asthma between the ages of 10 and 1888. Ten of these sites were replicated in an independent cohort. Epigenetic clocks may unravel the relationships between DNAm, asthma and sex, and how they are associated with the mechanisms of sex-reversal in asthma prevalence.