A Novel Polymorphism rs1329149 of CYP2E1 and a Known
Polymorphism rs671 of ALDH2 of Alcohol Metabolizing
Enzymes Are Associated with Colorectal Cancer in a
Southwestern Chinese Population
Huan Yang,1Yanhong Zhou,1Ziyuan Zhou,1Jinyi Liu,1Xiaoyan Yuan,1Ketaro Matsuo,2
Toshiro Takezaki,2Kazuo Tajima,2and Jia Cao1
1Department of Hygienic Toxicology, College of Preventive Medicine Key Laboratory of Medical Protection for Electromagnetic Radiation, Ministry
of Education of China, Third Military Medical University, Chongqing, China and
Research Institute, Nagoya, Japan
2Division of Epidemiology and Prevention, Aichi Cancer Center
Background: To screen for tagging single nucleotide
polymorphisms (tagSNP) in the major alcohol metabo-
lizing enzymes: ADH1B, ALDH2, and CYP2E1, and to
evaluate the association between these tagSNPs and
colorectal cancer (CRC) in a southwestern Chinese
Methods: A hospital-based case-control study of 440
CRC patients and 800 cancer-free controls was con-
ducted. Personal information was collected by a Semi-
Quantitative Food Frequency Questionnaire. The
tagSNPs were screened in the HapMap with Haploview
by setting the minor allele frequency at 0.03 with the
highest score of r2form each block. Genotypes were
identified by using the SNPLex System. Both crude
and adjusted odds ratio (OR) and 95% confidence inter-
val (CI) were used to evaluate the risk of each SNP.
Results: Sixteen tagSNPs were selected, and 13
were successfully genotyped. A novel CYP2E1 locus
rs1329149 and a known ALDH2 locus rs671 were found
to be significantly associated with CRC risk. The
adjusted OR was 1.86 (95% CI, 1.12-3.09) for the
rs671 A/A genotype and 4.04 for the rs1329149 T/T
genotype (95% CI, 2.44-6.70), compared with their
common homozygous genotypes. Interaction was
found between alcohol consumption and gene poly-
morphisms on CRC, the adjusted OR was 7.17 (95%
CI, 2.01-25.53) for drinking habits combined with
rs671 A/A or rs1329149 T/T genotype.
Conclusion: The results of this study suggest that
rs671 A/A and the first reported locus rs1329149 T/T
genotypes increase the susceptibility to CRC, and
gene-environmental interaction between the two loci
and alcohol use existed for CRC in Southwestern
Chinese. Larger studies are warranted to verify our
findings. (Cancer Epidemiol Biomarkers Prev 2009;
Studies have shown that 3.6% of cancers of the upper di-
gestive tract, liver, colorectum, and breast could be at-
tributed to chronic alcohol consumption worldwide (1)
and this association is strong in colorectal cancer
(CRC; refs. 2-5). The risk of CRC was increased at the
level of 1.07- to 3.50-fold in western countries and
1.42- to 2.19-fold in Asian populations (Japanese and
Koreans) among drinkers (4, 5). Furthermore, meta-
analyses also suggested a positive dose-response rela-
tionship between alcohol consumption and CRC (6, 7).
In China, as in other countries, alcoholism is a serious
social and health problem, and it is becoming wide-
spread, with the frequent consumption and abuse of
alcohol (8). Our previous epidemiologic study revealed
that alcohol consumption was associated with CRC in
a Southwestern Chinese population, leading to a 7.77-
fold increased risk for colon cancer and 1.73-fold in-
crease in the risk of rectal cancer (9).
After alcoholis absorbed,the concentration of alcohol in
the colon is as high as that is found in the blood. The
primary metabolite of alcohol in humans is acetaldehyde,
which is known as a carcinogen. In animal experiments, it
has been shown that the acetaldehyde concentration can
in piglets and rats, respectively, after 2.5 grams/kg bw i.v.
alcohol administration for rats (10, 11). Acetaldehyde con-
centrations above 50 to 100 μmol/L are considered to be
mutagenetic, and the high levels of acetaldehyde resulting
from alcohol metabolism have been implicated in alcohol-
associated carcinogenesis of the gastrointestinal tract (12).
