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浙江大学学报（农业与生命科学版） 40(4): 413~420, 2014
Journal of Zhejiang University (Agric. & Life Sci.)
http://www.journals.zju.edu.cn/agr
E-mail: [email protected]
DOI: 10.3785/j.issn.1008-9209.2014.04.214
Impacts of cigarette smoking on epistasis and gender-specific effects of
FEV1/FVC ratio in human
Xu Changwei1, Zhu Jun1,2,3* (1. Department of Mathematics, Zhejiang University, Hangzhou 310058, China; 2. Department of
Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310058, China; 3. Research Center for Air
Pollution and Health, Zhejiang University, Hangzhou 310058, China)
Summary The ratio of FEV1 (forced expiratory volume in one second) to FVC (forced vital capacity) is an index for
pulmonary obstruction measurement and one of the most significant predictors for chronic obstructive pulmonary disease
(COPD), which is a heritable multi-factorial disease. We present genome-wide association study (GWAS) to map the
genetic architecture of this trait and investigate the networks between the external factors (smoking and gender) and genetic
factors. By using a mixed linear model and a conditional model, we conducted GWAS in a cohort suffered COPD from the
U.S. National Heart, Lung and Blood Institute. Among 561 467 single nucleotide polymorphisms, we found 12 significant
quantitative trait SNPs (QTSs) fitted the full model. And for each of them, we demonstrated the mechanisms and
relationship between pulmonary function and genes detected. STIM2 and MRE11A (PEW-value<1×10–5) showed
unambiguous evidence of association with COPD. APOL3 (PEW-value<1×10–5) was influenced by different genders in
different ways and previous studies also implicated its associations with smoking behavior. The variation of genes MRE11A
and DNAJC15 was related to lung adenocarcinoma, which is a serious complication of COPD. The significant epistasis
effects of these genes suggested the possibility of multiple functional polymorphisms. These associations offer mechanistic
insight into pulmonary function regulation and networks between genetics factors and environmental factors, which
indicate potential ways for interventions to COPD and many other respiratory diseases.
Key words genome-wide association study; chronic obstructive pulmonary disease; epistasis; gender
CLC number Q 811.4; R 394.3
Document code A
吸烟对控制FEV1/FVC比率的基因上位性及性别互作效应的影响(英文).浙江大学学报（农业与生命科
学版）, 2014,40(4):413− 420
许昌巍1， 朱军1,2,3*（1.浙江大学数学系，杭州 310058；2.浙江大学农业与生物技术学院农学系，杭州 310058；3.
浙江大学空气污染与健康研究中心，杭州 310058）
摘要 1秒呼出气体体积（forced expiratory volume in one second，FEV1）与最大肺活量（forced vital capacity，
FVC）是肺部活动的重要指标.FEV1/FVC指数是诊断肺部疾病的重要指标，与基因、性别、吸烟和空气污染有
关.本文基于dbGaP数据库下载的不同民族人群疾病性状基因组和表现型数据，运用我们提出的混合线性模型方
法和关联分析软件QTXNetwork，对FEV1/FVC指数的遗传变异进行了全基因组关联分析.在561 467个单核苷酸
Foundation item: Project supported by the National Science Foundation of China (No. 31371250).
*Corresponding author: Zhu Jun, E-mail: [email protected]
Received: 2014-04-21; Accepted: 2014-06-09; Published online: 2014-07-25
URL:http://www.cnki.net/kcms/doi/10.3785/j.issn.1008-9209.2014.04.214.html
414
浙江大学学报（农业与生命科学版） 第 40 卷
多态性中，发现12个显著的数量性状SNPs (quantitative trait with single nucleotide polymorphisms，QTSs)，并
运用我们研制的BiopubInfo搜索工具验证了每个QTS的基因功能及其与肺功能之间的关系.结果表明：基因
STIM2和MRE11A（PEW 值<1×10–5 ）与慢性阻塞性肺病高度关联；基因APOL3（PEW 值<1×10–5）的影响因不同
性别而异，以往的研究也检测到该基因与吸烟的关联；基因MRE11A和DNAJC15与肺腺癌存在关联，这是慢性
阻塞性肺病的严重并发症.检测到显著的基因上位性效应,揭示了控制复杂性状基因功能的多效性；遗传关联结
果揭示了遗传效应与环境因素的关系，为检测和治疗慢性阻塞性肺病和其他呼吸系统疾病提供了潜在新途径.
