Relationship between cystathionine gamma-lyase gene polymorphism and essential hypertension in Northern Chinese Han population.
ABSTRACT Hydrogen sulfide (H(2)S) plays an important role in the smooth muscle cell relaxation and thereby participates in the development of hypertension. Cystathionine gamma-lyase is the key enzyme in the endogenous production of H(2)S. Up to now, the reports on the relationship between the polymorphisms of cystathionine gamma-lyase gene (CTH) and essential hypertension (EH) are limited. This study was designed to assess their underlying relationship.
A total of 503 hypertensive patients and 490 age-, gender- and area-matched normotensive controls were enrolled in this study. Based on the FASTSNP, a web server to identify putative functional single nucleotide polymorphisms (SNPs) of genes, we selected two SNPs, rs482843 and rs1021737, in the CTH gene for genotyping. Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method (PCR-RFLP). The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. The program Haplo. stats was used to investigate the relationship between the haplotypes and EH.
These two SNPs were in Hardy-Weinberg Equilibrium in both cases and controls. The genotype distribution and allele frequencies of them did not significantly differ between cases and controls (all P > 0.05). In the stepwise logistic regression analysis we failed to observe their association with hypertension. In addition, none of the four estimated haplotypes or diplotypes significantly increased or decreased the risk of hypertension before or after adjustment for several known risk factors.
The present study suggests that the SNPs rs482843 and rs1021737 of the CTH gene were not associated with essential hypertension in the Northern Chinese Han population. However, replications in other populations and further functional studies are still necessary to clarify the role of the CTH gene in the pathogenesis of EH.
- [show abstract] [hide abstract]
ABSTRACT: To investigate the risk of stroke in subjects with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and combined systolic and diastolic hypertension (SDH) in a Japanese general population, we used 24-h ambulatory blood pressure (ABP) and casual-screening blood-pressure (CBP) readings. Subtypes of hypertension were defined based on systolic blood pressure (SBP) >135 mm Hg or diastolic blood pressure (DBP) >80 mm Hg for 24-h ABP, and SBP >140 mm Hg or DBP >90 mm Hg for CBP. We obtained 24-h ABP and CBP data for 1271 (40% male) subjects aged > or =40 years (mean age, 61 years) without a history of symptomatic stroke; their stroke-free survival was then determined. The prognostic significance of each subtype of hypertension was determined by Cox proportional hazard analysis. There were 113 symptomatic strokes during follow-up (mean time, 11 years). Compared with normotension, among the hypertension subtypes determined by 24-h ABP, the adjusted relative hazards (RHs) of stroke were 2.24 for ISH (P = .002) and 2.39 for SDH (P = .0004). The association was less marked among subtypes determined by CBP (RH = 1.40 and P = .13 for ISH; RH = 2.07 and P = .017 for SDH). The IDH group was excluded from the Cox analysis because both the prevalence and the number of events were low in this group. Isolated systolic hypertension, as determined by 24-h ABP measurements, was associated with a high risk of stroke, similar to that found in SDH subjects; this suggests that the prognosis of hypertensive patients would be improved by focusing treatment on 24-h systolic ABP.American Journal of Hypertension 11/2007; 20(10):1125-31. · 3.67 Impact Factor
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ABSTRACT: In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al.  and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.Human Heredity 02/2003; 55(1):56-65. · 1.57 Impact Factor
- Circulation 12/1993; 88(5 Pt 1):2460-70. · 15.20 Impact Factor
Chin Med J 2008;121(8):716-720
Relationship between cystathionine γ-lyase gene polymorphism
and essential hypertension in Northern Chinese Han population
LI Yun, ZHAO Qi, LIU Xiao-li, WANG Lai-yuan, LU Xiang-feng, LI Hong-fang, CHEN Shu-feng, HUANG Jian-feng
and GU Dong-feng
Keywords: cystathionine γ-lyase; diplotype; haplotype; hypertension; single nucleotide polymorphism
Background Hydrogen sulfide (H2S) plays an important role in the smooth muscle cell relaxation and thereby
participates in the development of hypertension. Cystathionine γ-lyase is the key enzyme in the endogenous production
of H2S. Up to now, the reports on the relationship between the polymorphisms of cystathionine γ-lyase gene (CTH) and
essential hypertension (EH) are limited. This study was designed to assess their underlying relationship.
Methods A total of 503 hypertensive patients and 490 age-, gender- and area-matched normotensive controls were
enrolled in this study. Based on the FASTSNP, a web server to identify putative functional single nucleotide
polymorphisms (SNPs) of genes, we selected two SNPs, rs482843 and rs1021737, in the CTH gene for genotyping.
Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method
(PCR-RFLP). The frequencies of the alleles and genotypes between cases and controls were compared by the
chi-square test. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH.
Results These two SNPs were in Hardy-Weinberg Equilibrium in both cases and controls. The genotype distribution
and allele frequencies of them did not significantly differ between cases and controls (all P>0.05). In the stepwise logistic
regression analysis we failed to observe their association with hypertension. In addition, none of the four estimated
haplotypes or diplotypes significantly increased or decreased the risk of hypertension before or after adjustment for
several known risk factors.
Conclusions The present study suggests that the SNPs rs482843 and rs1021737 of the CTH gene were not
associated with essential hypertension in the Northern Chinese Han population. However, replications in other
populations and further functional studies are still necessary to clarify the role of the CTH gene in the pathogenesis of EH.
Chin Med J 2008;121(8):716-720
to increase by 60% to a total of 1.56 billion patients by
2025.1 Essential hypertension (EH) accounts for 90%–95%
of patients diagnosed with hypertension. Uncontrolled
hypertension increases the risks of cardiovascular and
chronic kidney disease2 and there is a direct relationship
between the risks of stroke,3 heart attack,4 heart failure,5
kidney disease6 and the severity of hypertension. It is
widely believed that EH is a complex disease influenced
by multiple factors. Although numerous physiological
alterations have been studied in hypertensive individuals,
including abnormalities of renal sodium handling,
neurohormonal and adrenergic overactivity, endothelial
dysfunction, vascular hypertrophy, systemic inflammation,
reduced fibrinolytic potential and enhanced oxidative
stress, the etiopathogenisis of hypertension is still not
The endogenous production of hydrogen sulfide (H2S)
and its physiological functions, including membrane
hyperpolarization and smooth muscle cell relaxation,
place this gas in the family of gas transmitters together
with nitric oxide (NO) and carbon monoxide (CO).9 The
physiological function of H2S in the cardiovascular
system has been studied recently. An intravenous bolus
ypertension affects approximately 25% of the adult
population worldwide and its prevalence is predicted
injection of H2S transiently decreased blood pressure (BP)
in rats by 12–30 mmHg.10 Two pyridoxal-5’-phosphate
-dependent enzymes, cystathionine β-synthase (CBS) and
cystathionine γ-lyase (CSE), are responsible for the
endogenous production of H2S in mammalian tissues.
CBS is the predominant H2S-generating enzyme in the
brain and nervous system,11 and CSE is mainly expressed
in liver, kidney and vascular smooth muscles.10 The gene
expression and the activity of the CSE in thoracic aorta
were suppressed in hypertensive rats,12 and the expression
of the CSE mRNA is down-regulated in pulmonary
Department of Evidence Based Medicine and Division of
Population Genetics, Cardiovascular Institute and Fuwai Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing 100037, China (Li Yun, Zhao Qi, Liu Xiao-li,
Wang Lai-yuan, Lu Xiang-feng, Li Hong-fang, Chen Shu-feng,
Huang Jian-feng and Gu Dong-feng)
National Human Genome Center at Beijing, Beijing 100176, China
(Li Yun, Zhao Qi, Liu Xiao-li, Wang Lai-yuan and Gu Dong-feng)
Correspondence to: Prof. GU Dong-feng, Department of Evidence
Based Medicine and Division
Cardiovascular Institute and Fuwai Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College, No. 167
Beilishi Road, Beijing 100037, China (Tel: 86-10-68331752. Fax:
86-10-88363812. Email: email@example.com )
This work was supported by the grants of the National Basic
Research Program of China (No. 2006CB503805) and the Beijing
Natural Science Foundation (No. 7061006).
of Population Genetics,
Chinese Medical Journal 2008; 121(8):716-720
hypertension rats.13 Therefore, it is possible that CSE,
which is encoded by the CTH gene, may participate in the
regulation of BP and even in the development of EH.
However, no study to date has assessed the relationship
between CTH gene variations and hypertension.
In this study, we performed a case-control study to
investigate whether the CTH gene is associated with EH
in Northern Chinese Han population.
