Gene-Environment Interactions in Asthma: With Apologies to William of Ockham

Abstract

Many environmental factors and a large number of genetic polymorphisms have been reported to be associated with asthma risk in different locales and at different ages. It seems that what we call asthma is a heterogeneous set of conditions for which the only common feature is recurrent airway obstruction that is at least partially responsive to usual asthma therapy. Recent studies in which environmental factors and genetic variants were studied concomitantly have suggested a potential unifying concept for the disease. It seems that asthma is a genetically mediated development dysregulation of diverse immune and airway responses to a variety of specific and nonspecific exposures. It thus seems improbable that most genetic variants associated with asthma influence the disease regardless of which environmental factors trigger it and at which lifetime phase they are present. More likely, the most important gene variants for asthma are polymorphisms that exert their influence on the network system controlling biological responses to asthma-related exposures.

Effect of Toll-like receptor 4 gene polymorphisms on work-related respiratory symptoms and sensitization to wheat flour in bakery workers

“…24 In recent years, the suggestion was made that the genetic effects of TLR4 polymorphisms on the biological responses to endotoxin exposure should be considered as controlling factors for work-related respiratory diseases under the concept of a gene-environment interaction. 25 Several studies have been performed to investigate the effects of TLR4 gene polymorphisms on occupational asthma induced by organic dust in, for example, swine farms or laboratories. 26,27 In this study, we found that workers exhibiting variants of the TLR4 promoter at -2027 AϾG and -1608 TϾC had lower work-related lower respiratory symptoms.…”

Status of Childhood Asthma in the United States, 1980–2007

“…This theory postulates that reduced exposure to infectious disease and environmental microbial contamination shifts the balance in children's developing immune systems away from fighting infection and toward atopic responses. [32][33][34] Numerous epidemiological associations with asthma and lung development have been documented, including increased body mass, 35,36 exposures to environmental risks (eg, close proximity to major roadways 37,38 ), and use of medications such as antibiotics and antiinflammatory agents. 39,40 There are inconsistencies across studies, and the relative contributions of these and other factors to the increase in asthma prevalence and/or the recent stabilization remain unknown.…”

“…There is growing agreement that asthma represents a spectrum of syndromes with multiple complex causes. 12,33,34 Research efforts continue to develop a better understanding of interactions between environmental factors and genotypes/phenotypes and differing susceptibility to risk factors.…”

The era of genome-wide association studies: opportunities and challenges for asthma genetics

“…There are several possible explanations for these discordant findings including insufficient power, linkage disequilibrium, population admixture, gene/environment (G/E) and gene/gene (G/G) interactions. 6,20 However, more importantly, the lack of replication may be a result of the complex pathogenesis of asthma, which involves genetic heterogeneity and polygenic mode of inheritance, with numerous disease-causing alleles of likely incomplete penetrance, individually small effects, possible parent of origin imprinting and co-existent environmental risk factors.…”

“…This is not unexpected considering allelic heterogeneity 17 and gene-by-environment interactions. 20 …”