Sage Journals: Discover world-class research

Abstract

Objective:

The angiotensinogen (AGT) gene has been shown to be involved in the development of coronary heart disease (CHD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to clarify the associations between AGT polymorphisms and CHD risk among the Chinese population.

Methods:

Published literature from PubMed, the China National Knowledge Infrastructure and Wanfang Data were searched. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model.

Results:

Fourteen studies (2540 cases and 2173 controls) for M235T polymorphism and five studies (655 cases and 815 controls) for T174M polymorphism were included in the meta-analyses. The results showed that M235T polymorphism was significantly associated with CHD risk under a recessive model (OR=1.65, 95% CI 1.22–2.25). There was also significant association between T174M polymorphism and CHD risk under a homogeneous co-dominant model (OR= 4.20, 95% CI 1.90–9.29) and a recessive model (OR=4.15, 95% CI 1.88–9.15). Further sensitivity analyses confirmed the significant association.

Conclusions:

The meta-analyses indicated the significant associations of two AGT polymorphisms (M235T, T174M) with CHD risk in the Chinese population.

Keywords

Angiotensinogen gene polymorphism coronary heart disease meta-analysis Chinese

Introduction

Coronary heart disease (CHD) is a main cause of morbidity and mortality in developed and developing countries. Epidemiological studies have shown that smoking, a diet high in fat, lack of physical activity, hypertension and cholesterol are the major risk factors of CHD.¹ However, emerging evidence has indicated the great contribution of genetic factors.

The rennin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, vascular remodeling and sodium homeostasis.² Several genes that belong to RAS have been suggested to be associated with risk of CHD. However, inconsistent results have been reported. The most studied genetic polymorphisms include the insertion/deletion (I/D) polymorphism in the angiotensin I-converting enzyme (ACE) gene and two polymorphisms (M235T, T174M) in the angiotensinogen (AGT) gene. Two meta-analyses confirmed the significant association between I/D polymorphism in the ACE gene and CHD in Europeans³ as well as among the Chinese population.⁴ In addition, another two meta-analyses investigated the associations of two polymorphisms (M235T, T174M) in the AGT gene with CHD risk.^5,6 However, these two meta-analyses included only limited studies related to the Chinese population, and most studies published in Chinese local journals were not included. Therefore, we performed a meta-analysis to clarify the associations between two polymorphisms (M235T, T174M) in the AGT gene and CHD risk among the Chinese population.

Materials and methods

Literature and search strategy

We searched the literature databases including PubMed, the China National Knowledge Infrastructure and Wanfang Data. The search strategy to identify all possible studies involved the use of the following keywords: (angiotensinogen or AGT) and (variant or variation or polymorphism) and (coronary disease or coronary heart disease or myocardial infarction or coronary artery disease or ischemic heart disease or CAD or MI or CHD or IHD) and (China or Chinese). All relevant studies were limited to ones published in the English and Chinese languages. The reference lists of retrieved articles were hand-searched. If more than one article was published using the same case series, only the study with the largest sample size was included. The literature search was updated on 20 March 2012.

Inclusion criteria and data extraction

The studies included in the meta-analysis must meet all the following inclusion criteria: (1) evaluating the association of M235T or T174M polymorphism in the AGT gene with CHD risk; (2) using case-control or cohort design; and (3) providing sufficient data for calculation of odds ratio (OR) with 95% confidence interval (CI). The following information was extracted from each study: (1) name of the first author; (2) year of publication; (3) region; (4) sample size of cases and controls; (5) genotype distribution in cases and controls; and (6) P value for Hardy-Weinberg equilibrium (HWE) test in controls. Two authors independently assessed the articles for compliance with the inclusion/exclusion criteria, resolved disagreements and reached a consistent decision.

