Abstract
OBJECTIVE:
The angiotensin-converting enzyme gene is one of the most studied candidate genes related to atrial fibrillation. Among the polymorphisms of the angiotensin-converting enzyme gene, the 2350 G/A polymorphism (rs4343) is known to have the most significant effects on the plasma angiotensin-converting enzyme concentration. The aim of the present study was to investigate the association of the angiotensin-converting enzyme 2350 G/A polymorphism with atrial fibrillation in Han Chinese patients with essential hypertension.
METHODS:
A total of 169 hypertensive patients were eligible for this study. Patients with atrial fibrillation (n = 75) were allocated to the atrial fibrillation group, and 94 subjects without atrial fibrillation were allocated to the control group. The PCR-based restriction fragment length polymorphism technique was used to assess the genotype frequencies.
RESULTS:
The distributions of the angiotensin-converting enzyme 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the atrial fibrillation subjects (p = 0.037). The frequency of the A allele in the atrial fibrillation group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA and AA genotypes had an increased risk for atrial fibrillation. Additionally, atrial fibrillation patients with the AA genotype had greater left atrial dimensions than the patients with the GG or GA genotypes (p<0.01 and p<0.05, respectively).
CONCLUSIONS:
The results obtained in this study indicate that the angiotensin-converting enzyme 2350 G/A polymorphism is associated with atrial fibrillation and that the A allele shows an increased risk for atrial fibrillation in Han Chinese patients with essential hypertension.
Angiotensin-converting enzyme ; Genetic polymorphism; Atrial fibrillation; Essential hypertension; China
INTRODUCTION
Atrial fibrillation (AF) is a rapidly evolving epidemic, representing a multifactorial, dynamic
disorder with serious health consequences (11. Pan M, Zhu JH, Jiang WP, Liu ZH, Li HM, Yu XH, et al. Inflammation: a possible
pathogenic link to atrial fibrillation. Med Hypotheses. 2006;67(6):1305-7,
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2. Liu T, Korantzopoulos P, Xu G, Shehata M, Li D, Wang X, et al. Association
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atrial fibrillation: a meta-analysis. Europace. 2011;13(3):346-54,
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Predictors of the risk of falls among elderly with chronic atrial fibrillation. Clinics.
2012;67(4):305-11, http://dx.doi.org/10.6061/clinics/2012(04)02.
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-66. Gu JY, Xu JH, Yu H, Yang YQ. Novel GATA5 loss-of-function mutations underlie
familial atrial fibrillation. Clinics. 2012;67(12):1393-9,
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). The prevalence of AF is strongly age-dependent, affecting
approximately 0.5% of persons aged 40-50 years old and 5-15% of individuals aged 80 years old (33. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines
for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation
of the European Society of Cardiology (ESC). Eur Heart J.
2010;31(19):2369-429.,77. Li J, Song J, Jiang MH, Zheng JG, Gao SP, Zhu JH, et al. Interleukin-6 promoter
polymorphisms and susceptibility to atrial fibrillation in elderly han chinese patients with
essential hypertension. J Interferon Cytokine Res. 2012;32(11):542-7,
http://dx.doi.org/10.1089/jir.2012.0033.
http://dx.doi.org/10.1089/jir.2012.0033...
). In China, the
morbidity related to AF is 0.77% in the adult population (88. Hu D, Sun Y. Epidemiology, risk factors for stroke, and management of atrial
fibrillation in China. J Am Coll Cardiol. 2008;52(10):865-8,
http://dx.doi.org/10.1016/j.jacc.2008.05.042.
http://dx.doi.org/10.1016/j.jacc.2008.05...
).
AF not only is an independent risk factor for death but also confers a significant risk of morbidity
from stroke associated with cardiogenic thromboembolisms (99. Gao SP, Deng XT, Ge LJ, Luan H, Zheng JG, Chen C, et al. Is inflammation linked
to thrombogenesis in atrial fibrillation. Int J Cardiol.