关键词 全基因组关联分析； 慢性阻塞性肺病； 基因上位性； 性别
Chronic obstructive pulmonary disease (COPD),
also known as chronic obstructive lung disease (COLD),
chronic obstructive airway disease (COAD), chronic
airflow limitation (CAL), is the occurrence of chronic
bronchitis or emphysema, a pair of commonly co-existing
diseases of the lungs in which the airways become
narrowed[1]. COPD is the sixth leading cause of death
worldwide, the fourth leading cause of death in the United
States and the only leading cause of death that is steadily
increasing in frequency[2]. Unlike other lung diseases,
COPD is poorly reversible and usually gets worse over
time. In England, the estimated 842 100 of 50 million
people have a diagnosis of COPD[3]. In 1998, in an effort
to bring more attention to COPD, its management and its
prevention, a committed group of scientists encouraged
the U.S. National Heart, Lung, and Blood Institute and the
World Health Organization to found the Global Initiative
for Chronic Obstructive Lung Disease (GOLD)[4].
COPD can be caused by a lot of factors. The
primary risk factor for COPD is chronic smoking, and
in the United States, 80% to 90% of COPD cases are
due to smoking[5]. Cigarette smoking is the major risk
factor for COPD, but smokers show considerable
variation in their risk of developing airflow obstruction.
Familial aggregation studies suggest a strong genetic
component to this risk[6–7]. Air pollution, work
exposures and genetics are also important risk factors.
Previous research suggested that alpha 1-antitrypsin
deficiency caused by genetic susceptibility is
responsible for 2% causes of COPD. However, only
one gene (SERPINA1) is proved responsible for directly
leading to COPD, and the gene mutation at this locus
may cause alpha 1-antitrypsin deficiency, which is a
member of the serine proteinase inhibitor (serpin)
superfamily and a potent inhibitor of neutrophil elastase.
In previous studies, many genes have been detected but
it is hard to replicate due to different heterogeneities of
population and different phenotypes for COPD[8–9].
The ratio of FEV1 (forced expiratory volume in one
second) to FVC (forced vital capacity) is the most
important index for doctors to diagnose some particular
pulmonary diseases. The normal range for this index is
from 70% to 85%[10]. People with the value below 0.7 are
expected to have chronic pulmonary diseases. FEV1/FVC
is also an important index for airway obstruction
measurement[11]. The entry criteria for COPD cases were
post-bronchodilator FEV1<80% predicted and FEV1/
FVC<0.7. FEV1/FVC is an innate characteristic of
human[12]. According to the previous studies, it shows
strong relationship with genetic factor and is also
influenced by environmental factors such as smoking, air
pollution and chemical particle in the air. As all the above
attributes of FEV1/FVC, researchers use this index as an
important predictor of COPD. In order to investigate the
genetic architecture of COPD, we used the quantitative
trait FEV1/FVC as phenotype and SNPs (single nucleotide
polymorphisms) as genotype to perform genome-wide
association study (GWAS) mapping candidate genes.
1 Methods
Phenotypic and genotypic data of 1 189 COPD
cases (COPD stage 2 to 4) and the raw data set were
downloaded from dbGaP (phs000179. v3. p2). Genetic
epidemiology of COPD (COPDGene) was funded by
the U.S. National Heart, Lung, and Blood Institute.
