Genetics and Gene-Environment Interactions in Childhood and Adult Onset Asthma

Abstract

Asthma is a heterogeneous disease that results from the complex interaction between genetic factors and environmental exposures that occur at critical periods throughout life. It seems plausible to regard childhood-onset and adult-onset asthma as different entities, each with a different pathophysiology, trajectory, and outcome. This review provides an overview about the role of genetics and gene-environment interactions in these two conditions. Looking at the genetic overlap between childhood and adult onset disease gives one window into whether there is a correlation, as well as to mechanism. A second window is offered by the genetics of the relationship between each type of asthma and other phenotypes e.g., obesity, chronic obstructive pulmonary disease (COPD), atopy, vitamin D levels, and inflammatory and immune status; and third, the genetic-specific responses to the many environmental exposures that influence risk throughout life, and particularly those that occur during early-life development. These represent a large number of possible combinations of genetic and environmental factors, at least 150 known genetic loci vs. tobacco smoke, outdoor air pollutants, indoor exposures, farming environment, and microbial exposures. Considering time of asthma onset extends the two-dimensional problem of gene-environment interactions to a three-dimensional problem, since identified gene-environment interactions seldom replicate for childhood and adult asthma, which suggests that asthma susceptibility to environmental exposures may biologically differ from early life to adulthood as a result of different pathways and mechanisms of the disease.

Keywords: adulthood; asthma; childhood; environmental exposures; gene environment interactions; genetics.

Figure 1

MZ twin recurrence risk ratio vs. heritability under the multifactorial threshold model (probit-normal mixed model, MFT) for three levels of population prevalence (1 to 10%), which might represent asthma of different levels of severity. Note that the recurrence risk ratio is bounded by the trait prevalence (e.g., cannot exceed 10 if the prevalence is 10%). The recurrence risk to an ordinary sibling will correspond to the value for half the heritability (the kinship coefficient for sibs is 0.5).

Figure 2

Top association peaks from Pividori et al. (34) and Johansson et al. (24).

Figure 3

In (A), the adult asthma SNP, rs12617922, from Pividori et al. (34), and all top asthma SNPs from Zhu et al. (26) vs. their relationship to smoking status in the UK Bio Bank analysis of Canela-Xandri et al. (32). Red color denotes an asthma association P-value in Canela-Xandri et al. (32) <5 × 10⁻⁸. For smoking status, only the P-values for rs12617922 and rs301805 are <5 × 10⁻⁸. The rs301805 SNP also shows a strong association with eosinophil count, and was flagged by Ferreira et al. (35) as an allergy locus. In (B), smoking-associated SNPs [GWAS Catalog 2018] are tested—red color now denotes a smoking association P-value in Canela-Xandri et al. (32) < 5 × 10⁻⁸.

Figure 4

Estimated odds ratios for 24 independent top self-reported “any” asthma associated SNPs from 23 and Me (99) and the UK Biobank (32) samples: exact same SNP in or near RORA, ZBTB10, ZPBP2, GATA3, ID2, IL33, CD247, TSLP, RAD50, HLAC, STAT6, D2HGDH, RAD51B, ADAMTS4, SMAD3, TLR1, BACH2, PEX14, ADORA1, TNFSF4, CDHR3, CLEC16A, LPP, LRRC32.