It has been shown that when aldehyde dehydrogenase
(ALDH) activity was inhibited, tumorigenesis was ob-
served in the colon of rats (13). Additionally, bacteria
in the large intestine can also metabolize alcohol into
Received 4/28/09; revised 6/20/09; accepted 7/7/09; published OnlineFirst 8/25/09.
Grant support: Major International (Regional) Joint Research Projects (30320140461)
and General Program (no. 30771841, no. 30700676, no. 30800933) grants from the
National Natural Science Foundation of China and by a Grant-in Aid for Scientific
Research on Special Priority Areas of Cancer from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (12670383).
Note: H. Yang and Y. Zhou are cofirst authors.
Requests for reprints: Jia Cao, Department of Hygienic Toxicology, College of
Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Phone: 86-23-687-52271; Fax: 86-23-687-52589. E-mail: email@example.com or
Copyright © 2009 American Association for Cancer Research.
Cancer Epidemiol Biomarkers Prev 2009;18(9). September 2009
acetaldehyde, butbacteria donot metabolize acetaldehyde
to acetic acid for detoxification (13, 14).
In humans, alcohol is mainly metabolized by the
alcohol dehydrogenase pathway, microsomal ethanol-
oxidizing system, and to a lesser extent, by catalase.
Any of these pathways can metabolize alcohol into
acetaldehyde then into acetic acid (15). In humans, the
major enzymes involved in the alcohol metabolizing
pathways are alcohol dehydrogenase IB (ADH1B), alde-
hyde dehydrogenase-2 (ALDH2), and cytochrome P450
2E1 (CYP2E1). Although these enzymes are expressed
mainly in the liver, they are also present in the gastroin-
testinal tract (16). ADH1B and CYP2E1 can both metabo-
lize alcohol into acetaldehyde, the latter also leading to
increased generation of reactive oxygen species (15),
whereas ALDH2 can metabolize acetaldehyde into acetic
acid for detoxification (13). CYP2E1 can be induced by
drugs, such as pyrazole (17), and low molecular weight
compounds such as alcohol (17-19). In humans, the induc-
tion of CYP2E1 was observed in subjects who consumed
40 grams of alcohol daily for just 1 week, with even great-
er induction after 4 weeks of daily alcohol consumption
(20). However, this increase varies between individuals,
indicating that heritage may be responsible for differences
in the expression and activity as well as the subsequent
metabolites generated by the enzyme (20).
Polymorphisms in genes responsible for these path-
ways can affect the amount of acetaldehyde and reactive
oxygen species generated during the metabolic process,
altering the effects of alcohol, potentially leading to carci-
nogenesis (21-23). Moreover, a recent study reported that
the activity of alcohol dehydrogenase and ALDH in CRC
patients differed from that in healthy controls and that the
increased enzymes activities were due to the enzymes re-
leased by CRC cells or metastatic CRC cells (24).
Several studies have reported associations between
polymorphisms of alcohol metabolizing enzymes and
CRC risk in Japanese, Korean, and Eastern Chinese popu-
lation (21-23, 25-27). The most frequently reported loci are
ADH1B Arg47His (because the activity of ADH1B de-
creased by 40-fold in ADH1B His/His individuals),
ALDH2 Glu487Lys (equally to rs671, which affects the
Kmof this enzyme for alcohol with loss of the enzyme ac-
tivity in individuals with the ALDH2 Lys/Lys phenotype),
and CYP2E1 Rsa1(rs2031920) and Dra1(rs6413432; be-
cause rs2031920 affects the transcription and rs6413432 af-
fects the activity of the enzyme; ref. 26). However, all these
studies werefocused on the functional loci reported in oth-
er diseases but there is no reported comprehensive study
that investigated novel loci that have not been reported.
The genome-wide haplotype structure in Chinese Han
people has been described in the International HapMap
Consortium. It is known that there are ∼10 millions of
single nucleotide polymorphisms (SNP) in the whole-
genome, and we cannot assess all SNPs in the entire
genome for each subject. However, representative infor-
mation abstracted from the whole genome according
to the linkage disequilibrium theory can help resolve
this problem. By selecting a small fraction of tagging
SNPs (tagSNP) for mapping purposes, we can significant-
ly reduce the need for extensive genotyping without
much loss of power, because haplotype tagSNPs can
represent strong linkage disequilibrium blocks without
much information loss (28, 29).