Phenotype of FEV1/FVC ratio was used for identifying
significant SNPs for pulmonary function. Setting
cigarette smoking per day as control factor. A two-step
mapping strategy for GWAS was employed to dissect
第 4 期 许昌巍，朱军：吸烟对控制 FEV1/FVC 比率的基因上位性及性别互作效应的影响（英文） genetic architecture. First, GMDR (generalized
multifactor dimensionality reduction) method was used
to scan 561 467 SNP markers of 1 189 COPD cases for
1D and 2D significant candidate SNP markers. The
GMDR method that permits adjustment for discrete and
quantitative covariates is applicable to both
dichotomous and continuous phenotypes in various
population-based study designs[13]. In the second step, a
GPU (graphics processing unit) parallel computing
software QTXNetwork (http://ibi.zju.edu.cn/software/
QTXNetwork/) was used to dissect the genetic
architecture in the COPD cohort population[14].
A mixed linear model with or without cofactor
CigPD (cigarette smoking per day) was used to fit a full
genetic model in the studies. The genetic model for the
phenotypic value of the k-th individual in the h-th
gender population (yhk) can be expressed by the
following mixed linear model:
yhk    eh  chk   ai u Aik   di u Dik 
i
i
 aaij u AAijk   adij u ADijk   ddij uDDijk 
i< j
i j
i
 ide
  aaeijhu AAEijhk 
deihihuuDE
 aei hu AEihk  
DEihk
ihk
i
i j
i
 adeij hu ADEijhk   ddeijhuDDEijhk   hk ,
i j
i j
where μ is the population mean; eh is the fixed effect of
the h-th gender population; chk is the fixed cofactor
values; ai is the additive effect of the i-th locus with
coefficient u Aik ; dj is the dominance effect of the i-th
locus with coefficient uDik ; aaij, adij, and ddij are the
digenic epistasis effects with coefficients u AAijk , u ADijk ,
and uDDijk ; aeih is the additive × race interaction effect
of the i-th locus in the h-th ethnic population with
coefficient u AEihk ; deih is the dominance × race
interaction effect of the i-th locus in the h-th ethnic
population with coefficient uDEihk ; aaeijh, adeijh, and
ddeijh are the digenic epistasis × race interaction effects
in the h-th ethnic population with coefficient u AAEijhk ,
u ADEijhk , and u DDEijhk ; and εhk is the residual effect of the
k-th individual in the h-th gender population.
Significant quantitative trait SNPs (QTSs)
associated with phenotypic variants were analyzed by
setting a total of 2 000 permutation tests to calculate the
critical experiment-wise P value (PEW-value) for
415
controlling the experiment-wise type I error, thus the
PEW-value<0.05 was considered statistically significant.
The QTS effects were predicted by using the Monte
Carlo Markov chain method with 20 000 Gibbs sampler
interactions[14].
We also ran bioinformatics analysis by a newly
developed search engine BiopubInfo (http://ibi.
zju.edu.cn/biopubinfo/) for the detected candidate
genes. The detected genes were used as seed genes for
searching genetic network between the seed genes with
chemicals, diseases, pathways, functions, and other
genes based on gene-disease association, gene ontology,
protein-protein interactions, pathway interactions and
database.
2 Results
2.1 QTSs not affected by cigarette smoking
For both the traits FEV1/FVC and
FEV1/FVC|Cig, eight QTSs and a pair of epistasis
genes were presented in Table 1, including predicted
genetic effects, minus log10 PEW-values (−L(P)) for
significant test, and heritability. These detected
QTSs for both traits were not influenced by the
cofactor (cigarettes smoking per day). This group of
QTSs influenced strongly on FEV1/FVC but was
not apparently changed by the behavior of cigarette
smoking. Six out of eight QTSs had dominance
effects and other two had additive effects on
FEV1/FVC. This pair of epistasis QTSs had strong
relationship with gender, and one gene GLUD2
having significant female-specific effect was
located on sex chromosome. Genes STIM2,
MRE11A, DNAJC15, APOL3 and GLUD2 had
highly significant effects and strong relationship
with FEV1/FVC. These genes can increase or
decrease the value of FEV1/FVC deviated from the
normal value (0.70−0.85).
