CHRONIC OBSTRUCTIVE PULMONARY DISEASE RISK
AND SMOKING CESSATION CHANGES INDUCED
BY CHRNA5-A3 AND CHRNB3-A6 VARIATION
IN A CHINESE MALE POPULATION
Zhao L1,, Zou L-Y2,, Cheng B-F3, Yu X-J4, Zou J-H5,*, Han W6,*
*Corresponding Author: Dr. Wei Han, Department of Pulmonary Medicine, Qingdao Municipal Hospital,
Qingdao University, No. 5 Donghai Mid Road, Qingdao, People’s Republic of China. Tel: +86-185-
6185-7838. E-mail: sallyhan1@163.com. And: Dr. Jian-Hong Zou, Center of Diseases Control of Qingdao
Shi-Bei District, No. 3 Deping Road, Qingdao, People’s Republic of China. Tel: +86-185-6185-7599.
E-mail: 277517366@qq.com
-Long Zhao, Ling-Yan Zou contributed equally to this study.
page: 51
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DISCUSSION
The purpose of our study was to investigate whether
SNPs in the two gene clusters are related to COPD and
smoking cessation in the Chinese population. We did not
find a significant association between the SNPs and COPD
risk in the smoking subjects. However, the SNP rs667282
in CHRNA3-A5 and rs4950 in CHRNB3-A6 showed a significant
association with an increased rate of successful
smoking cessation, in the Chinese COPD population, but
the rs3743073 did not show an association with smoking
cessation. These results suggest that the polymorphisms
of CHRNA3-A5 and CHRNB3-A6 may play a key role in
successful smoking cessation in Chinese COPD patients.
As far as we know, this is the first study to reveal the relationship
between SNP in CHRNA3-A5 and CHRNB3-A6
genes and COPD and smoking cessation.
Nicotinic acetylcholine receptor (CHRN) genes code
nAChRs, which bind to nicotinic that cause nicotinic dependence
and smoking-related diseases. Recently, the associations
of rs3743073 and rs667282 in CHRNA3-A5 and
rs4950 in CHRNB3-A6 with tobacco consumption and lung
cancer risk have been discovered [11,12,14,15]. Chronic
smoking and environmental factors contribute to the development
of lung cancer. Some studies show that COPD
is a risk factor for lung cancer, even in early stage COPD
[16-18]. The association between CHRNs and COPD and
lung cancer has been confirmed [11,19]. We speculate that
rs3743073, rs667282 and rs4950 may be associated with
COPD in smokers, but we did not study the role of CHRN
genetic variants with lung cancer. In addition, consistency
with the conclusions of the study of Budulac et al. [20],
CHRN gene variants are closely correlated with smoking
habits, but do not directly cause COPD.
The main reason that smokers are unable to quit is
nicotine dependence, and nicotine dependence has a relationship
with a series of diseases, especially COPD [21].
Smoking cessation is the only evidence-based intervention,
which can reduce the risk of developing COPD and slow
down the accelerated decline of lung function in patients
with COPD [21]. Nicotine dependence and smoking cessation
are influenced by genetic factors [14,15,22,23].
The study of Pérez-Rubio et al. [24] demonstrated that
rs6313 in HTR2A increased the risk for the early onset of
smoking. Nicotine dependence is strongly associated with
the decreased rate of initial abstinence and the high risk
of transition from lapse to relapse [25]. Gold and Lerman
[26] found that nicotine dependence and smoking cessation
have their respectively unique regulatory genes. Although
these phenotypes may share some genetic effects, it cannot
be considered that the genetic association of nicotine
dependence will translate into smoking cessation or vice
versa [26]. Studies have shown that CHRNs are strongly
associated with nicotine dependence [14,15,21,27]. Given the limited genetic contributions in nicotine dependence
and smoking cessation, more research of the genetic study
of smoking cessation is needed.
We observed a significant association between the
SNPs rs667282, and rs4950 and smoking status (still
smoking vs. non smoking: n = 823), indicating CHRNs
variants are associated with smoking cessation. Our results
agree with previous studies which show CHRNs
were significantly related to smoking cessation in different
populations [28,29]. Moreover, a number of other studies
concluded that association of CHRNs and smoking
cessation is limited [30,31]. For instance, Freathy et al.
[31] found that among Caucasian smokers, there was no
significant relationship between CHRNA5-A3-B4 gene
variation and smoking cessation treatment results. These
different conclusions may come from different groups of
people for each study, but further investigation is needed.
In the stratified study, the relationship between the
rs667282 genotype and successful smoking cessation was
more obvious in older subjects and lighter smokers. It is
remarkable that the successful smoking cessation was more
likely in older smokers than in younger smokers. The result
agrees with study of Chen et al. [32], which reported on
the CHRNA5-CHRNA3-CHRNB4 haplotypes. Compared
with low-risk haplotype (H1), high-risk haplotype (H3)
is associated with a later quitting age [30]. Knowing that
there is a genetic role in smoking cessation, individualized
treatment is particularly important. Doctors can adapt
a precise program for the smokers, especially for those
who have failed several attempts at cessation, based to
the genotypes of CHRNA5-A3-B4.
Our study also has its limitations. First, this was a
hospital-based case control study with limited numbers
of samples, and selection bias or recall bias may exist that
might affect the results. Secondly, COPD and smoking
cessation are influenced by complex factors. In terms of
genetic factors, there are multiple gene interaction, and
other unobserved variables could alter the results. Finally,
our results are only applicable to male smokers; a further
study of female smokers is needed.
In conclusion, this study reveals that CHRNA3-A5
and CHRNB3-A6 are associated with increased successful
smoking cessation in COPD smokers, and this could
provide a basis for formulation of a specific smoking cessation
program. As this study is a hospital-based case control
study, a larger multi-center study is needed to confirm the
conclusions, and more studies are needed to establish data
for different ethnic populations.
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