Because there is no reported tagSNP-based association
study on CRC, we conducted a tagSNP-based research on
the association between genes encoding major alcohol
metabolizing enzymes and CRC, as a part of the Japan,
Korea, and China Colorectal Cancer collaboration study.
We obtained SNP information of the genes coding
ADH1B, ALDH2, and CYP2E1 in Chinese Han population
from HapMap project and applied the software Haplo-
view for screening of the tagSNPs. We then examined
whether the selected tagSNPs in these three genes are as-
sociated with CRC risk.
Materials and Methods
Subject Recruiting. A total of 478 CRC patients and 838
controls between ages 30 and 80 y were recruited between
2001 and 2003 from the three largest hospitals in Chong-
qing, the biggest city in southwest China. Most patients
were from Chongqing, the others were from parts of
Sichuan, Yunnan, and Guizhou provinces in southwest
China, adjacent to Chongqing. The recruitment followed
the Japan, Korea, and China Colorectal Cancer collabora-
tion Group guidelines. As such, all of the patients were
required to have lived in the study area continuously for
>15 y, or for >30 y in total with no >5 y spent in another
district. All CRC cases were histopathologically diagnosed
as primary CRC, but ileocecal junction tumors and anal
canal tumor were excluded. The patients were newly diag-
nosed in 6 mo, and had not been treated by any medical
treatments. Patients were excluded who were suffering
from: (a) recurrence of CRC; (b) familial adenomatous
polyposis; (c) hereditary nonpolyposis CRC; (d) other tu-
mors; (e) severe digestive tract diseases over 2 y; and (f)
diabetes, fatty liver, hepatic cirrhosis, metabolism syn-
drome, and severe cardiovascular diseases. Having pro-
vided a written informed consent, each patient donated
a 5-mL peripheral venous blood sample and completed
a Semiquantitative Food Frequency Questionnaire, with
assistance from study interviewers, which collected demo-
graphic information as well as information about dietary,
smoking, and alcohol habits. For each eligible case, one or
two control patients, matched by age within 5 y, sex, and
residence, were recruited from the Departments of Gener-
al Surgery, Orthopedics, or Trauma who wereadmitted for
trauma, bone fracture, appendicitis, arthritis, or varicose
vein. Control patients with (a) tumors; (b) severe digestive
tract diseases over 2 y; (c) diabetes, fatty liver, hepatic cir-
rhosis, metabolism syndrome, and severe cardiovascular
diseases were excluded. All controls also provided their
written informed consent, Semiquantitative Food Fre-
quency Questionnaire, and blood samples as the CRC pa-
tients group. In this study, we excluded patients and
controls whose drinking habits were absent, as a result,
a sample of 440 patients and 800 controls were studied.
Drinking Habits. Data about drinking habits was col-
lected by Semiquantitative Food Frequency Question-
naire, and the population was divided into two groups
by their average daily alcohol consumption under or
above 15 grams, the recommended level of daily alcohol
consumption suggested by China Health Care Associa-
tion (8). Additionally, our previous study showed a signif-
icant increase in CRC susceptibility, when average alcohol
consumption exceeded 15 grams/d.
Cancer Epidemiol Biomarkers Prev 2009;18(9). September 2009
2523Cancer Epidemiology, Biomarkers & Prevention
Screening for Candidate SNPs in Genes Related to
Alcohol Metabolism. The SNP information for the Chi-
nese Han population of full-length genes plus 2,000 bp
in the upper stream of each candidate gene was obtained
from the HapMap (version 33). After setting the minor al-
lele frequency at 0.03, the Haploview software was used
to screen for the tag-SNPs from ADH1B, ALDH2, and
CYP2E1 (Table 1). Only one SNP was selected in each of
linkage disequilibrium blocks. As a result, a total of 16
tagSNPs from the 127 reported SNPs of the three major
genes metabolizing alcohol.
Genotyping of Selected TagSNPs. DNA was extracted
from 2.5-mL whole blood with a Promega DNA Purifica-
tion Wizard kit according to the manufacturer's instruc-
tions and diluted to 37 ng/μL by Tris-EDTA, and then
aliquoted into sealed 96-well plates and stored at −20°C.