Based on the results presented in Table 1,
BiopubInfor searching results were presented in
Fig.1. Gene MER11A was interacted with
other 15 genes by protein-protein interaction and
database, and also connected to gene PSD3
through gene MLH1 . The gene GLUD2
浙江大学学报（农业与生命科学版） 416
controlled chemicals of sodium glutamate,
L -glutamate, and C5 H10 ClNO4 based on database
and experiment. Five biological functions
(integral to membrane, plasma membrane,
mitochondrion,
membrane
and
cytoplasm)
were controlled by gene network of six genes
( PSD3 , TSPAN8 , GLUD2 , DNAJC15 , APOL3 and
第 40 卷
STIM2 ) based on gene-ontology. Although five
genes (PSD3 , SPINK8 , TSPAN8 , APOL3
and STIM2 ) detected by this study were not
affected by cigarette smoking, but jointly
connected to tobacco-use disorder, type 2
diabetes,
and
obesity
by
gene-disease
association.
Table 1 Detected QTSs for no cofactor (FEV1/FVC) and cigarette smoking per day as cofactor (FEV1/FVC|Cig)
Chr_SNPID
Gene name
Effect
3_rs11708617
SPINK8
d
4_rs1488274
STIM2
8_rs7833694
PSD3
FEV1/FVC
FEV1/FVC|Cig
Predict
–L(P)
h2/%
Predict
–L(P)
h2/%
0.04
3.75
2.84
0.04
3.44
2.60
d
0.05
5.30
4.20
0.05
5.56
4.49
d
–0.03
2.70
1.92
–0.04
3.40
2.56
11_rs607146
MRE11A
d
0.05
5.96
4.80
0.05
6.00
4.88
12_rs7306184
TSPAN8
a
0.02
2.15
0.48
0.01
1.74
0.37
13_rs1028734
DNAJC15
d
0.05
6.46
5.30
0.05
6.52
5.29
22_rs132683
APOL3
d
0.05
6.42
5.26
0.05
6.68
5.44
X_rs2507237
GLUD2
ae2
–0.04
7.36
3.07
–0.03
5.76
2.33
ade2
–0.06
3.11
7.46
–0.05
2.56
5.73
11_rs607146 ×
13_rs1028734
MRE11A ×
DNAJC15
dae1
–0.06
2.56
6.18
–0.05
1.96
4.27
dde2
–0.10
3.55
20.60
–0.10
3.29
1.90
d: Dominance effect; a: Additive effect; ae2: Male-specific additive effect; ade2: Female-specific additive-by-dominance epistasis effect;
dae1: Male-specific dominance-by-additive epistasis effect; dde2: Female-specific dominance-by-dominance epistasis effect; –L(P): Minus log10 (PEW-value);
h2: Heritability.
Fig.1 Gene network for FEV1/FVC not affected by cigarette smoking
第 4 期 Recent studies have suggested that alpha
1-antitrypsin deficiency, main genetic cause of
COPD, was caused by a point mutation
(substitution of lysine for glutamate at residue
342)[15]. According to Fig.1, the gene GLUD2 has
strong relationship with biological-chemical
components, such as sodium glutamate, which is
the cause of mutation. In this study, we also focus
on epistasis research in order to indicate
co-expression of two genes. In Table 1 we could see
a pair of epistasis gene has been detected named
MRE11A × DNAJC15 . They have three kinds of
co-expressions, which appears in both traits and
has strong relationship with gender. Two
co-expressions related to female have much higher
heritability. All these co-expressions have negative
impacts on FEV1/FVC because of negative predict
values.
2.2 QTSs caused by cigarette smoking
In Table 2, we can clearly see that some genes are
only detectable in FEV1/FVC but not in
FEV1/FVC|Cig. It is suggested that cigarette smoking
could cause expression of these genes. When removing
cigarette smoking in FEV1/FVC|Cig, two genes
(SPTLC2 and LRP1B) are disappeared. It is apparent
that the expressions of these two genes are due to
cigarette smoking. By searching from BiopubInfo,
there was no evidence supporting that these two genes
connected with diseases. From Table 2, we can also find
that the gene LRP1B had positive female-specific
predicted effect, indicating that women are more
invulnerable than men when they are exposed to
long-term smoking.
