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© Kamla-Raj 2002

IJHG 2(1): 27-31 (2002)

The Role of Gene-Environment Interactions in the Development of Respiratory Disorders

Dharam P. Agarwal

Institute of Human Genetics, University of Hamburg, 22529 Hamburg, Butenfeld 42, Germany

KEY WORDS Pulmonary diseases; single gene defects; environmental risk factors; adaptive responses.

ABSTRACT Gene-environment interactions are thought to be critical for several respiratory diseases such as COPD and lung cancer. For some pulmonary diseases, the etiology is well understood as a function of single gene defects; for others, the etiology is mainly determined by exposure to some strong environmental risk factor. But for the overwhelming majority of diseases of the respiratory systems, it is clear that the greatest magnitude of disease burden relates to complex interactions between multiple determinants in one’s environment and one’s genetic blueprint. Understanding the fundamental gene-environmental interactions in the development of respiratory disorders such as asthma should lead to earlier identification of susceptible individuals and more effective approaches for disease prevention. Moreover, identifying the genes and the pathways that serve as genetic modifiers of adaptive responses to the changing environmental stimuli could lead to new insights into respiratory biology and the identification of new therapeutic targets.

INTRODUCTION

action between genes and the environment plays a major role in the pathogenesis of the most com- mon respiratory diseases. Environmental stimuli may activate conserved genetic responses in the lungs and blood inflammatory cells, and thereby initiate or modify the course of the disease pro- cess, acting to promote or suppress the disease phenotype. In many instances, discrete signal- ing pathways are triggered that allow people to adapt to new environmental stimuli or acquired disease states. Identifying the genes and the pathways that serve as genetic modifiers of adap- tive responses to the changing environmental stimuli could lead to new insights into respira- tory biology and the identification of new thera- peutic targets. The primary focus of this presen- tation is to review the interrelationship between (1) certain environmental factors and genetic susceptibility to respiratory diseases; and (2) evaluate candidate genes that have been linked to most common respiratory diseases in ongo- ing molecular genetics studies (Xu et al. 2001).

Great progress has been made in understand- ing the genetic and environmental basis of respi- ratory diseases. For some pulmonary diseases, the etiology is well understood as a function of single gene defects; for others, the etiology is mainly determined by exposure to some strong environmental risk factor. But for the overwhelm- ing majority of diseases of the respiratory sys- tems, it is clear that the greatest magnitude of disease burden relates to complex interactions between multiple determinants in one’s environ- ment and one’s genetic blueprint (Au et al. 2001). Even conditions with a single gene defect have widely differing phenotypes within and between families, partly based on gene modifications and distinctive cellular milieus and partly on the ba- sis of divergent environments. Thus, the inter-

Correspondence to: Dr. Dharam P. Agarwal, Ph.D., D.Sc., Professor of Human Genetics, Institute of Human Genetics, University of Hamburg, Butenfeld 42, 22529 Hamburg, Germany Phone: (+4940) 42803 4586; Fax: (+4940) 42803 3122, Email: agarwal@uke.uni-hamburg.de

GENETIC FACTORS

Recent attention is focused on understand- ing the genetic basis for individual susceptibil- ity to the development of allergic as well as res- piratory diseases (Feijen et al. 2000; Silverman, 2001). In more recent studies, an emphasis has been concentrated on establishing an associa- tion between inheritance of polymorphic chemi- cal metabolizing genes and development of en- vironmental cancer (e.g., lung cancer among ciga- rette smokers). The early reports of such asso- ciations have been very encouraging (Mucci et al. 2001). However, some reported positive asso- ciations were not substantiated in subsequent studies using larger sample sizes and different ethnic populations (Au et al. 2001). Some con- founding factors that contribute to the discrep- ancies include ethnic-dependent distribution of variant gene alleles, differential expression of metabolizing genes, and inadequate study de- sign.

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