© 2002 American Thoracic Society
Genomics and Acute Respiratory Distress SyndromeDepartment of Anesthesiology and Intensive Care Medicine University of Bonn Bonn, Germany Research is starting to provide answers to questions regarding the incidence, severity, and outcome of lung failure by analyzing an individual's unique genetic code. What was exotic research just a few years ago is now becoming mainstream: genomics and acute complex diseases. What was a challenge to laboratory as well as epidemiologic techniques not long ago is about to be incorporated into broad clinical research, and it promises new diagnostic tools to prevent and cure organ failure. In this issue of AJRCCM (pp. 646–650), Marshall and coworkers very elegantly report on a genomic polymorphism of the angiotensin-converting enzyme (ACE) and its allele and genotype frequencies in patients with acute respiratory distress syndrome (ARDS) (1). For the first time, a positive association of a candidate gene displaying polymorphic variants (in this case, a well-known insertion/deletion polymorphism) with the incidence of, and outcome from, ARDS has been found. ARDS patients homozygous for the deletion and therefore carriers of the ACE DD genotype appear to be at high risk. Researchers understand that the pathophysiology of acute lung failure involves complex systems of inflammation, endothelial cell responses, modulation of fibroblast activity, and other mechanisms. This is one reason that improving the course and outcome of ARDS represents a major challenge for intensivists. The other reason is the lack of knowledge. Developing a definition of ARDS hardly helps in the understanding of this disease, and it does not recommend specific treatment. We do not know the key processes nor their timelines for causing ARDS. We do not know about proteins and messengers modulating responses to noxious injuries that determine the incidence and course of ARDS in an individual. Our understanding of inflammation, endothelial damage, and repair still resembles a patchwork. In comparison to severe sepsis, where key mediators and pathophysiologic processes are named and demonstrated according to Koch's postulate, lung failure, which appears simpler, is still obscure. Molecular tools are now used to extend our knowledge and from diagnostics to therapy will ultimately help improve outcome from lung failure. How can this happen? Marshall and colleagues show the way. Their approach of associating a candidate gene (ACE) with the incidence of and outcome from ARDS is promising. Intensivists are in need of diagnostic tools to identify populations at risk to direct resources and conduct therapeutic trials that employ individual inclusion criteria. In this view, the findings by Marshall and coworkers contribute to a set of genomic markers defining populations at risk in the future. Not every study is going to present a "new member" in this team of markers (2), but approaches examining functional genomics help find important candidate genes (3). Expression patterns of molecules upregulated or downregulated in pathophysiologic states like ARDS will augment our knowledge tremendously. Even genes that have not been previously associated with lung failure or have yet to be discovered will become detectable and screened for genomic variations and association with disease. The reported insertion/deletion ACE polymorphism has been tested in many other diseases like hypertension (4), type 2 diabetes (5), and myocardial infarction (6). In many studies, positive associations with incidence and/or severity of a disease were detectable, although conflicting results were presented in a minority of studies (7). These conflicting results may reflect differences in study populations and design as well as statistical power. Nevertheless, the pleiotropic gene product, ACE, may contribute not only to blood pressure–related diseases but may also regulate inflammatory states. This hypothesis is underlined by a very interesting study in children with meningococcal disease (8). Homozygotes with the DD ACE genotype showed markedly increased severity of illness when compared with heterozygotes. Thus, the ACE insertion/deletion polymorphism has to be regarded as a strong candidate in inflammatory diseases such as sepsis. A candidate gene for the association with disease counts as a strong candidate in case of functional implications of the particular genomic variation. In an elegant same-sex twin pair study, genomic variations were found to account for 43% of the ACE plasma level (9). ACE is a zinc metallopeptidase that not only converts angiotensin I to angiotensin II but also degrades bradykinin, which regulates vascular tone and cardiac functions. Other functions include neuronal metabolism, hematopoiesis, reproduction, and digestion. ACE is derived mainly from endothelial cells (10). As the lung represents the body's largest endothelial surface, individual differences, which may account for half of the variance of ACE plasma levels, may affect the incidence and course of ARDS, just as was demonstrated by Marshall and colleagues (1). Very clearly, this ACE genomic variation has its place in the set of candidate markers to be tested and retested in upcoming epidemiologic studies. Equivocal results in different well-powered studies will be needed to establish a genomic diagnostic tool that is capable of improving our daily practice. This study is the first step in a right direction. REFERENCES
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