Table 2
417
许昌巍，朱军：吸烟对控制 FEV1/FVC 比率的基因上位性及性别互作效应的影响（英文） Detected QTSs for only setting no cofactor
(FEV1/FVC)
Chr_SNPID
Gene name
Effect
Predict
–L(P)
h2/%
14_rs10151712
SPTLC2
d
–0.04
4.62
0.65
d
0.03
2.73
1.98
de2
0.05
2.98
4.17
2_rs11688725
LRP1B
d: Dominance effect; de2: Female-specific dominance effect;
–L(P): Minus log10 (PEW-value); h2: Heritability.
2.3 QTSs suppressed by cigarette smoking
Compared with traits FEV1/FVC|Cig
FEV1/FVC, three genes and a pair of epistasis
genes were detectable only when not cigarette
smoking (Table 3). It is indicated that the
expressions of genetic effects of these genes can be
suppressed when cigarette smoking. Although
epistasis genes MRE11A × DNAJC15 were also
detected in traits FEV1/FVC and FEV1/FVC|Cig,
the addictive-by-dominance epistasis effect of
MRE11A × DNAJC15 was completely new.
Table 3 Detected SNPs for FEV1/FVC when setting CigPD
as cofactor
Chr-SNPID
Gene name
Effect
Predict
–L(P)
h2/%
2_rs1495922
GPC1
ae1
–0.02
1.54
0.74
12_rs7306184
TSPAN8
d
–0.02
1.33
0.80
d
–0.03
2.50
1.76
de2
–0.03
1.82
2.15
ad
–0.03
1.38
1.40
18_rs1430540
FBXO15
11_rs607146×
13_rs1028734
MRE11A×
DNAJC15
ae1: Male-specific additive effect; d: Dominance effect;
de2: Female-specific dominance effect; ad: Additive-by-dominance effect;
–L(P): Minus log10 (PEW-value); h2: Heritability.
According to Fig.2 given by BiopubInfo, GPC1
and MRE11A linked with 16 other genes based on
database, protein-protein interaction, and gene
ontology. Chemical cyclosporine was connected to
four genes FBXO15, TSPAN8, MRE11A and GPC1
based on database. The genes TSPAN8 and GPC1
were linked with two diseases. The genes TSPAN8
and DNAJC15 were also jointly connected with
membrane and integral to membrane by gene
ontology. All five genetic effects of QTSs
suppressed by cigarette smoking were significantly
negative on FEV1/FVC ratio. It is indicated that the
FEV1/FVC ratio can be increased when these five
negative-effect genes are suppressed by cigarette
smoking.
2.4 Predicted gender-specific genotype effects
In this study of genetic epidemiology of COPD
(COPDGene), the cases included 3 713 subjects
with mean ± standard deviation ( x ± s)=0.495±0.131,
and the controls included 4 516 subjects with
x ± s=0.788±0.515. After analyzing the genetic
and
effects
not
affected
by
smoking,
caused
by
浙江大学学报（农业与生命科学版） 418
smoking, or suppressed by smoking, we can further
predict gender-specific genetic contributions in
homozygotes and heterozygotes. The predicted
第 40 卷
gender-specific genotype effects of specific
genotypes for FEV1/FVC and FEV1/FVC|Cig were
listed in Table 4.
Fig.2 Gene network for FEV1/FVC suppressed by cigarette smoking
Table 4 Predicted gender-specific genotype effects for FEV1/FVC and FEV1/FVC|Cig
Entry
Male
Female
FEV1/FVC
FEV1/FVC|Cig
FEV1/FVC
FEV1/FVC|Cig
Mean of gender
0.65
0.65
0.65
0.65
QQ
–0.08
–0.04
–0.11
–0.07
qq
–0.16
–0.12
–0.13
–0.11
Qq
0.12
0.08
0.07
0.04
Superior homozygote (+)
0.01
0.00
0.02
0.04
Superior homozygote (–)
–0.16
–0.15
–0.14
–0.10
Superior heterozygote (+)
0.13
0.11
0.18
0.17
Superior heterozygote (–)
–0.16
–0.19
–0.14
–0.11
QQ: Homozygote for all major alleles; qq: Homozygote for all minor alleles; Qq: Heterozygote for all alleles; Superior homozygote (+): Homozygote with the
largest values; Superior homozygote (–): Homozygote with the smallest values; Superior heterozygote (+): Heterozygote with the largest values; Superior
heterozygote (–): Heterozygote with the smallest values.