The identified 16 tagSNPs were genotyped by SNPLex
(Applied Biosystems Incorporated). Loci were submitted
online to ABI, probes were designed and synthesized by
ABI. The OLA, purification, and PCR reactions were done
on an Eppendorf 5333 Mastercycler, and allele inspection
was done on an ABI 3130xl Gene Analyzer. All the steps
were carried out as the recommendation in the SNPlex
Genotyping System 48-plex User Guide. The main re-
agents used in reactions and allele inspection were pro-
vided by ABI in the SNPlex Genotyping System 48-plex
kit. After the information was collected, 10% of the sam-
ples were randomly repeated to verify the results. The in-
formation about the SNPs was collected using Data
Collection Software version 3.0, and the genotypes were
analyzed by GeneMapper Software version 4.0. One locus
(rs2480259) failed in probe synthesis due to the SNPLex
technological limitation, and another locus (rs440) could
not be genotyped in the reactions, as a result, 13 loci were
successfully genotyped and analyzed.
Statistical Analysis. Genotype frequencies were deter-
mined by direct counting, and Hardy-Weinberg equilibri-
um in control group was assessed by χ2test. Associations
between polymorphisms and CRC were estimated by
odds ratios (OR) with 95% confidence interval (CI), using
an unconditional logistic regression model. The ORs were
adjusted for age, sex, smoking, and alcohol consumption.
The population was divided into two subgroups based on
their average daily alcohol consumption, with those who
drank no >15 grams/d considered “nondrinkers,” and
the rest considered “drinkers.” All calculations were car-
ried out using Statistical Analysis System (version 9.0;
SAS Institute, Inc.).
Subject Characteristics. As shown in Table 2, a total of
genotyped in this study. In both of the groups, male was
more than female, but no significant difference in sex
existed between the two groups (P > 0.05), suggesting the
matching was adequate. The average age of the studied
age groups by an interval of 10 y; however, there was sig-
(P < 0.01), suggesting the matching was not adequate,
which needs additional adjustment in later multivariate
analysis. Considering the people consuming no >15 grams
of pure alcohol per day as nondrinkers and the rest as
drinkers, the study population was divided into two
tributed differently between cases and controls (P < 0.01).
No difference was observed for smoking status (P > 0.05).
TagSNPs Genotyping and Association with CRC
Risk. Within the control group, all tested loci were
in Hardy-Weignberg equilibrium except for rs915908
(Table 3). By setting the ancestral allele defined in dbSNP
database or common allele (no ancestral allele is defined
for rs1329149 in the dbSNP database) as the reference
allele, two (rs671 and rs1329149) of the 13 loci were found
to be significantly associated with CRC risk (Table 3).
In the CRC associated loci, the rs671 A/A genotype
was associated with an increase risk for CRC risk with
age-, sex-, smoking-, and alcohol consumption–adjusted
OR of 1.86 (95% CI, 1.12-3.09), and the rs1329149 T/T ge-
notype was associated with moderately increased risk of
CRC with age-, sex-, smoking-, and alcohol consumption–
adjusted OR of 4.04 (95% CI, 2.44-6.70).
When the recessive model was assumed, we found that
the rs671 A/A genotype was associated with an increased
risk of CRC (OR, 1.95; 95% CI, 1.19-3.21), compared with
A/G and G/G genotypes and that the rs1329149 T/T ge-
notype was associated with an increased risk of CRC
(OR, 4.09; 95% CI, 2.48-6.74) compared with C/T and
C/C genotypes (Table 4).
Table 1. TagSNPs screened from the ADH1B, ALDH2, and CYP4502E1 genes
GeneTotal no. of reported SNPstagSNPs*
rs2075633, rs17033, rs1229984
rs440, rs4767939, rs4767944, rs671, rs16941669, rs886205, rs7296651
rs1329149, rs2249695, rs2480259, rs8192772, rs8192775, rs915908
*Sixteen loci screened from the three genes that were related to alcohol metabolism.
Table 2. Demographic distributions in a hospital-
based case-control study in Southwestern China
CharacteristicsCRC patients (%) Controls (%)P
Age in years
No (=15 grams/d)
Yes (>15 grams/d)
432 (100)788 (100)
*The level to define drinking or not drinking based on the recommended
level of China Health Care Association.