2011;149(2):260-1.,1010. Mansur AP, Takada JY, Avakian SD, Strunz CM. Warfarin doses for anticoagulation
therapy in elderly patients with chronic atrial fibrillation. Clinics. 2012;67(6):543-6,
http://dx.doi.org/10.6061/clinics/2012(06)01.
http://dx.doi.org/10.6061/clinics/2012(0...
). Despite current achievements in the
pharmacological and non-pharmacological treatments of AF, its management remains a difficult task
(22. Liu T, Korantzopoulos P, Xu G, Shehata M, Li D, Wang X, et al. Association
between angiotensin-converting enzyme insertion/deletion gene polymorphism and
atrial fibrillation: a meta-analysis. Europace. 2011;13(3):346-54,
http://dx.doi.org/10.1093/europace/euq407.
http://dx.doi.org/10.1093/europace/euq40...
).
Essential hypertension (EH) is the most common cardiac condition associated with AF (1111. Verdecchia P, Reboldi G, Gattobigio R, Bentivoglio M, Borgioni C, Angeli F, et
al. Atrial fibrillation in hypertension: predictors and outcome. Hypertension. 2003;41(2):218-23,
http://dx.doi.org/10.1161/01.HYP.0000052830.02773.E4.
http://dx.doi.org/10.1161/01.HYP.0000052...
). The risk of AF in EH subjects, compared with normotensive
subjects, was increased by 1.9 times in the Framingham Heart Study (1212. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic
atrial fibrillation: the Framingham study. N Engl J Med.
1982;306(17):1018-22.) and by 1.4 times in the Manitoba Follow-up Study (1313. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of
atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study.
Am J Med. 1995;98(5):476-84.). However, contemporary approaches to prevent AF in EH patients have been limited by
inefficacy and intolerance (1414. Rienstra M, Van Veldhuisen DJ, Crijns HJ, Van Gelder IC. Enhanced cardiovascular
morbidity and mortality during rhythm control treatment in persistent atrial fibrillation in
hypertensives: data of the RACE study. Eur Heart J. 2007;28(6):741-51,
http://dx.doi.org/10.1093/eurheartj/ehl436.
http://dx.doi.org/10.1093/eurheartj/ehl4...
).
Recently, the rennin-angiotensin system (RAS) has been implicated in the development of AF (1515. Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C, et al. Increased
expression of extracellular signal-regulated kinase and angiotensin-converting
enzyme in human atria during atrial fibrillation. J Am Coll Cardiol.
2000;35(6):1669-77, http://dx.doi.org/10.1016/S0735-1097(00)00611-2.
http://dx.doi.org/10.1016/S0735-1097(00)...
16. Iravanian S, Dudley SC Jr. The renin-angiotensin-aldosterone system (RAAS) and
cardiac arrhythmias. Heart Rhythm. 2008;5(6 Suppl):S12-7,
http://dx.doi.org/10.1016/j.hrthm.2008.02.025.
http://dx.doi.org/10.1016/j.hrthm.2008.0...
-1717. Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of
its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J.
2006;27(5):512-8, http://dx.doi.org/10.1093/eurheartj/ehi668.
http://dx.doi.org/10.1093/eurheartj/ehi6...
), and the inhibition
of RAS activity has been shown to reduce AF vulnerability (1818. Novo G, Guttilla D, Fazio G, Cooper D, Novo S. The role of the renin-angiotensin
system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS. Br J Clin
Pharmacol. 2008;66(3):345-51.). Therefore, over the past decade, the key enzyme of this system, the
angiotensin-converting enzyme (ACE), has become one of the most studied candidate genes in AF. Many
studies have attempted to shed some light on the possible association between the
ACE gene insertion/deletion (I/D) polymorphism and the risk of AF. However,
previous reports have shown inconsistent and even contradictory results (22. Liu T, Korantzopoulos P, Xu G, Shehata M, Li D, Wang X, et al. Association
between angiotensin-converting enzyme insertion/deletion gene polymorphism and
atrial fibrillation: a meta-analysis. Europace. 2011;13(3):346-54,
http://dx.doi.org/10.1093/europace/euq407.
http://dx.doi.org/10.1093/europace/euq40...
).
