be reversed. Asthma is a chronic inflammatory disorder characterised by airflow obstruction. The inflammatory process involves mast cells, antigen presenting cells, eosinophils, neutro- phils, airway epithelial cells and TH2 lympho- cytes. These cells produce a broad array of pro inflammatory mediators and cytokines that lead to the pathophysiological changes seen in asthma. The improved understanding of this com- plex disease, the specific cells and the complex mediators has lead to newer insights into the efficacy of various novel and potential therapies (Babu and Holgate 2000).
Asthma has strong genetic and environmen- tal components that interact both in the induc- tion and subsequent expression of the disease phenotypes (Barnes 1999; Holgate 1999; Weiss 1999; Wiesh et al. 1999). Asthma is a complex disease with a phenotype that has been clini- cally difficult to define. Associated phenotypes including bronchial hyperresponsiveness and atopy have provided useful objective alterna- tives in genetic and epidemiologic studies. Al- though asthma genes have not yet been identi- fied, much progress has been made toward this goal. Genetic studies indicate that multiple genes are involved in the pathogenesis of this disease, and chromosomal regions likely to harbor asthma susceptibility genes have been replicated in sev- eral studies. Environmental factors, including smoking, diet, and viral respiratory infections, have also been implicated in the etiology of asthma. Directly linking these exposures as causes of asthma, however, has also proved dif- ficult.
Furthermore, interaction between susceptibil- ity genes and environmental factors is probable and is a challenge currently being pursued by investigators worldwide. This phenomenon— denoted as effect modification of environmental exposure by genetic constitution, or gene by environment interaction—suggests that some genetic markers could indicate susceptibility to environmental factors. Thus, understanding the fundamental gene-environmental interactions in the development of asthma should lead to earlier identification of susceptible individuals and more effective approaches for disease prevention.
Lung cancer is a result of multiple gene-envi- ronment interactions occurring over several de- cades (Haugen et al. 2000; Almand and Carbone 2001). Lung cancer is a useful model for the study
DHARAM P. AGARWAL
of the interplay between genetic factors and en- vironmental exposure since the primary etiology is well established. Several polymorphic enzymes that may be important determinants of suscepti- bility have been demonstrated (Reszka and Wasowicz 2001). Data also provide evidence for sex differences in lung cancer susceptibility. Fur- thermore, certain chemical carcinogens may con- tribute to the carcinogenic process in the lung epithelial cells by inducing genomic instability either directly or indirectly through inflammatory processes. Our understanding of lung cancer biology has rapidly expanded in recent years. Lung cancer, unlike most human cancers, can be traced to an environmental risk factor in the ma- jority of cases, and this fact is reflected in the vast number of genetic alterations discovered in lung tumors whose pathogenesis is believed to be mediated by carcinogen exposure. The dis- covery of these alterations has led to a greater understanding of tumor development.
A vast number of studies are focused on in- vestigating genetic polymorphism in order to estimate genetic contribution to the development of cancer. Possible cancer susceptibility genes have been sought among oncogenes, tumor sup- pressor genes, DNA repair genes and genes en- coding phase I and phase II enzymes (Shields and Harris 2000).
Genetic Polymorphism of Glutathione S-Trans- ferase and Lung Cancer Risk
Large individual differences in the biotrans- formation of xenobiotics have been explained on the basis of genetic polymorphisms in some detoxifying enzymes, regardless of environmen- tal and occupational exposure (Mucci et al. 2001). Among these enzymes, glutathione S-trans- ferases (GST) constitute a large multigene family of phase II enzymes involved in detoxification of potentially genotoxic chemicals (Reszka and Wasowicz 2001). Five genetic polymorphisms of GST have been well documented (Strange et al. 2001). Total or partial deletions and (or) single nucleotide polymorphisms in alleles encoding GSTM1, GSTM3, GSTPI, GSTT1, GSTZ1 are as- sociated with reduction of enzymatic activity to- ward several substrates of different GST isoen- zymes. In addition, molecular epidemiology stud- ies indicate that a single genetic polymorphism of glutathione S-transferase appears to be a mod- erate lung cancer risk factor (Hou et al. 2001). However, the risk is higher when interactions with more GST polymorphisms and other risk factors