Statistical analysis

The association of M235T or T174M polymorphism in the AGT gene with CHD risk was estimated by calculating pooled OR and 95% CI under co-dominant, dominant and recessive genetic models, respectively. The significance of pooled OR was determined by Z test (p<0.05 was considered statistically significant). A Q test was performed to evaluate whether the variation was due to heterogeneity or by chance. A random- (DerSimonian-Laird method⁷) or fixed- (Mantel-Haenszel method⁸) effects model was used to calculate pooled OR in the presence (p<=0.10) or absence (p>0.10) of heterogeneity, respectively. Meta-regression analysis was used to explore the source of heterogeneity. Sensitivity analysis, after removing one study at a time, was performed to evaluate the stability of the results. Publication bias was assessed by Egger’s test⁹ (p<0.05 was considered statistically significant). Data analysis was performed using STATA version 11 (StataCorp LP, College Station, TX, USA).

Results

Characteristics of the studies

The literature search identified a total of 81 potentially relevant papers. Forty-two papers were excluded because of obvious irrelevance to our study aim. In addition, 16 papers were excluded because they were duplicate publications, reviews, investigated associations with other polymorphisms of the AGT gene or did not provide sufficient data for calculation OR with 95% CI. Therefore, 23 papers met the primary inclusion criteria.^{10

–31} However, the genotypes of M235T polymorphism in controls were not in HWE for five papers; they were then excluded.^24,28
–31 Ultimately, 14 studies for M235T polymorphism^{10

–23} and five studies for T174M polymorphism^24
–27 were included in the meta-analyses. A flowchart describing the process of study inclusion/exclusion is displayed as Figure 1. The characteristics of the included studies are listed in Table 1.

Figure 1.

Flowchart of meta-analysis for exclusion/inclusion of studies.

Table 1.

Characteristics of the studies included in the meta-analysis.

Study	Region	Sample size		Genotype frequency						P _HWE
				Cases			Controls
		Cases	Controls	11	12	22	11	12	22
M235T variant
Ko et al., 1997	Taiwan	267	337	6	36	225	4	54	279	0.454
Chen et al., 1998	Shanghai	57	76	4	13	40	13	31	32	0.258
Sheu et al., 1998	Taiwan	102	145	1	26	75	1	37	107	0.247
Xie et al., 2001	Jiangsu	106	86	8	29	69	11	30	45	0.108
Zhu et al., 2002	Jiangsu	118	106	14	48	56	10	42	54	0.661
Gu et al., 2003	Jiangxi	129	90	12	31	86	7	30	53	0.354
Li et al., 2004	Henan	120	80	11	60	49	14	41	25	0.689
Lin et al., 2005	Guangdong	274	73	32	75	167	6	31	36	0.851
Ren et al., 2005	Shanxi	47	70	2	10	35	13	26	31	0.087
Liang et al., 2006	Guangdong	133	154	2	30	101	10	60	84	0.870
Tsai et al., 2007	Taiwan	735	519	15	195	525	5	111	403	0.382
Niu et al., 2008	Guangdong	105	110	8	32	65	9	47	54	0.783
Zhu et al., 2010	Hunan	151	127	9	27	115	20	51	56	0.153
Peng et al., 2011	Guangdong	196	200	14	54	128	18	86	96	0.840
T174 M variant
Ko et al., 1997	Taiwan	268	336	222	45	1	270	64	2	0.387
Liu et al., 2002	Shanghai	115	90	97	16	2	73	17	0	0.322
Ning et al., 2005	Hebei	55	60	41	10	4	50	9	1	0.442
Zhang et al., 2005	Hebei	105	201	78	19	8	166	32	3	0.321
Sun et al., 2006	Jiangsu	112	128	84	18	10	105	21	2	0.434

P_HWE: P value for Hardy-Weinberg equilibrium test in controls. For M235T variant, 11,12 and 22 represent MM, MT and TT, respectively; for T174 M variant, 11,12 and 22 represent TT, MT and MM, respectively.

