Rethinking genetic models of asthma: the role of environmental modifiers

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Asthma is a common, chronic disease with a complex etiology. To date, more than 35 genes have been associated with asthma or related phenotypes in multiple populations, but none of them has been shown to contribute to risk in all populations studied. We suggest that genetic susceptibility is both context dependent and developmentally regulated, and that ignoring the environmental context will miss many important associations and clues to pathogenesis. We define ‘environment’ broadly to include the in utero environment, maternal affection status and sex, and propose that epigenetic mechanisms are the link between our genes and our environment.

Introduction

The past few years have witnessed remarkable progress in unraveling the genetics of asthma using both genome-wide linkage and candidate-gene-association approaches. An appreciation of the complexity of asthma susceptibility together with the availability of powerful genetic and genomic tools have resulted in the identification of >35 genes that are likely to contribute to asthma susceptibility and pathogenesis (Table 1). Recent studies have further demonstrated that genetic susceptibility is both context dependent and developmentally regulated. In this review, we will discuss the evidence for this statement and the different layers of environmental context that might influence risk, focusing on papers published since 2004.

Section snippets

Asthma gene discovery 2005

Nearly six years after the first genome-wide linkage study for asthma and related phenotypes was reported in 1996 [1], an asthma and bronchial hyperresponsivenss (BHR) gene was identified by positional cloning following linkage studies in human families [2]. Shortly thereafter, five additional asthma, BHR or atopy genes were positionally cloned by groups from around the world (Table 1; [3, 4, 5, 6•, 7]). These studies both validate the utility of genome-wide approaches to gene discovery and, as

Gene–environment interactions and asthma susceptibility

The importance of gene–environment interactions for asthma susceptibility is supported by the sheer number of studies published on this topic in the past few years (reviewed in [13, 39, 40, 41]). Significant interactions, demonstrated in both linkage and association studies, indicate that many early life exposures influence the risk for asthma and related phenotypes in a genotype-specific manner. These include exposure to endotoxins [36, 42, 43•], viruses [44, 45], pets [46], daycare

The in utero environment: maternal effects and asthma susceptibility

The early life environment influencing risk for asthma and atopy begins in utero [56, 57]. Although all relevant exposures are not known, the greater risk for asthma in children of mothers with asthma compared with children of fathers with asthma [40, 57, 58, 59] attests to the importance of the prenatal environment on subsequent risk. A ‘parent-of-origin’ effect, in which an allele is associated with asthma or atopy only when it is inherited from the mother (in this example), has been reported

Sex as an environmental factor

Although sex is genetically determined, by six weeks gestation the molecular, cellular and physiological milieus differ between male and female fetuses, and these differences persist throughout life. In this context, therefore, sex can be considered an environmental factor that could influence disease risk in a genotype-specific manner. This might be particularly important to consider for diseases with skewed sex ratios, such as asthma. In fact, it is perhaps one of the best established

Epigenetics: the link between genes and environment

Epigenetics refers to stable and heritable (or potentially heritable) changes in gene expression that do not involve changes in DNA sequence [69••]. Epigenetic mechanisms, such as DNA methylation, histone deacetylation and other modes of chromatin remodeling, ensure that genes are appropriately expressed or silenced with respect to developmental stage and cell type. In the context of human disease, epigenetics has been most extensively studied in the context of imprinting, in which DNA

Conclusions and future directions

We propose four models of asthma susceptibility that include interactions with environmental variables (Figure 2). Although the focus of this review has been on ‘environmental’ factors that influence risk for asthma in a genotype-specific manner, however, the biology is even more complex. Not only are gene–environment interactions important contributors to risk but also gene–gene and gene–gene–environment and gene–environment–environment interactions, and so on. For example, maternal asthma and

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank Nancy Cox and Fernando Martinez for helpful discussions. This work was supported in part by grants from the National Institutes of Health: HL56399, HL66533, HL70831, HL72414; EET is supported by T32 HL07605.

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