Cancer Epidemiol Biomarkers Prev 2009;18(9). September 2009
2524CYP2E1 and ALDH2 Variants and Colorectal Cancer
Gene-Gene Interaction. We combined the loci reported
in Table 4 to analyze the interaction between ALDH2
rs671 and CYP2E1 rs1329149 polymorphisms on CRC
risk. However, no significant interaction was found be-
tween the two loci, and only the increased risk trend
was found in the number of A and T allele combination.
Gene-Alcohol Consumption Interaction. In the reces-
sive model, an interaction between alcohol consumption
and rs671 or rs1329149 was found. After dividing the
population into two groups by drinking or not drinking,
compared with the reference genotype (rs671 G/G+A/G
and rs1329149 C/C+C/T), we found a 7.2-fold increased
risk (95% CI, 2.01-25.53) of CRC in drinkers but only
2.5-fold increased risk (95% CI, 1.70-3.81) of CRC in
nondrinkers (Table 5).
Chronic alcohol consumption has been reported by many
studies to be associated with various cancers (1). In China,
a recent investigation covered 25 provinces including
Chongqing indicated that 15.2% adolescents started
drinking alcohol before age 18 years, and up to 65.39%
of these young drinkers drank frequently and/or exces-
sively, with an average consumption of 41.04 grams pure
alcohol per instance (8), which exceeded the 20 grams de-
fined as the safe drinking level by International Center for
Alcohol Policies (30), and also the 15-gram level sug-
gested as the safe drinking level by China Health Care As-
sociation (8). In Chinese drinking population, the average
drinking frequency was 0.6 times per day, with >36% of
drinkers consuming alcohol more than once per day (8).
Thus, excessive alcohol consumption is a serious and
worsening social problem that is likely to lead to severe
health problems in the Chinese population.
Our previous study showed that alcohol consumption
was associated with an increased risk of CRC (9). In this
study, we investigated genetic variants in the three genes
encoding the major alcohol metabolizing enzymes
(ADH1B, ALDH2, and CYP2E1). To our knowledge, this
is the first report on the association between tag SNPs in
Table 3. Distributions of screened SNPs loci in case and control groups
SNPs Genotype*Cases ControlsP for genotypes' distributionsP for H-W equilibrium
rs16941669 0.96 0.66
NOTE: The total number for each tagSNP was less than the total number of the study population due to some missing genotyping data.
*The reference allele was determined following the ancestral allele defined in dbSNP, except for rs1329149 that was not defined in the database. The common
allele in locus rs1329149 was defined as reference allele.
†The distributions of the genotypes were significantly different between controls and patients.
Cancer Epidemiol Biomarkers Prev 2009;18(9). September 2009
2525Cancer Epidemiology, Biomarkers & Prevention
these alcohol metabolizing enzymes and CRC risk in Chi-
nese populations. Among the 127 reported SNPs, 16
tagSNPs were selected by the Haploview software, of
which two loci, rs671 in ALDH2 and rs1329149 in CY-
P2E1ADH1B, were found to be significantly associated
with CRC risk.
The rs671 G > A base change causes a glutamic acid
change to lysine, and the A allele encodes a lysine subunit
which is catalytically inactive, often described as
ALDH2*2 (15).Theoretically, when ALDH2 activity is de-
creased, the blood acetaldehyde level should increase in
the mucosa of the large intestine as well as in the blood,
which would result in an increased risk of CRC. However,
previously published studies have generated some incon-
sistent results. The A allele showed risk effects in some
studies but protective effects in some other studies. In a
recent study in a Chinese Han male population of 190
CRC cases and 222 controls, Gao CM et al. (22) found that
rs671 A/G and A/A genotypes were both protective
against CRC risk, but our results showed an opposite ef-
fect. As ALDH2 is the major enzyme metabolizing acetal-
dehyde, its inactivation (with an A allele in the gene)
brings the accumulation of acetaldehyde, which may
cause a series of symptoms that may prevent someone
from drinking. According to a survey, drinking habits be-
tween the two populations were different, the percentage
of drinkers who continue drinking even they had symp-
toms of alcohol intoxication is higher in southwestern
population than that in Gao's study population (8). This
behavioral difference may partially explain why the re-
sults were opposite in different geographic populations
in Chinese Han population.