All the DNA samples and clinical data from the studied
subjects were selected
Collaborative Study of Cardiovascular Disease in Asia
(InterASIA in China).14 The InterASIA used a four-stage
stratified sampling method to select a nationally
representative sample of the general population aged 35
to 74 years in China. To maximize the potential genetic
differences and statistical power for the association
analysis we selected 993 subjects as a subsample
containing 503 hypertensive patients (systolic blood
pressure (SBP) ≥ 160 mmHg and/or diastolic blood
pressure (DBP) ≥ 100 mmHg, or self-reported current
treatment for hypertension
medications) and 490 age-, gender- and area-matched
normotensive controls (SBP < 140 mmHg and DBP < 90
mmHg) from the main study population.15 Blood pressure
values from subjects remaining on antihypertensive
medications were nonparametrically
treatment effects according to the algorithm used in
analyses of the Framingham data.16
During clinic or home visits trained research staff
administered a standard questionnaire. Information on
demographic characteristics including age, gender,
ethnicity, education, occupation and household income
was collected. The interview also included questions
related to the diagnosis and treatment of hypertension.14
weight, waist and hip circumferences were taken
according to standard protocols. Concentrations of serum
lipids, including total cholesterol (TC), high-density
lipoprotein cholesterol (HDL-C), low-density lipoprotein
cholesterol (LDL-C) and triglyceride (TG), were
determined by standard protocols under the quality
control of Lipid Research Laboratory of Disease
Controlling and Prevention Center, USA.
Three BP measurements were obtained from each
participant by trained and certified observers according to
a standard protocol recommended by the American Heart
Association.17 BP was measured with the participant in
the sitting position after 5 minutes of rest. In addition,
participants were advised to avoid alcohol, cigarette
smoking, coffee/tea and exercise for at least 30 minutes
before their BP measurement. Subjects with a clinical
from the International
history of secondary hypertension, coronary heart disease,
diabetes and chronic kidney disease were excluded from
the study. The protocol was approved by the local
bioethical committee and informed consent was obtained
from each participant.
The CTH gene is located on chromosome 1 at p31.1 and
spans 28kb with 12 exons. There were 136 entries of
SNPs in the CTH gene in the public NCBI Single
Nucleotide Polymorphism Database (dbSNP, build 127;
last accessed September 19, 2007), and 35 of them had
available frequency data among the Han Chinese in
Beijing, China (CHB) in the International HapMap
project website (http://www.hapmap.org/; HapMap Public
Release #22/phaseII; last accessed September 19, 2007).
In this study we selected SNPs for genotyping by the
CandidateGeneSearch.jsp), a web server which allows
users to efficiently identify and prioritize high-risk SNPs
according to their phenotypic risks and putative
functional effects. It assesses the risk of a SNP based on a
decision tree proposed by Tabor et al18 and extended by
Yuan et al.19 The decision tree classifies a SNP into 1 of
13 types of the functional effects, each of which is
assigned a risk ranking number between 0 and 5. A high
risk rank implies a high-risk level. FASTSNP extracts the
functional effect information from 11 external web serves
at query time using a team of web wrapper agents, so the
information used for SNP prioritization in FASTSNP is
always up to date.
We selected two SNPs (rs482843 and rs1021737) with
putative functions reported by FASTSNP and with minor
allele frequencies (MAF) ≥ 0.05 in CHB validated by the
HapMap. These two SNPs locate in the promoter region
and the exon 12 of the CTH gene, respectively. Both of
their risk ranking numbers fluctuate from 1 to 3.
Blood for genotyping was taken into ethylenediamine
tetraacetic acid (EDTA)-containing receptacles; DNA was
extracted according to a standard phenol-chloroform
method20 and stored at −20°C until required for batch
Two SNPs were genotyped according to polymerase
chain reaction and restriction
polymorphism method (PCR-RFLP). The primers and
DNA amplification conditions are shown in Table 1. Ten
percent of the individuals were randomly selected for
genotyping again for quality control with complete
Statistical analysis were conducted using the SPSS 13.0
program and the HWE program, in conjunction with the
Haplo.stats package, a suite of S-PLUS/R routines for the
analysis of indirectly measured haplotypes.
Chin Med J 2008;121(8):716-720
Table 1. Primers and conditions for genotyping for rs482843 and rs1021737
Sense: 5’- AGCAACCCCGTTAGTTCCTT-3’
Quantitative data was presented as mean ± SD.
Hardy-Weinberg equilibrium (HWE) was assessed by
Fisher’s exact test using HWE program. The differences
in clinical characteristics between hypertensive cases and
controls were assessed by a t test for quantitative
variables and chi-square test for qualitative ones. The
frequencies of the alleles and genotypes between cases
and controls were compared by the chi-square test. A
stepwise logistic regression was conducted to adjust for
covariates including age, gender, body mass index (BMI),
glucose (Glu), TG, TC, HDL-C, creatinine (Cr) and
smoking and drinking status.