The physiological role of the I/D polymorphism has not yet been clarified. This polymorphism is
likely in strong linkage disequilibrium with another functional mutation within the gene (1919. Pan M, Jiang MH, Wei MF, Liu ZH, Jiang WP, Geng HH, et al. Association of
angiotensin-converting enzyme gene 2350G>A polymorphism with myocardial
infarction in a Chinese population. Clin Appl Thromb Hemost. 2009;15(4):435-42,
http://dx.doi.org/10.1177/1076029608316013.
http://dx.doi.org/10.1177/10760296083160...
). Recently, a genome-scan analysis by the Framingham Heart Study
found strong evidence for a quantitative-trait locus on chromosome 17 that was close to the
ACE gene (2020. Levy D, DeStefano AL, Larson MG, O'Donnell CJ, Lifton RP, Gavras H, et al.
Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for
longitudinal blood pressure phenotypes in subjects from the framingham heart study. Hypertension.
2000;36(4):477-83, http://dx.doi.org/10.1161/01.HYP.36.4.477.
http://dx.doi.org/10.1161/01.HYP.36.4.47...
). Among the 13 polymorphisms of
the ACE gene recently reported, a dimorphism in exon 17, 2350G/A (rs4343), had the
most significant effects on the plasma ACE concentration (2121. Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, et al. Linkage
and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE
concentration and blood pressure. Am J Hum Genet. 2001;68(5):1139-48.).
Based on these findings, we conducted a case-control study of the ACE 2350 G/A polymorphism for a putative association with AF in Han Chinese patients with EH.
MATERIALS AND METHODS
A total of 169 patients with EH were eligible for this study. They were all unrelated Han
nationality residents and were enrolled at the Affiliated Hospital of Nantong University. Patients
with AF (n = 75) were allocated to the AF group, and 94 subjects without AF were
allocated to the control group. EH was defined according to the Joint National Committee on the
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) criteria (2222. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72,
http://dx.doi.org/10.1001/jama.289.19.2560.
http://dx.doi.org/10.1001/jama.289.19.25...
). AF was defined according to the European Society of Cardiology
(ESC) Guidelines for the management of AF (33. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines
for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation
of the European Society of Cardiology (ESC). Eur Heart J.
2010;31(19):2369-429.), based on the
replacement of sinus P waves by rapid oscillations or fibrillatory waves that varied in size, shape,
and timing, which were associated with an irregular ventricular response when atrioventricular
conduction was intact. The presence of AF was determined based on patient history, followed by
serial electrocardiography or ambulatory electrocardiographic monitoring. Details regarding the
medical history, family history, and clinical symptoms were obtained from all participants using a
standardized questionnaire in addition to information on drug intake and cigarette smoking. Blood
pressure, height, weight, and waistline were measured by trained physicians or nurses, according to
standardized protocols. Patients were excluded if they had acute coronary syndrome; hypertrophic
cardiomyopathy; significant valvular disease; left ventricular dysfunction (ejection fraction
<50%); or neoplastic, renal, liver, or thyroid diseases. All study participants were unrelated
Han nationality residents. The study was approved by the Medical Ethics Committee of Nantong
University, and written informed consent was obtained from all participants.
Venous blood samples were obtained after at least a 10-hour overnight fast. The samples were then
centrifuged at 2500 rpm for 30 minutes at 4°C and immediately stored at -80°C until
analysis. The measurement of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C),
low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) was performed as described
previously (77. Li J, Song J, Jiang MH, Zheng JG, Gao SP, Zhu JH, et al. Interleukin-6 promoter
polymorphisms and susceptibility to atrial fibrillation in elderly han chinese patients with
essential hypertension. J Interferon Cytokine Res. 2012;32(11):542-7,
http://dx.doi.org/10.1089/jir.2012.0033.
http://dx.doi.org/10.1089/jir.2012.0033...
,1919. Pan M, Jiang MH, Wei MF, Liu ZH, Jiang WP, Geng HH, et al. Association of
angiotensin-converting enzyme gene 2350G>A polymorphism with myocardial
infarction in a Chinese population. Clin Appl Thromb Hemost. 2009;15(4):435-42,
http://dx.doi.org/10.1177/1076029608316013.
http://dx.doi.org/10.1177/10760296083160...