There were no differences in means of gender
for FEV1/FVC and FEV1/FVC|Cig between males
and females. Heterozygote subjects (Qq)
tended to be better than homozygote subjects (QQ
and qq). The impacts of cigarette smoking were
quite different between superior homozygote and
superior heterozygote. When quitting smoking,
superior heterozygote (–) subjects will be worse for
males but better for females, and the reverse was
observed for superior homozygote (–) subjects. As
considering subjects of superior heterozygote ()
and superior homozygote (), suspending cigarette
smoking will be unhealthier for males and females
in superior heterozygote () subjects, but can
improve health for females in superior homozygote
(+) subjects.
3 Discussion
We identified eight significant QTSs for
pulmonary function and they are not influenced by
smoking. In addition, we detected MRE11A and
第 4 期 419
许昌巍，朱军：吸烟对控制 FEV1/FVC 比率的基因上位性及性别互作效应的影响（英文） DNAJC15 have additive by dominance epistasis
effects on FEV1/FVC. Furthermore, in this
study, we identified seven genes related to
FEV1/FVC and smoking, two of which were caused
by smoking and five QTSs were suppressed by
smoking.
Among ten genes not related with smoking,
five of them show significant relationship with
FEV1/FVC. The gene GLUD2 (glutamate
dehydrogenase 2) encodes protein which acts as
homohexamer to recycle glutamate during
neurotransmission. It could increase or decrease
metabolism of glutamate, which has been proved to
associate with lung function and COPD[16-17]. The
gene STIM2 is a member of the stromal interaction
molecule (STIM) family and this family has been
proved to associate with PASMC (pulmonary
arterial smooth muscle cells), which plays an
important role in pulmonary function[18-19]. The
gene MRE11A encodes a nuclear protein involved in
homologous recombination, telomere length
maintenance, and DNA double-strand break repair.
This gene associates with ATLD (ataxia
telangiectasia-like syndrome)[20], which could
also influence the function of lung and lung
adenocarcinoma[21]. These three genes associate
with pulmonary function closely but each of
them links with lung in different way. The genes
MRE11A and DNAJC15 are a pair of epistasis
genes.
Removing
smoking
factor,
their
epistasis
effect
is
gender-specific.
Lung
adenocarcinoma is one of serious complications
related to COPD, which could reduce the ratio
of FEV1/FVC greatly and it is also a gender-related
disease.
Between two QTSs caused by smoking,
14_rs10151712 located in intron of SPTLC2 with
official name “serine palmitoyl transferase, long
chain base subunit 2”. Serine palmitoyl transferase
is a key enzyme of sphingolipid metabolism, which
is significantly high in lung and kidney
microsomes[22]. Serine palmitoyl transferase also
has relationship with nicotine[23]. These findings
leave open the possibility of shared genetic
determinants of lung function and kidney function.
The last part, the addictive-dominance epistasis
effects of MRE11A × DNAJC15 would be influenced
by smoking. As we present above, lung
adenocarcinoma is a key disease related to MRE11A
and it has been proved that non-smoking people get
more easily lung adenocarcinoma[24].
By examining all the genes identified in this
study, we have presented main function of them and
drawn the connection among them. Further work is
required to elucidate the mechanisms underlying the
association signals we have described. More
specifically, all these significant genes we detected
in our study seem to be involved either in
developmental tissue of lung or in cause of some
lung diseases that might be expected to alter airway
architecture. In conclusion, in this study, the genes
identified show strong relationship with lung-function,
gender-specific, and with or without cigarette smoking.
Behavior of smoking could also affect lung function in
different ways to different genders.
Acknowledgments
We acknowledge the use of genotype
and phenotype data in Genetic Epidemiology of COPD from
dbGaP funded by the U.S. National Heart, Lung, Blood
Institute. We are grateful to Dr. Ming D. Li for his comments
on a draft of this manuscript.
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