To test the associations of statistically inferred haplotypes
with EH we used the Haplo.score approach as outlined by
Schaid et al.21 The method models an individual’s
phenotype as a function of each inferred haplotype,
weighted by their estimated probability, to account for
haplotype ambiguity. To obtain odds ratios (ORs) of risk
haplotypes the Haplo.glm approach was performed.22
Both Haplo.score and Haplo.glm were implemented in
the Haplo.stats software. A diplotype analysis was then
performed by using a weighted logistic regression, with
the weights being the probability for each possible
haplotype pair combination for an individual as estimated
by Haplo.score. Only the haplotypes and diplotypes with
frequency >5% were considered for the haplotype and
diplotype analyses, respectively. All statistical tests were
two-tailed and P<0.05 was considered statistically
The demographic and clinical data of all subjects
included in this study are summarized in Table 2. The age
and gender were not significantly different between cases
and controls. The cases had a lower HDL-C and higher
BMI, TC, TG, glucose and creatinine levels than the
controls. There were no significant differences in the
prevalence of drinking and smoking between the case and
Association analysis of single polymorphism
Table 3 summarizes the genotype distributions and allele
frequencies of the two SNPs in the CTH gene among the
cases and controls. Both of the two SNPs were in HWE
among the cases and the controls. Under three genetic
models we failed to observe any significant difference in
the genotype distributions or allele frequencies between
the cases and the controls. In the logistic regression
analysis we also failed to observe any association
between the two SNPs and hypertension (Table 4).
Table 2. Characteristics of essential hypertension patients and
Variables EH (n=503)
Male (%) 52.1
Age (years) 53.6±9.3
SBP (mmHg) 177.07±28.05
DBP (mmHg) 104.34±12.28
TC (mmol/L) 5.23±0.99
TG (mmol/L) 1.70±1.06
HDL-C (mmol/L) 1.25±0.30
LDL-C (mmol/L) 3.19±0.86
Glu (mmol/L) 5.93±1.79
Cr (µmol/L) 70.83±15.21
Smokers (%) 40.6
Drinkers (%) 34.4
EH: essential hypertension patients; HDL-C: high density lipoprotein cholesterol;
BMI: body mass index; TC: total cholesterol; TG: triglyceride; Glu: glucose; Cr:
creatinine; LDL-C: low density lipoprotein cholesterol.
Table 3. Genotype distributions and allele frequencies
of the two CTH gene SNPs
P value (χ2 test)
Dominant and recessive models are based on minor allele of each locus. *With
degree of freedom 2; #With degree of freedom 1.
Table 4. Logistic regression parameters of single loci in essential
hypertension patients and healthy controls
OR (95% CI) P value
BMI 1.152 (1.109-1.195)0.000
TG 1.183 (1.022-1.369)0.024
GLU 1.111 (1.022-1.206)0.016
GG vs AA
ORs are adjusted for gender, age, BMI, smoking, drinking and blood lipid levels.
Furthermore, none of the interactions between age,
gender, BMI, drinking or smoking status and individual
polymorphism were significant.
Haplotype and diplotype analysis
There was significant linkage disequilibrium between the
two SNPs with D’=0.665 and P<0.001. Table 5 shows the
results of the haplotype and diplotype analyses. In the
haplotype analyses we found that all four haplotypes
constructed by these two SNPs had frequencies >0.05 and
accounted for 100% of the haplotype variations. We did
not observe any haplotype which might significantly
0.938 0.9760.741 0.905
OR (95% CI)
GT vs GG
TT vs GG
AG vs AA
Chinese Medical Journal 2008; 121(8):716-720
Table 5. Associations between haplotypes, diplotypes, and essential hypertension
hap1-hap1 0.433 0.433
hap1-hap2 0.066 0.067
hap1-hap3 0.154 0.164
hap1-hap4 0.229 0.219
aLoci are arranged in the order rs482843-rs1021737. bHaplotype A-G(Hap1) is chosen to be the reference haplotype. cDiplotype Hap1-Hap1 (Dip1) is chosen to be the
reference diplotype.*Covariates are adjusted for age, gender, BMI, smoking, drinking and blood lipid levels.
increase or decrease the risk of hypertension before or
after adjustment for age, gender, BMI, smoking and
drinking. The diplotype analysis showed similar results
and, moreover, none of the interactions between age,
gender, BMI, drinking or smoking status and the
haplotypes or the diplotypes were significant.
