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National Heart and Lung Institute, Imperial College, London, United Kingdom
Correspondence and requests for reprints should be addressed to William O.C. Cookson M.D., D.Phil., Professor of Respiratory Genetics, National Heart and Lung Institute, Imperial College, London, UK. E-mail: william.cookson{at}imperial.ac.uk
Complex genetic diseases are illnesses that cluster in families and are due to a combination of environmental and genetic factors. A genetic component to chronic obstructive pulmonary disease (COPD) is suggested by the observation that most smokers do not develop chronic irreversible airflow limitation. In addition, familial clustering of COPD is well recognized and well documented (1, 2), and the rate of decline in lung function in the general population has a heritability of approximately 50% (3).
COPD is unique among complex genetic diseases in that the environmental inducer of the disease is usually completely obvious, and that the level of exposure can usually be documented with some precision. The high mortality and morbidity associated with COPD, and its chronic and progressive nature, has prompted the use of molecular genetic studies in an attempt to identify susceptibility factors for the disease. The eventual aim of such studies is to develop effective therapy. In addition, the early identification of genetic susceptibility to COPD among cigarette smokers may be an essential element in prevention of disease.
MOLECULAR GENETICS
The science of genetics depends on the study of variation (polymorphism), and the molecular geneticist is trying to identify polymorphism in DNA that results in an altered phenotype (the presence of disease) in particular environmental circumstances.
Gene identification depends on two general approaches. The first of these involves the study of candidate genes, in which polymorphisms are identified in genes of interest, and then are tested for differences in frequency in cases and control subjects with disease. Association studies may also be carried out in families. Family-based tests of association such as the transmission disequilibrium test (TDT) may be of particular value because they control for the effects of genetic admixture in the population to be studied (4).
Candidate gene studies address only a narrow range of hypotheses that revolve around the known function of the gene selected for study. The alternative approach is that of positional cloning (originally known as reverse genetics). Positional cloning begins with the finding of chromosomal regions that are consistently inherited with the disease in families (genetic linkage).
CANDIDATE GENES IN COPD
The biomedical literature is now filling rapidly with candidate gene studies. Unfortunately, many reports of positive results fail to be reproduced. In interpreting such studies it is important to realize that any gene contains many polymorphisms (usually single nucleotide polymorphisms or SNPs) that occur approximately every 500 base pairs. The great majority of these SNPs will not affect coding sequences. Although susceptibility to common complex diseases may often be mediated through regulatory sequences of genes, most SNPS do not have any impact at all on gene function.
The large number of SNPs in any given gene makes it facile for inexperienced investigators to carry out multiple comparisons which are often uncorrected and which easily lead to spurious claims of significance. These difficulties have been reviewed recently by Ott (5). He suggests that the prior probability that any SNP will indeed impact on disease susceptibility is very small and that this prior probability should be taken into account in estimating whether a novel association is real. He indicates that the minimum criterion for acceptance of a report of association in a biomedical journal should be a p value less than 0.005, after correction for multiple comparisons (5). In order to take a candidate gene study seriously, it is also desirable, if not mandatory, for some evidence to be provided that the associated SNPs impact on function.
There have been several studies of various candidate genes in COPD (reviewed in Reference 6). The archetypical COPD susceptibility gene is 
1-antitrypsin. 1-Antitrypsin is a SERPIN (reviewed by David Lomas in this issue; see pages 499–501) which has a highly selective action against neutrophil elastase.
Given the specificity of the action of 1-antitrypsin for a particular substrate, it may be naïve to carry out a blanket search for the effects of other proteinase inhibitors on COPD susceptibility. The suggestion that 1-antichymotrypsin may be a susceptibility factor has not been replicated (6). Matrix metalloproteinases have been implicated in murine models of COPD (7), but polymorphisms in these genes have not yet found a clear role in human COPD. However, other SERPINS may have effects on COPD, in particular those that may be discovered to be expressed in the airway epithelium. SERPINE2 is an inhibitor of plasminogen activator and has been implicated by genetic mapping studies on chromosome 2q33-35 (DeMeo and colleagues, this issue, page 502; Reference 8).
Other studies have examined xenobiotic metabolizing enzymes (such as microsomal epoxide hydrolase [EPHX1] and glutathione S-transferases [GSTM1 and GSTT1 and GSTP1]) (6). Antioxidants such as Heme oxygenase 1 (HMOX1) have also been tested. The results from all of these studies have not in general been replicated (6, 9).