CYP2E1 has been extensively studied in alcohol-related
diseases. CYP2E1 is a well-conserved gene encoding an
enzyme that metabolizes a broad range of organic sol-
vents, such as N-nitroso-dimethylamine, vinyl chloride,
benzene, and alcohol. Many of the substrates exert a high
affinity for the enzyme (31). In both humans and animals,
a 10- to 20-fold increase in hepatic CYP2E1 was observed
after chronic alcohol consumption (32). Alcohol metabo-
lized by CYP2E1 leads to the formation of reactive oxygen
species, which causes oxidative injury leading to various
diseases, including cancer (16). In animal experiments, the
induction of CYP2E1 correlates with increased NADPH
oxidase activity, the generation of HER, lipid peroxida-
tion, and the severity of hepatic injury, all of which could
be prevented by chlormethiazole, a CYP2E1 inhibitor (33).
These indicate that CYP2E1 may play an important role in
alcohol-mediated liver pathology and cancer develop-
ment. The most frequently studied SNPs in CYP2E1 were
rs2031920 in the 5′-flanking region and rs6413432 in in-
tron 6, and to a less extent, the rs2070676 in intron 7. Al-
though no association was found between CYP2E1 SNPs
and esophageal cancer (34) or hepatic cancer (35), in meta-
analyses, the CYP2E1 rs2031920 T allele was associated
with a decreased risk of rectal cancer (OR, 0.71) in a Jap-
anese population (36). In contrast, Gao et al. (22) reported
that the Tallele was a risk factor for CRC (OR, 1.55; geno-
type T/T versusC/C) in Chinese males.
We genotyped six CYP2E1 tagSNPs and found that
rs1329149 was significantly associated with CRC risk.
This locus was in the block consisting of 19 loci. Locus
rs1329149 is located in intron 6,766 bp from the nearest
exon (exon 7) and is characterized by a C>T base change.
However, no other information was available in the liter-
ature about this locus, nor its functional study or associ-
ation with cancers. In this block, several loci (including
rs2070676, rs2070677, and rs2515641) were recorded in
the SNP500 Cancer Project. The nearest locus to
rs1329149 is rs2070676, which is located in intron 7, and
exon 7 is located between these two loci. Thus, it is likely
that the observed association between rs1329149 and CRC
Table 5. Analysis of genotypes and combined with alcohol consumption
Alcohol Combined genotypes*Cases (%)Controls (%) Adjusted OR (95% CI)†
*Combined genotypes: 1 = rs671 AG+GG and rs1329149 CT+CC and 2 = rs671 AA and rs1329149 CT+CC, or rs671 GG+AG and rs1329149 TT, or rs671 AA
and rs1329149 TT.
†Adjusted for age, sex, and smoking.
‡P < 0.01.
§P < 0.001.
Table 4. Association between CRC risk and the two tagSNPs (rs671 and rs1329149)
Locus GenotypeCases n (%)Controls n (%)Adjusted OR (95% CI)*P
*Adjusted for age, sex, smoking, and alcohol consumption.
†P < 0.05.
‡P < 0.01.
Cancer Epidemiol Biomarkers Prev 2009;18(9). September 2009
2526 CYP2E1 and ALDH2 Variants and Colorectal Cancer
may be related to rs2070676. We genotyped rs2070676 in
the same population and found rs2070676 G allele were at
higher risk of developing CRC, the OR was 2.60, and 95%
CI was 1.06 to 6.39 (P = 0.04), which indicated the poly-
morphisms in this block may associated with CRC devel-
opment and rs1329149 was a representitive SNP. Further
studies are needed to explore the mechanism underlying
the association between rs1329149 and CRC.
In summary, a novel locus CYP2E1 rs1329149 and a
known locus ALDH2 rs671 were found to be associated
with a moderate increase in the risk of developing CRC
in a population from southwest China. However, further
studies in different populations and with a larger sample
size are needed to confirm the association between these
loci and CRC, especially for locus rs1329149.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby
marked advertisement in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
We thank the research staff from the Preventive Medicine Col-
lege, Third Military Medical University, and the staff from the
General Surgery, Orthopedics, and Clinical Trauma department
of Southwest Hospital, Xin-qiao Hospital, and Da-ping Hospital,
which are affiliated with Third Military Medical University; and
Dr. Zhibin Hu (Nanjing Medical University of China) for advice
on statistical analysis.
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