Trends in Genetics
ReviewGene–environment interactions in human disease: nuisance or opportunity?
Section snippets
The problem: accounting for the heritability of common human diseases
Dissecting the genetics of common human diseases with complex etiologies continues to be challenging and the genetic architectures of these diseases remain elusive. Despite the many successes of genome-wide association studies (GWAS) during the past 4 years (e.g. 1, 2), there is a growing consensus that the common variants with modest effects on disease risk discovered through GWAS do not account for the majority of the estimated heritabilities of these diseases. This observation was initially
Asthma as a model for studying GEIs
Asthma is a heterogeneous disease that is characterized by reversible airway obstruction and airway inflammation. It is among the most common chronic diseases, affecting more than 300 million people worldwide [9]. Similar to other immune-mediated diseases, the prevalence of asthma is highest among inhabitants of developed countries and has risen significantly over the past few decades [10], especially in countries transitioning to a western lifestyle [9], attesting to the importance of
Microbial exposure, genotype and protection from asthma
One of the most-established and best-replicated GEI on risk for asthma or allergic disease is that resulting from interactions between the genotype for a promoter polymorphism (-159C/T, a.k.a. -260C/T or rs2569190) at the locus encoding a subunit of the endotoxin receptor on mononuclear cells (CD14) and exposure to microbes, as assessed by house-dust endotoxin levels 51, 52, having a pet in the house at birth 53, 54, working with laboratory animals [55], contact with farm animals [56] and
Epigenetics: the link between genes and environment?
Understanding the mechanisms that underlie GEIs is a formidable challenge. It is difficult enough to characterize the impact of polymorphisms on gene expression and function under static conditions (i.e. within a constant environment); it is considerably more challenging to elucidate the dynamic intertwining of polymorphic variation and environmental stimuli. This is why little has been published to date about the mechanisms of GEIs, and no major finding has yet been reported for asthma.
GWAS, GWIS and GEIs
The question of how much of the ‘missing’ heritability in GWAS will be accounted for by GEIs remains at this time, although genome-wide interaction studies (GWIS) are beginning to emerge. One of the greatest challenges for this unbiased approach to gene (or interaction) discovery is that of power (see 97, 98 for further discussion). The first GWIS for childhood asthma and farming exposures has recently been completed in approximately 1700 children from four rural regions in central Europe who
Conclusions and perspectives
It is for this and related reasons that animal models are often proposed as powerful tools for studies of complex interactions [102]. Although we agree that studies in model systems can provide valuable insights into the architecture of gene–gene, gene–environment and gene–gene–environment interactions [100], it is unclear that animal models will offer insights into specific interactions contributing to disease risk in humans because of the context dependency of these effects. By contrast,
Acknowledgments
This work was supported by National Institutes of Health grants HL085197, HL70831, HL101651 to C.O. and HL100800, HL66391, AI076715 to D.V. The authors acknowledge S.A. Willis-Owen and W. Valdar for first using the expression ‘nuisance or opportunity’ in the context of GEIs in their 2009 review and F.D. Martinez, J.E. Gern, R.J. Lemanske, E. von Mutius and M. Ege for helpful discussions. The authors apologize to those investigators whose work was not cited owing to space constraints.
Glossary
- Bronchial hyper-responsiveness (BHR)
- a clinical measure of airway reactivity, usually in response to inhaled methacholine, which many studies use as a criterion for asthma diagnosis.
- CD4+T cells
- the population of T cells (typically, with helper function) that express the CD4 surface marker and, depending on the cytokine milieu, will differentiate along the Th1 or Th2 pathway.
- Eczema
- an inflammatory skin disease that is particularly common in young children (also called atopic dermatitis).
- Endotoxin
- a
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