The term environment is used in the most
„ „ g e n e r a l w a y t d o s i g n i f y a l l c h e m i c a l , p h y s i c a l , a n biologic agents with which humans come in con- tact, whether that contact is via air, water or food, and whether the contact is occupational, resi- dential, lifestyle, or whatever. In addition, it in- cludes the social milieu which mediates those contacts and which provides a psychological dimension to the human environment. There are a wide variety of known and suspected environ- mental risk factors for respiratory diseases (Weiss 1999; Walter et al. 2000). Epidemiologic research has demonstrated the important roles played by such factors as smoking, diet, alcoholism, pov- erty, social support networks, urban air pollu- tion, sedentary lifestyle, infectious agents, and a variety of occupational dusts and fumes (Barnes 1999). These factors have been linked to one or more classes of respiratory disease. Whether measured externally (e.g., industrial hygiene) or internally (e.g., biomarkers of exposure), it is be- coming possible to gain greater knowledge of the complex environments in which we live. In regard to chronic diseases, the challenge is not only to measure environmental factors, but to measure those that were present at the etiologi- cally relevant time (i.e., years or even decades
before clinical manifestation of disease).
By taking into account both of these dimen- sions (gene and environment) simultaneously, it will be possible to dramatically increase the ca- pacity to understand what is happening in the genetic dimension and in the environmental di- mension (Walter et al. 2000). This will improve our capacity to: a) identify and characterize the genetic determinants of disease; b) identify and characterize the environmental determinants of disease so that preventive strategies can be planned; c) identify high-risk individuals in the population for targeted prevention; d) reveal novel pathways in these diseases as targets for new therapeutic strategies; and e) tailor drug therapy using genotype information to maximize the beneficial effects and minimize the adverse side effects of new pharmacological therapies.
Few diseases are the consequence of a single genetic or environmental event (Williams 2001). For example, only a small percentage of all can- cer cases can be attributed to a single defective or mutant gene, typically identified from familial
DHARAM P. AGARWAL
clusters of disease (Almand and Carbone 2001). Instead, common allelic variants of susceptibil- ity genes with relatively low penetrance account for a higher percentage of cancers and other chronic diseases overall. Thus, properly control- ling environmental, occupational, or lifestyle ex- posures could prevent more diseases than just those caused by rare, highly penetrant alleles that lead to familial clusters. To get a more accu- rate picture of risk from exposures, researchers need to understand the nature, significance, and distribution of susceptible genotypes in the gen- eral population. Molecular and genetic tech- niques advanced by the Human Genome Project now make possible studies of individual differ- ences in susceptibility to diseases and dysfunc- tion linked to environmental exposure.
EXMPLES OF GENE-ENVIRONMENT INTERACTIONS IN RESIPIRATORY DISEASES
Chronic Obstructive Pulmonary Disease (COPD)
Chronic obstructive pulmonary disease, or COPD, is a disease that encompasses one or more of the following: (1) emphysema; (2) chronic bron- chitis; and (3) chronic asthma. Current under- standing of the pathogenesis of COPD, a source of substantial morbidity and mortality, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental fac- tors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflamma- tory protective mechanisms likely underlies the heritability of COPD observed in family studies (Miki and Satoh 1999; Weiss 1999; Silverman, 2001).
A variety of studies have examined candidate gene loci with association studies, comparing the distribution of variants in genes hypothesized to be involved in the development of COPD in COPD patients and control subjects. For most genetic loci which have been tested, there have been inconsistent results (Silverman 2001). Ge- netic heterogeneity could contribute to difficulty in replicating associations between studies. In addition, case-control association studies are susceptible to supporting associations based