The hypothesis that subjects who develop COPD have genetic susceptibility to high-risk environments requires substantiation through an integrative model. The two most frequently used approaches in conditions in which gene-environment interactions are suspected include the “bottom-up” and “top-down” methods.
In the “bottom-up” approach, individual genetic and environmental factors are identified. The limitations of this approach are the difficulties in establishing statistical validity and in quantifying the gene-gene and gene-environment interactions. The “top-down” approach considers the risks at the population level, using twin and family association studies, as well as data on environmental factors in determining the trait. The major limitation of this approach is the impact of multiple genetic variants, as well as the whole genome sequence of each individual, on disease susceptibility, which leads to an increasingly intractable algebra (Wallace 2006
In the “bottom-up” approach, genetic susceptibility studies have demonstrated that in addition to familial aggregation, TNF-α and IL-13 promoter polymorphisms, as well as TIMP-2 polymorphisms, are significantly associated with the presence of smoking-related COPD, whereas SNPs in MMP1 and MMP12, in the anti-oxidant genes GSTM1, GSTT1, GSTP1, HMOX-1, and mEPHX are associated with an accelerated decline of lung function in COPD (Molfino 2004a
). More recently, SNPs have also been reported in relatives of patients with COPD, or associated with lung hyperinflation or other sub phenotypes (eg, signs, symptoms, or exercise tests in COPD).
Few of these results have been reproduced in other studies (Molfino 2007a
). One potential explanation maybe the low frequency of SNPs with an occurrence of approximately one SNP in 300–500 base pairs in the human genome, it is possible that some of the associations were random. Therefore, a P
value <0.005 and some plausible pathophysiological mechanism by which the SNP is relevant in COPD are highly desirable (Cookson 2006
). Furthermore, in the “bottom-up” approach, rather than searching for direct main-effect associations between candidate genes and COPD, other experimental designs may identify how the genotype can moderate the response of a subject to environmental stimuli. In this regard, subjects carrying a variable number of tandem repeat polymorphisms in the D4 dopamine receptor gene experienced a craving significantly more often when in the presence of another smoker (Hutchinson et al 2002
). Results of psychiatry studies will add complexity to the possible gene-environment interaction in COPD, since addiction is the main cause of cigarette smoking.
New approaches such as genome-wide association studies (GWAS) may be able to pinpoint genetic loci associated with COPD or its subphenotypes (Silverman 2006
) This approach can be robust if one assumes the presence of non-confounder factors and no interaction with the environment. Advantages include reduced costs, since GWAS often follow a staged design, in which a proportion of samples are genotyped first and a proportion of the most promising markers are genotyped later in the remaining samples (Ye et al 2005
). The standard approach is to focus on findings that are statistically significant when stage 2 data are analyzed; an alternative method is to analyze the results from different stages jointly (Skol et al 2007). In GWAS, the associations of the genome information (eg, SNPs) among different subjects, and the associations between different genetic loci and the phenotype (eg, FEV1
decline) can be expressed using probability functions. Based on these functions, reliable conclusions can be obtained about the associations between phenotype and genes using SNPs—called tagging SNPs (Molfino 2007a
). Some limitations of GWAS include: the phenotype must be well characterized to enable selection of patients likely to share the genetic cause of COPD; thousands of patients and control subjects are needed to ensure the statistical reliability of the study; and bioinformatics challenges remain regarding identification of true positives. Another potential limitation involves the possibility of missing particular mutations in COPD, which may not be tagged by a specific SNP (Molfino 2007a
). Moreover, the sequence of the human genome continues to uncover other forms of genetic variation (apparently normal) such as copy-number variation. Copy-number variations are frequent and inheritable, and include the deletion or duplication of DNA in ≥1 gene and the presence of ≥2 copy-number variations. They may influence susceptibility to the environment because they can change gene dose and expression (Conrad and Antonarakis 2007
; Kehrer-Sawatzki 2007
; Stranger et al 2007
). Unless COPD is produced by a single gene disorder, it is possible that GWAS in COPD will only reveal genes that are associated with minimal or moderate susceptibility, as is the case with the already known environmental factors (Wallace 2006
Since the development of COPD appears to require that a highly predisposed individual be present in a high-risk environment, a 4-category model may also be useful as a starting point for “top-down” analysis () (Molfino 2007b
). This model, developed by Khoury and Wagener (1995)
, abandons the classical assumptions of twins studies, as well as the Fisher (1918)
assumption, which suggests that genes are risk factors for common traits in a manner dominated by an additive polygenic term. This model has been adapted and shown that there may be limited potential for reducing the incidence of common diseases, such as COPD, through environmental interventions targeted by genotype (Wallace 2006
Four-category model of gene-environment interaction in chronic obstructive pulmonary disease (COPD).
It appears that the individual genotype that determines the susceptibility to complex disease tends to be exaggerated by the classical models due to the assumption of “equal environment” in twin studies or no gene-environment interactions at all. The model proposed by Wallace reveals that inherited genetic variants may be important in determining susceptibility only for the relatively rare familial forms of disease (Wallace 2006
). Thus, the studies of familial aggregation may be incorrect, and the search for additional susceptibility genes may turn out to be largely fruitless.
It appears that there is a need to revise our assumptions on how COPD develops (Caspi and Moffitt 2006
; Molfino 2007b
) (). The gene-to-COPD approach assumes direct linear relations between genes and COPD (eg, PiZZ with severe phenotype). This model has been used to study a number of COPD phenotypes (eg, in broader COPD populations than the PiZZ homozygous). Subphenotypes are thought to have simpler genetic underpinnings than COPD itself. Thus, this assumption pursues the hypothesis that it will be easier to identify genes associated with subphenotypes than with the whole constellation of COPD signs and symptoms. This approach adds an intermediate measure to the final diagnosis of COPD (eg, the BODE index: body mass index, FEV1
, dyspnea, and exercise capacity index; ) (Celli et al 2004
Figure 4 Assumptions in models of gene-environment interactions in chronic obstructive pulmonary disease (COPD). BODE, multidimensional index including body mass index, airflow obstruction, dyspnea, and exercise capacity index. Adapted from Caspi and Moffitt (2006) (more ...)
A third approach () seeks to incorporate information about the environment (eg, pollutants). This approach of environment-gene interaction differs fundamentally from the “main-effects” approach, which assumes that genes cause COPD, an approach used in single-gene diseases (Fisher 1918
). The environment-gene approach assumes that the environment causes the disorder and that genes cause the susceptibility to pathogens (eg, women and children in SSA). There is no expectation of an association between gene and COPD in this model in the absence of environmental pollutants or pathogens. The environment-gene approach in COPD is based on the fact that COPD is due to a major environmental cause and that subjects show a heterogeneous response to that cause. The fourth approach is more complex because it includes an additional co-morbidity such as nicotine addiction (Caspi and Moffit 2006
). Therefore, it may be applicable to the majority of patients with COPD in the industrialized world.