TGF-ß1 is an important antiinflammatory and profibrotic chemokine, and polymorphisms in its gene have been consistently associated with COPD in different studies (10, 11). The understanding of the mechanisms of this gene in COPD is rudimentary. TNF- is a proinflammatory cytokine with known polymorphisms that influence many inflammatory disorders, but the evidence for its involvement has been equivocal (6).
OTHER POTENTIAL CANDIDATE GENES
It may be of interest to speculate about other potential classes of candidate genes. Patients with COPD exhibit exceptional patterns of behavior, in that they continue to smoke cigarettes despite feeling the dramatic effects of progressive ill health. Addictive behavior is among the most heritable psychiatric traits (12), and the public health impact of gene discovery for addiction vulnerability is potentially very large (13). Intriguingly, variants in the SLC6A3 dopamine transporter and the DRD2 dopamine receptor have been suggested to modify smoking behavior (14, 15). It might therefore be worthwhile to address some attention to the type of study design that could systematically identify genes for cigarette addiction in patients with COPD.
The results of several studies have indicated the potential importance of apoptosis in generating emphysema and COPD (16, 17), and it is quite possible that polymorphisms in genes upstream of apoptosis effectors may be of relevance to the disease process. Histone deacylases (HDACs) show disordered regulation in COPD (18), and these genes might also be considered to be novel candidates.
Asthma and COPD are both airway diseases, and it is likely that they share some mechanisms. The identification of genes causing susceptibility to asthma is consistently emphasizing the importance of innate rather than adaptive immunity (19). Several of these genes, including GPRA, PHF11, and DPP10, warrant examination for a role in COPD.
GENETIC LINKAGE STUDIES AND COPD
Positional cloning is much more likely than candidate gene studies to identify novel genetic effects. Genetic linkage studies are very powerful for the study of single gene disorders, but have limited power in complex genetic disorders when many genes are likely to be acting and there is no established model for the inheritance of a given disease. For this reason and for many diseases, even highly ambitious genetic linkage studies involving several hundreds of families have often failed to deliver conclusive results.
The first genetic linkage study for COPD was carried out by Silverman and coworkers (20, 21). These investigators studied families with severe early onset COPD, reasoning that genetic effects were more likely to be found in these individuals. Their initial study identified several regions of weak linkage, but no regions that showed genome-wide significance or unequivocal evidence for a susceptibility gene on a particular chromosomal segment (20). Subsequently they recruited further families and studied additional phenotypes such as the FEV1/FVC ratio (21). These additional studies strengthen the evidence for linkage on chromosome 2, in a region which contains the SERPINE2 gene.
An independent genome-wide scan of pulmonary function measures in the National Heart, Lung, and Blood Institute Family Heart Study found that the FEV1/FVC ratio was significantly linked to the short arm of chromosome 4, with no obvious overlap of linkages with the COPD studies described above. A genome screen of a large multicenter family collection has been carried out by GlaxoSmithKline (Stvenage, UK) and their collaborators. The results of this substantial study are awaited with interest.
POST-GENOME GENETICS
Although positional cloning can discover more that is new and unexpected than candidate gene studies, it is now recognized that genetic linkage statistics are far less powerful than those that detect association (22). The challenge has then become the development of systematic association studies of all human genes, or "whole genome association." The estimates of the number of polymorphisms necessary to cover all human genes vary between 100,000 and 500,000.
Following the completion of the human genome project, the entire human genetic sequence is publicly available and a systematic search for all common human genetic variation (the Hapmap project: http://www.hapmap.org/) is well advanced. These advances in knowledge have been matched with advances in technology that allow high throughput genotyping of thousands of polymorphisms on hundreds or thousands of subjects, together with the examination of the expression of all human genes in samples of cells or tissues. As a consequence, the molecular geneticist now has a remarkable set of tools to aid in gene discovery.
CONCLUSIONS
Genetic studies of the pathogenesis of COPD are at a very early stage. However, awareness of the need for large samples of carefully phenotyped patients, together with the ready availability of technology that allows large-scale genotyping of candidate genes as well as whole genome association testing, will have a significant impact on COPD within the short to medium term.
FOOTNOTES
Conflict of Interest Statement: W.O.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 16, 2006; accepted in final form April 13, 2006)
REFERENCES
This article has been cited by other articles:
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  Z. Ammous, N. R. Hackett, M. W. Butler, T. Raman, I. Dolgalev, T. P. O'Connor, B.-G. Harvey, and R. G. Crystal Variability in Small Airway Epithelial Gene Expression Among Normal Smokers Chest, June 1, 2008; 133(6): 1344 - 1353. [Abstract] [Full Text] [PDF]
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