).
Genomic DNA was extracted from peripheral blood leukocytes by the salting-out method, with
minimal modifications. The determination of the ACE 2350 G/A genotypes was
performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)
analysis, as described previously (1919. Pan M, Jiang MH, Wei MF, Liu ZH, Jiang WP, Geng HH, et al. Association of
angiotensin-converting enzyme gene 2350G>A polymorphism with myocardial
infarction in a Chinese population. Clin Appl Thromb Hemost. 2009;15(4):435-42,
http://dx.doi.org/10.1177/1076029608316013.
http://dx.doi.org/10.1177/10760296083160...
,2323. Pan M, Zhu JH, Liu ZH, Jiang WP, Cui ZC, Yu XH, et al.
Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left
ventricular hypertrophy but not essential hypertension. Hypertens Res. 2007;30(1):31-7,
http://dx.doi.org/10.1291/hypres.30.31.
http://dx.doi.org/10.1291/hypres.30.31...
,2424. Liang S, Pan M, Hu N, Wu YY, Chen H, Zhu JH, et al. Association of
angiotensin-converting enzyme gene 2350 G/A polymorphism with diabetic retinopathy
in Chinese Han population. Mol Biol Rep. 2013;40(1):463-8,
http://dx.doi.org/10.1007/s11033-012-2081-2.
http://dx.doi.org/10.1007/s11033-012-208...
).
All continuous variables are expressed as means and standard deviations (SDs). Student's
t-test and analysis of variance (ANOVA), followed by the Newman-Keuls test, were used to compare
continuous variables between two groups and among multiple groups, respectively. The genotype and
allele frequencies were obtained by direct counts. Differences in the distributions of the alleles
and genotypes between the groups and the deviation from Hardy-Weinberg equilibrium were assessed by
the χ2 test. All significant tests were two-tailed and were considered statistically
significant at p<0.05. SAS software (version 8, SAS Institute, Cary, NC, USA)
was used in all statistical analyses. The present sample size of 169 — 75 AF patients and 94
controls — revealed an 87.28% power to detect a significant association (α<0.05)
for a 7% prevalence of AF in the population (88. Hu D, Sun Y. Epidemiology, risk factors for stroke, and management of atrial
fibrillation in China. J Am Coll Cardiol. 2008;52(10):865-8,
http://dx.doi.org/10.1016/j.jacc.2008.05.042.
http://dx.doi.org/10.1016/j.jacc.2008.05...
) using the
dominant inheritance model.
RESULTS
The clinical characteristics of all the participants enrolled in the study are depicted in Table 1. No significant differences were observed between the two groups with regard to age, gender, body mass index (BMI), blood pressure, left ventricular ejection fraction (LVEF), serum lipid levels, diabetes, smoking status, or the use of antihypertensive drugs. However, compared with the controls, the AF patients had larger left atrial dimensions.
Table 2 summarizes the distribution of the ACE 2350 G/A genotypes and allele frequencies for the two groups. The genotype distribution among the subjects was in Hardy-Weinberg equilibrium in both the control (χ2 = 1.5071, p = 0.2196) and AF (χ2 = 0.1332, p = 0.7151) groups. The distributions of the ACE 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the AF subjects (p = 0.037). The frequency of the A allele in the AF group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA genotype had a 2.44-fold increased risk of AF (95% confidence interval [CI] = 1.1346-5.2297, p = 0.0261), and the AA genotype had a 4.15-fold increased risk of AF (95% CI = 1.7469-9.8650, p = 0.0016). After adjustments for gender, age, BMI, blood pressure, LVEF, plasma lipid parameters, smoking status, prevalence of diabetes, and left atrial dimensions, these associations persisted.
The effects of the different genotypes on the clinical parameters are shown in Table 3. There were no significant differences regarding gender, age, BMI, blood pressure, or serum lipid parameters between the genotypes in the AF and control groups. However, the AF patients with the AA genotype had greater left atrial dimensions than the patients with the GG and GA genotypes (p<0.01, p<0.05).
