Genetic findings suggest that COPD is associated with the chromosome 15q25 region, which includes the CHRNA5-CHRNA3-CHRNB4
cluster of cholinergic nicotinic receptor subunit genes [6
]. Our study only focused on the available case-control COPD studies for this region, and it is the most comprehensive meta-analysis to date on COPD and nAChR genetic susceptibility. We performed both allele-based and genotype-based comparisons. We also had data from the most recent published GWA studies (Bergen and COPACETI cohort [25
]). Of 7 reported variants in CHRNA
, we identified rs1051730 with an adequate number of studies for quantitative pooled-analysis. As shown, A-allele of rs1051730 was significantly associated with a risk of having COPD (OR 1.26, 95%CI 1.18-1.34, p < 10-5
). In addition, AA genotype, compared to GG genotype, showed statistically significant evidence of association with lower FEV1
% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and higher incidence of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).
There was limited data about the association between the susceptibility to COPD and other variants in CHRNA
. In the COPD GWA study, rs16969968 (which is in strong linkage disequilibrium with rs1051730) showed a weaker association than rs1051730 [26
]. In the same GWA study, rs8034191 was related to a higher risk of having COPD. An association between rs8034191 and FEV1 in emphysema was observed in individual studies [24
]. In a recently published meta-analysis with the primary objective to identify the variants affecting smoking quantity in chromosome 15q25, 3 data sets with COPD trait were used to analysis the relationship between COPD and rs16969968, rs588765, and rs578776, but only rs16969968 showed a suggestive association [12
The overlap of nAChR polymorphisms for nicotine dependence and COPD has led to the debate whether polymorphisms in CHRNA
have a direct effect on COPD or merely mediate smoking habits [8
]. Saccone et al
] reported a weak association between rs16969968 and COPD (OR 1.12, 95%CI 1.01-1.23, p = 0.01) after adjusting for cigarettes-per-day, and the estimate was lower than that for cigarettes-per-day. However, the analysis of Saccone et al
] included self-reported COPD and chronic bronchitis, and this might weaken the association between SNPs and COPD. Results of the current study indicated a stronger association between SNP rs1051730 and spirometer-confirmed COPD, and SNP rs1051730 directly impacts the development of COPD. ORs of SNP rs1051730 for COPD were increased whether the smoking amount was comparable between COPD and control group or not, although the statistical power was stronger when the smoking exposure amount was larger in COPD group than control group (Table ).
The acetylcholine receptors are expressed throughout the lung and mediate the direct effects of nicotine [31
]. Besides regulating cholinergic activities in the airways, recent studies demonstrated that they also played a role in cellular proliferation and inflammatory response in the lung [18
]. Therefore the nAChRs could not only be correlated to smoking traits such as cigarettes-per-day and smoking addition, but also could be related to other biological effects. Polymorphism of rs1051730 in 15q25 locus represents a synonymous G to A nucleotide exchange in the CHRNA3
gene. The genetic variant was correlated to the mRNA expression of nAChRs subunits [11
]. At the same time, SNP rs1051730 is in linkage disequilibrium with rs16969968, which changes an amino acid (D398N) in alpha5 nicotinic receptor subunits and alters receptor function [15
]. These two genetic variants in CHRNA3/5
gene cluster might work together and alter the function of nicotinic receptor in lung tissue and further increase the risk for COPD. Our findings showed that SNP rs1051730 was associated with a reduced FEV1
(Figure ), and this might be explained by the increase in airway contraction and mucus secretion due to the altered receptor function. An association was also observed with the presence of emphysema (Table ). In another study, rs1051730 was reported to be associated with emphysema severity in ex-smokers [24
]. The data was not included into the current pooled-analysis, because the emphysema severity was expressed in quantitive CT values and the genotype counting was not available. It is plausible that the alteration in peripheral nicotinic receptors might have an impact on tobacco induced tissue destruction. To confirm the direct effect of rs1051730 on COPD, further investigation is needed to measure the mRNA and protein expressions of nAChRs subunits in COPD lungs, as well as the impact of SNP rs1051730 on the functional alterations and its role in the development of COPD and in different subtypes of COPD.
COPD is a multi-factorial disease, and therefore, a variety of genes in the biological pathway of COPD might act together in the development and progression of the disease, and single polymorphism might have interactions with other genetic factors. Apart from SERPINA1
gene encoding the alpha-1 antitrypsin protein [33
], a series of genetic factors other than nAChR variants have been identified to influence susceptibility to COPD in 6 previous meta-analysis [5
]. These polymorphisms were the Tyr113His and His139Arg in EPHX1
variable number tandem repeat (VNTR) polymorphism, the GSTM1
null variant, Ile105Val (rs1695) in GSTP1
, rs2241712/rs1982073/rs6957/rs1800470 in TGFB1
, 308GA (rs1800629) in TNF
and rs1799896 in SOD3
. Furthermore, another gene IREB2
was also identified as a potential gene for COPD susceptibility [39
are both on chromosome 15q25. It was found that IREB2 protein and mRNA were increased in lung-tissue samples from COPD subjects in comparison to controls. However, further investigations are essentially required in order to understand more about the interaction between rs1051730 and other genes (such as IREB2
) for the pathogenesis of COPD in the future.
Our study has the following limitations. First, our study did not consider gene-by-smoking interactions. In all included studies except the Copenhagen City Heart Study, inclusion criteria on smoking history was similar in case and control group (Table ); however, the smoking amount were comparable only in COPACETIC cohort and LEUVEN cohort (Table ). Given the importance of smoking in the development of COPD and the known association between nAChR variants and smoking behavior[11
], future studies with equivalent smoking exposure in case and control subjects are required to address this limitation. Second, we only analyzed part of data of COPACETIC GWA study because the full set of results was not available. Third, the imaging protocols in the detection of emphysema are different in various studies. The number of studies for emphysema is therefore insufficient, because the heterogeneity of the calculating methods for emphysema severity. Fourth, all the subjects in the current meta-analysis are European-descendants. Future studies in Asian and African populations would help to determine the ethnic differences of the relationship between rs1051730 and COPD. Finally, publication bias might have influenced some of our results. Exclusion of case-reports, letters to editors and conference abstracts might have contributed to publication bias. Usually, studies with positive results have a greater chance to be published and studies with inconsistent results of association are usually not published, thus these can potentially increase publication bias in our analysis.
In summary, quantitative meta-analysis identified rs1051730 in CHRNA as a susceptibility variant for the development of COPD, in terms of both airway obstruction and parenchyma destruction. A-allele carriers have a higher risk for COPD, and have a lower FEV1%predicted and higher incidence of emphysema. However, many questions are still to be answered before establishing nAChRs as an interventional target for COPD. Epidemiologic analysis in different ethnic populations, the mediating effect of smoking exposure, and functional studies should be prioritized for further research.