This study showed that these two selected SNPs in the
CTH gene, rs482843 A/G and rs1021737 T/G, were not
associated with EH in Northern Chinese Han population.
No other study to date has assessed the relationship
between CTH gene variations and hypertension.
The CSE is a key enzyme in the trans-sulfuration pathway,
which uses L-cysteine to produce H2S. Endogenous
hydrogen sulfide possesses important functions in the
cardiovascular system. The SNP rs482843 and SNP
rs1021737 of the CTH gene possess higher estimated
risks than other SNPs of the CTH gene based on putative
function with an MAF ≥ 0.05 in CHB validated by the
HapMap. The SNP rs1021737 is a non-synonymous
variation in exon 12 of the CTH gene. Wang et al23 found
that the SNP rs1021737 variation of the CTH gene was a
determinant of plasma total homocysteine concentrations
in Caucasian subjects. Subjects with TT homozygotes had
significantly higher mean plasma total homocysteine
concentrations than subjects with other genotypes.
Elevated homocysteine contributes to elevated blood
pressure by diminishing the vasomotor regulation,
increasing the oxidative stress and stimulating the
proliferation of vascular smooth muscle cells. However,
we did not observe the association of either rs1021737 or
rs482843 with EH. One limitation of this study is that the
plasma levels of CSE were not determined. It is possible
that the absence of association between the two SNPs and
EH might be due to the fact that they do not substantially
influence the plasma CSE level which plays a key role in
generation of H2S.
To improve the power of this study we used a selective
genotyping approach proposed by Busst et al.24 The
power of this method depends on a number of factors,
including the size of the original group, the cutoff points
for selecting from the upper and lower ends of the
OR (95% CI)
P value *
phenotype distribution, the allele frequencies, the mode
of inheritance and the proportion of phenotypic variance
explained by the polymorphism.25 Sampling 100 subjects
from the upper and lower deciles of a population is
equivalent to sampling all subjects in these deciles from a
population of 1000 subjects.26 Busst et al24 undertook this
method to augment power to detect association by
sampling from the extremes of the population SBP
distribution. In our study, we used a similar but not
identical approach. We selected the hypertensive cases
with relatively high BP (SBP ≥ 160 mmHg or DBP ≥ 100
mmHg), which might improve the power by increasing
the differences in the frequencies of susceptibility alleles
between the cases and the controls. In addition, we
selected the SNPs with relatively high MAF, which might
also ameliorate the power in our study.
Our present study found that there was no association
between the two polymorphisms in the CTH gene and EH
in our sample after adjusting for covariates including age,
sex, BMI, drinking and smoking status and neither of the
haplotypes or diplotypes increased or decreased the risk
of EH. There is no other study to date that has assessed
the relationship between the CTH gene variations and
hypertension, so it is difficult to compare our results with
any published data. We should bear in mind several
aspects in interpreting our negative results. First, there is
essentially no association between the CTH gene and EH.
Although the CSE is responsible for the majority of the
endogenous production of H2S in mammalian tissues, the
polymorphisms of its encoded gene, CTH, does not
influence the transcription or biological activity of the
CSE. Second, the SNPs we selected can not cover the full
CTH gene. We selected SNPs on the basis of putative
function and a MAF ≥ 0.05 in CHB validated by the
HapMap, these SNPs may have a lack of LD with
functional SNPs which are associated with EH in the
CTH gene. Moreover, the rare variants (MAF < 0.05),
with low or high relative risk, were beyond the study.
Third, no association between
polymorphisms and EH was observed which were likely
due to the relatively minor effect of the CTH gene. In fact,
the power to confirm any functional effort of interesting
gene polymorphisms on EH is more than 80% in our
sample (allelic OR=1.3, MAF=0.2, 5% significance level,
two-side test). It is possible that we did not detect the
the CTH gene
Chin Med J 2008;121(8):716-720
effect of the SNPs with low relative risk. Finally, the
CTH gene cooperates with other candidate genes of EH
in the modulation of the BP. However, it is a limitation of
this study that we did not detect the interaction effects
between the CTH gene and other risk genes of EH.
Another limitation of this study is that we did not detect
the effects of the CTH gene on the markers of
In conclusion, the present study suggested that the
rs482843 A/G polymorphism and rs1021737 G/T
polymorphism of the CTH gene were not associated with
EH in the Northern Chinese Han population. In addition
to the well designed case-control studies, further study
based on different population-backgrounds should be
considered. It is also necessary to consider the
interactions between the CTH gene and other candidate
genes or risk factors in the pathophysiology of EH.
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Edited by SHEN Xi-bin