DISCUSSION
ACE is a dipeptidyl carboxypeptidase I (EC.3.4.15.1) that activates angiotensin I through
cleavage of the carboxyterminal dipeptide into the potent vasoconstrictor angiotensin II (ang II),
inactivating the vasodilator peptide bradykinin. Recent evidence has indicated that activation of
the RAS pathway plays an important role in the development and perpetuation of AF (1515. Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C, et al. Increased
expression of extracellular signal-regulated kinase and angiotensin-converting
enzyme in human atria during atrial fibrillation. J Am Coll Cardiol.
2000;35(6):1669-77, http://dx.doi.org/10.1016/S0735-1097(00)00611-2.
http://dx.doi.org/10.1016/S0735-1097(00)...
16. Iravanian S, Dudley SC Jr. The renin-angiotensin-aldosterone system (RAAS) and
cardiac arrhythmias. Heart Rhythm. 2008;5(6 Suppl):S12-7,
http://dx.doi.org/10.1016/j.hrthm.2008.02.025.
http://dx.doi.org/10.1016/j.hrthm.2008.0...
-1717. Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of
its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J.
2006;27(5):512-8, http://dx.doi.org/10.1093/eurheartj/ehi668.
http://dx.doi.org/10.1093/eurheartj/ehi6...
). ACE expression was
elevated in the atrial biopsies of patients with AF, and angiotensin II concentrations were
increased in a rapid ventricular pacing-induced congestive heart failure model of AF (22. Liu T, Korantzopoulos P, Xu G, Shehata M, Li D, Wang X, et al. Association
between angiotensin-converting enzyme insertion/deletion gene polymorphism and
atrial fibrillation: a meta-analysis. Europace. 2011;13(3):346-54,
http://dx.doi.org/10.1093/europace/euq407.
http://dx.doi.org/10.1093/europace/euq40...
). Angiotensin II and bradykinin have also been implicated in the
modulation of cardiac growth (2525. Iwashima Y, Horio T, Kuroda S, Takishita S, Kawano Y. Influence of plasma
aldosterone on left ventricular geometry and diastolic function in treated essential hypertension.
Hypertens Res. 2002;25(1):49-56, http://dx.doi.org/10.1291/hypres.25.49.
http://dx.doi.org/10.1291/hypres.25.49...
). Experimental studies have
suggested that angiotensin II might stimulate cardiac protein synthesis, whereas bradykinin may have
anti-proliferative effects (2626. Schunkert H, Hense HW, Holmer SR, Stender M, Perz S, Keil U, et al. Association
between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular
hypertrophy. N Engl J Med. 1994;330(23):1634-8.). In addition, clinical
evidence has suggested that inhibiting the activity of RAS might suppress AF (1818. Novo G, Guttilla D, Fazio G, Cooper D, Novo S. The role of the renin-angiotensin
system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS. Br J Clin
Pharmacol. 2008;66(3):345-51.). ACE is a key enzyme in the production of angiotensin II and in the degradation
of bradykinin (2727. Kawamoto R, Kohara K, Tabara Y, Miki T. An interaction between systolic blood
pressure and angiotensin-converting enzyme gene polymorphism on carotid
atherosclerosis. Hypertens Res. 2002;25(6):875-80,
http://dx.doi.org/10.1291/hypres.25.875.
http://dx.doi.org/10.1291/hypres.25.875...
). Our previous study, conducted in Chinese
EH patients, showed that the ACE 2350 G/A polymorphism was associated with left
ventricular hypertrophy but not EH (2323. Pan M, Zhu JH, Liu ZH, Jiang WP, Cui ZC, Yu XH, et al.
Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left
ventricular hypertrophy but not essential hypertension. Hypertens Res. 2007;30(1):31-7,
http://dx.doi.org/10.1291/hypres.30.31.
http://dx.doi.org/10.1291/hypres.30.31...
). These experimental
and clinical data were suggestive of a possible role for ACE in AF.
