Does RAGE protect smokers from COPD?

To the Editors:

We read with interest the article by Smith et al. [1], which showed a positive correlation between plasma soluble receptor for advanced glycation end-products (sRAGE) and forced expiratory volume in 1 s (FEV₁) in patients with chronic obstructive pulmonary disease (COPD). Here, we outline the results of recent genetic epidemiological studies that suggest the advanced glycosylation end product-specific receptor (AGER) gene, which encodes sRAGE, may also have a role in the development of COPD.

Two recent large genome-wide association (GWA) studies conclude that a locus on chromosome 6p21 is associated with lung function (FEV₁ and FEV₁/forced vital capacity) [2, 3], directly implicating the AGER gene, which is known to be expressed in alveolar epithelial cells [2]. However, this association was made in populations dominated by nonsmokers and did not specifically examine the effect in chronic smokers. We and others have proposed that COPD results from the combined effect of chronic smoking exposure and the presence or absence of a variable combination of protective and susceptible genetic variants [4, 5]. In this regard, we have examined the same AGER variant (single-nucleotide polymorphism (SNP)) reported in the GWA studies (rs2070600) in 484 smokers with normal lung function (“resistant” smokers) and 455 matched smokers with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage ≥2 on pre-bronchodilator spirometry). We found that the minor allele (T allele or CT/TT genotype) of the AGER SNP was more frequently found in resistant smokers compared with those with COPD (15 versus 10%; OR 0.60, 95% CI 0.40–0.91; p = 0.01) [6]. The T allele of this SNP converts glycine to serine at position 82 in the third exon encoding the sRAGE protein (a nonsynonymous change altering polarity at this position) and has been shown to be associated with both reduced serum sRAGE levels and increased sRAGE signalling compared with the more common C allele [1]. This change in sRAGE signalling affects downstream gene expression through mitogen-activated protein kinases and nuclear factor-κB, both of which have been implicated in the inflammatory response in COPD.

Collectively, these studies suggest that the AGER gene (encoding sRAGE) may play a role in the development of COPD. sRAGE has systemic anti-inflammatory activity that may have relevance in lung tissue, which is both highly vascular and extensively exposed to various pro-inflammatory aeropollutant insults [1]. Smoking is the most well-known of these aeropollutant exposures and also the most easily quantified, albeit retrospectively. This makes COPD an excellent model with which to examine gene–environment interactions in order to identify genetic variants conferring either protective or susceptibility effects. That COPD is associated with low plasma levels of a ubiquitous systemic anti-inflammatory mediator like sRAGE [1] is somewhat analogous to α₁-antitrypsin deficiency. It is also consistent with the findings that, when compared with resistant smokers, smokers with COPD less frequently carry other SNP variants implicated in pulmonary–systemic anti-oxidant/anti-inflammatory activity (e.g. extracellular superoxide dismutase (SOD3), protective effect [4]; Hedgehog-interacting protein (HHIP), protective effect 6; and the family with sequence familiarity 13 member A (FAM13A), protective effect [6]). These findings suggest that SNPs conferring a resistant (protective) effect maybe just as (or even more) important as susceptible SNPs.

Such an observation has major implications in the genetics of smoking-related lung disease, where exposure to smoking may result in quite different outcomes due to the genetic makeup of the person exposed. First, this is very relevant to study design, as prospective epidemiological studies show 60–70% of chronic smokers maintain normal or near-normal lung function (adjusted FEV₁) despite decades of smoking [7], while the remainder develop COPD of variable severity. In contrast with light smokers or nonsmokers, where the distribution of adjusted FEV₁ is normal, chronic smokers show a trimodal FEV₁ distribution consistent with a moderating genetic effect [8]. Therefore, recruitment of unaffected (resistant) smokers is as important as the recruitment of smokers with COPD to correctly assign smokers as resistant or susceptible. Secondly, if the mechanisms underlying the protective genetic effects can be better understood, then drugs simulating these protective effects (e.g. statins [9, 10]) may help prevent the development of COPD. While further genetic studies will be required to establish the functional variant(s) underlying the association of AGER with COPD, further discovery of novel pathogenetic pathways underlying responsiveness to smoking exposure (and development of COPD) are likely to emerge through well-designed genetic epidemiological studies.

• ©ERS 2011