Over the past decade, much attention has been devoted to assessing the role of the
ACE gene I/D polymorphism in AF after Rigat et al. (2828. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An
insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the
variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343-6,
http://dx.doi.org/10.1172/JCI114844.
http://dx.doi.org/10.1172/JCI114844...
) reported that more than half of the plasma ACE levels among individuals were under the
influence of the I/D polymorphism. Yamashita et al. (2929. Yamashita T, Hayami N, Ajiki K, Oikawa N, Sezaki K, Inoue M, et al. Is ACE gene
polymorphism associated with lone atrial fibrillation. Jpn Heart J. 1997;38(5):637-41,
http://dx.doi.org/10.1536/ihj.38.637.
http://dx.doi.org/10.1536/ihj.38.637...
)
first investigated the ACE gene I/D polymorphism in 77 Japanese lone AF patients
and found that the distribution of ACE genotypes was not significantly different
between the patients and healthy controls. The subsequent studies, however, yielded inconsistent and
even contradictory results (22. Liu T, Korantzopoulos P, Xu G, Shehata M, Li D, Wang X, et al. Association
between angiotensin-converting enzyme insertion/deletion gene polymorphism and
atrial fibrillation: a meta-analysis. Europace. 2011;13(3):346-54,
http://dx.doi.org/10.1093/europace/euq407.
http://dx.doi.org/10.1093/europace/euq40...
).
The ACE gene I/D polymorphic locus is located in a non-coding region; therefore,
it is more likely to be a genetic marker in linkage disequilibrium with the genuine functional
variation locus (2323. Pan M, Zhu JH, Liu ZH, Jiang WP, Cui ZC, Yu XH, et al.
Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left
ventricular hypertrophy but not essential hypertension. Hypertens Res. 2007;30(1):31-7,
http://dx.doi.org/10.1291/hypres.30.31.
http://dx.doi.org/10.1291/hypres.30.31...
). Zhu et al. (2121. Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, et al. Linkage
and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE
concentration and blood pressure. Am J Hum Genet. 2001;68(5):1139-48.) conducted a linkage and association analysis of 13 polymorphic loci of the
ACE gene, demonstrating that the 2350 G/A polymorphic locus at exon 17 had the
greatest effect on the plasma ACE levels: approximately 19% of the variations in the plasma ACE
levels were associated with this polymorphism. The I/D polymorphism was no longer related to the
plasma ACE levels after adjustment for the effects of the ACE 2350 G/A polymorphism. The results
indicated that the I/D polymorphism was in linkage disequilibrium with 2350 G/A and not the
functional variation locus.
We did not test the linkage disequilibrium between the I/D and 2350 G/A polymorphisms in the
present study. However, published studies, conducted in Emirati (3030. Saeed M, Saleheen D, Siddiqui S, Khan A, Butt ZA, Frossard PM. Association of
angiotensin converting enzyme gene polymorphisms with left ventricular hypertrophy. Hypertens Res.
2005;28(4):345-9, http://dx.doi.org/10.1291/hypres.28.345.
http://dx.doi.org/10.1291/hypres.28.345...
), Punjab (3131. Alvi FM, Hasnain S. ACE I/D and G2350A polymorphisms in Pakistani hypertensive
population of Punjab. Clin Exp Hypertens. 2009;31(5):471-80,
http://dx.doi.org/10.1080/10641960902825479.
http://dx.doi.org/10.1080/10641960902825...
), and Indian (3232. Vamsi UM, Swapna N, Reddy SS, Vishnupriya S, Tirunilai P. Risk of
angiotensin-converting enzyme (ACE) gene I/D and g.2350G>A polymorphisms in
causing susceptibility to essential hypertension. Asian Biomed (Res Rev News).
2012;6(2):255-64.) populations, have shown that the ACE I/D and ACE 2350 G/A polymorphisms were in
strong linkage disequilibrium. The 2350 G/A polymorphic locus, being located in an intron, is
unlikely to influence the expression of ACE mRNA directly or to be a functional
variant. This fragment has been hypothesized to also be in linkage disequilibrium with an unknown
DNA fragment that acts as a silencer. Therefore, the identification of these putative gene loci,
which would be in linkage disequilibrium with the 2350 G/A polymorphism, requires further
investigation.
The correlation between the ACE 2350 G/A polymorphism and AF has not yet been studied. In the present study, there was a strong association between the ACE 2350 G/A polymorphism and the risk of developing AF in EH patients. Compared with the wild-type GG genotype, the GA and AA genotypes showed 2.44-fold and 4.15-fold increased risks of AF, respectively. In the AF group, AA homozygotes also had greater left atrial dimensions than the GG homozygotes and GA heterozygotes. These findings suggest a strong association between the ACE 2350 G/A polymorphism and the risk of developing AF in Han Chinese patients with EH.
The ACE 2350 G/A polymorphism is a synonymous mutation; this type of mutation has traditionally
been regarded as “silent”. Recently, Duan et al. (3333. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, et al.
Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of
the receptor. Hum Mol Genet. 2003;12(3):205-16,
http://dx.doi.org/10.1093/hmg/ddg055.
http://dx.doi.org/10.1093/hmg/ddg055...
) reported a synonymous mutation of the human dopamine receptor D2 (DRD2). In contrast to
the previous idea that this type of mutation was “silent”, this synonymous mutation
could change mRNA folding, leading to a decrease in the stability and transcription level of the
mRNA and remarkably up-regulating the DRD2 induced by dopamine. That study indicated that some
synonymous mutations might also influence some functional effects. However, the ACE 2350G/A
polymorphism might not be the actual functional mutation in this context. It might be located near
another functional mutation, as yet undiscovered, in ACE or any other gene in this
region of chromosome 17 that could be in LD. Thus, the mechanisms of the association of the
ACE 2350G/A polymorphism with AF and the ACE concentrations should be examined in
future studies.
Previous case-control studies have shown that the frequency of the A allele in Chinese healthy
controls is 0.417-0.451 (1919. Pan M, Jiang MH, Wei MF, Liu ZH, Jiang WP, Geng HH, et al. Association of
angiotensin-converting enzyme gene 2350G>A polymorphism with myocardial
infarction in a Chinese population. Clin Appl Thromb Hemost. 2009;15(4):435-42,
http://dx.doi.org/10.1177/1076029608316013.
http://dx.doi.org/10.1177/10760296083160...
,2323. Pan M, Zhu JH, Liu ZH, Jiang WP, Cui ZC, Yu XH, et al.
Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left
ventricular hypertrophy but not essential hypertension. Hypertens Res. 2007;30(1):31-7,
http://dx.doi.org/10.1291/hypres.30.31.
http://dx.doi.org/10.1291/hypres.30.31...
,2424. Liang S, Pan M, Hu N, Wu YY, Chen H, Zhu JH, et al. Association of
angiotensin-converting enzyme gene 2350 G/A polymorphism with diabetic retinopathy
in Chinese Han population. Mol Biol Rep. 2013;40(1):463-8,
http://dx.doi.org/10.1007/s11033-012-2081-2.
http://dx.doi.org/10.1007/s11033-012-208...
). The A allele frequency in Chinese subjects
was significantly greater (p<0.05) than those in a Pakistani population
(0.298) (3434. Saeed M, Mekan SF, Rabbani MA, Arain FM, Arif M, Shaharyar S. Angiotensin
converting enzyme (ACE) gene polymorphisms and lupus disease severity: a promising link. Ann Rheum
Dis. 2005;64(1):164-5, http://dx.doi.org/10.1136/ard.2004.020834.
http://dx.doi.org/10.1136/ard.2004.02083...
) and a Malaysian cohort (0.207) (3535. Vasudevan R, Ismail P, Stanslas J, Shamsudin N. Association of G2350A
Polymorphism of Angiotensin Converting Enzyme Gene with Essential Hypertension and Type 2 Diabetes
Mellitus in Malaysian Subjects. J Biol Sci. 2008;8(6):1045-50.) but lower (p<0.05) than those in a
European sample (0.513-0.542) (3636. Kehoe PG, Katzov H, Feuk L, Bennet AM, Johansson B, Wiman B, et al. Haplotypes
extending across ACE are associated with Alzheimer's disease. Hum Mol Genet. 2003;12(8):859-67,
http://dx.doi.org/10.1093/hmg/ddg094.
http://dx.doi.org/10.1093/hmg/ddg094...
) and an Iranian sample
(0.591) (3737. Firouzabadi N, Tajik N, Shafiei M, Ebrahimi SA, Bakhshandeh H. Interaction of
A-240T and A2350G related genotypes of angiotensin-converting enzyme (ACE) is
associated with decreased serum ACE activity and blood pressure in a healthy Iranian population.
Eur J Pharmacol. 2011;668(1-2):241-7.). These data indicate that different ethnic
groups might have different ACE gene distributions (3838. Zhu TN, Pan JQ, Shen ZJ, Zhao YQ, Shen T. Gene polymorphisms of
rennin-angiotensin system and coronary artery thrombosis disease. Zhongguo Shi Yan Xue Ye Xue Za
Zhi. 2004;12(5):674-9.) and
that ethnic variation could play a major role in the genetic regulation of serum ACE activity (2424. Liang S, Pan M, Hu N, Wu YY, Chen H, Zhu JH, et al. Association of
angiotensin-converting enzyme gene 2350 G/A polymorphism with diabetic retinopathy
in Chinese Han population. Mol Biol Rep. 2013;40(1):463-8,
http://dx.doi.org/10.1007/s11033-012-2081-2.
http://dx.doi.org/10.1007/s11033-012-208...
).
This study has several potential limitations. First, we could not exclude the presence of previous asymptomatic AF in the control group because these conclusions were based solely on the medical histories obtained from interviews with the participants. Second, the absence of the assessment of serum ACE levels concordant with the ACE 2350G/A polymorphism might have limited the outcomes. Finally, although all the study subjects were from the Han Chinese population and the possibility of ethnicity as a confounding factor could thus be excluded, the association of the ACE 2350G/A polymorphism and AF in other populations remains unknown and requires further study.
In conclusion, our data indicate that the ACE 2350G/A polymorphism is associated with AF and that the A allele shows an increased risk for AF in Han Chinese patients with EH. The ACE 2350 G/A polymorphism should be evaluated in EH patients to quantify the risk of AF and, consequently, to improve efforts for preventing or delaying the myocardial remodeling associated with EH. Given the inherent limitations of case-control studies and the complex nature of genetic susceptibility for chronic degenerative diseases, prospective and interventional clinical studies with larger sample sizes will still need to be conducted in individual ethnic groups to verify our observations.
This study was supported by grants from the “Summit of the Six Top Talents” Program of Jiangsu Province (2009046) and by the Nantong Municipal Commission of Science and Technology (S2008021).
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35Vasudevan R, Ismail P, Stanslas J, Shamsudin N. Association of G2350A Polymorphism of Angiotensin Converting Enzyme Gene with Essential Hypertension and Type 2 Diabetes Mellitus in Malaysian Subjects. J Biol Sci. 2008;8(6):1045-50.
-
36Kehoe PG, Katzov H, Feuk L, Bennet AM, Johansson B, Wiman B, et al. Haplotypes extending across ACE are associated with Alzheimer's disease. Hum Mol Genet. 2003;12(8):859-67, http://dx.doi.org/10.1093/hmg/ddg094.
» http://dx.doi.org/10.1093/hmg/ddg094 -
37Firouzabadi N, Tajik N, Shafiei M, Ebrahimi SA, Bakhshandeh H. Interaction of A-240T and A2350G related genotypes of angiotensin-converting enzyme (ACE) is associated with decreased serum ACE activity and blood pressure in a healthy Iranian population. Eur J Pharmacol. 2011;668(1-2):241-7.
-
38Zhu TN, Pan JQ, Shen ZJ, Zhao YQ, Shen T. Gene polymorphisms of rennin-angiotensin system and coronary artery thrombosis disease. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2004;12(5):674-9.
-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Nov 2013
History
-
Received
12 Aug 2013 -
Reviewed
10 Sept 2013 -
Accepted
10 Sept 2013