Meta-analysis results

A total of 2540 cases and 2173 controls were identified for M235T polymorphism. The results showed that M235T polymorphism was significantly associated with CHD risk under a homogeneous co-dominant model (OR=1.61, 95% CI 1.03–2.51) and recessive model (OR=1.65, 95% CI 1.22–2.25, Table 2 and Figure 2). A total of 655 cases and 815 controls were identified for T174M polymorphism. There was also significant association between T174M polymorphism and CHD risk under a homogeneous co-dominant model (OR= 4.20, 95% CI 1.90–9.29) and recessive model (OR= 4.15, 95% CI 1.88–9.15, Table 2 and Figure 3).

Table 2.

Meta-analysis of associations of M235T and T174 M variants in the AGT gene with coronary heart disease risk.

Contrasts	Effect model	OR (95% CI)	P _Z	I² (%)	P _H	P _bias
M235T variant
TT vs. MM	Random	1.61 (1.03–2.51)	0.036	57.9	0.004	0.766
MT vs. MM	Fixed	0.92 (0.70–1.22)	0.574	0.0	0.581	0.584
TT+MT vs. MM	Random	1.32 (0.91–1.91)	0.143	43.5	0.042	0.733
TT vs. MT+MM	Random	1.65 (1.22–2.25)	0.001	80.9	0.000	0.443
T174 M variant
MM vs. TT	Fixed	4.20 (1.90–9.29)	<0.001	0.0	0.568	0.311
MT vs. TT	Fixed	0.96 (0.73–1.27)	0.798	0.0	0.695	0.446
MM+MT vs. TT	Fixed	1.13 (0.87–1.47)	0.342	33.7	0.197	0.392
MM vs. MT+TT	Fixed	4.15 (1.88–9.15)	<0.001	0.0	0.592	0.327

OR: odds ratio; CI: confidence interval; P_Z: P value for Z test; P_H: P value for between-study heterogeneity; P_bias: P value for Egger’s test.

Figure 2.

Forest plot of the association of the AGT M235T polymorphism with coronary heart disease risk under recessive model (TT vs. MT+MM).

Figure 3.

Forest plot of the association of the AGT T174 M polymorphism with coronary heart disease risk under recessive model (MM vs. MT+TT).

Sensitivity analysis

Sensitivity analysis was performed by excluding each study, one at a time. The results confirmed the significant association between M235T polymorphism and CHD risk under a recessive model (OR with 95% CI ranges from 1.53 (1.15–2.04) to 1.78 (1.37–2.30)), between T174M polymorphism and CHD risk under a co-dominant model (OR with 95% CI ranges from 3.56 (1.24–10.22) to 5.53 (2.28–13.41)) and a recessive model (OR with 95% CI ranges from 3.55 (1.24–10.26) to 5.39 (2.23–13.04)).

Publication bias

There was no evidence of publication bias for M235T and T174M polymorphisms under all genetic models (Table 2).

Discussion

To our knowledge, this is the first meta-analysis that comprehensively assessed the associations between AGT gene polymorphisms and risk of CHD in the Chinese population. The results indicated that both M235T and T174M polymorphisms were associated with CHD risk in the Chinese population. Our findings were different from those based on the two previous meta-analyses that suggested a marginally significant association among Europeans while significant publication bias existed.^5,6

The AGT gene is located on chromosome 1q42–43 and comprises five exons and four introns spanning 12 kb. Several molecular variants of this gene have been detected, and two polymorphisms (M235T, T174M) in exon 2 were the most studied. The M235T polymorphism was in strong linkage disequilibrium with the T174M polymorphism.³² The mechanisms by which M235T variant influences risk of CHD are still unclear. It has been suggested that M235T homozygotes were associated with increased AGT synthesis and angiotensin II production. The pleiotropic actions of angiotensin II and artery wall injury should be considered.³³ Further experimental studies are required to explore the mechanisms of the AGT polymorphisms in the implication of CHD.

Several limitations should be considered. First, the present meta-analysis was based primarily on unadjusted effect estimates and the confounding factors were not controlled for. Second, the effect of gene-gene and gene-environment interactions was not addressed in this meta-analysis because most studies did not provide related data. Third, the results of T174M polymorphism should be interpreted with caution because of limited statistical power. Fourth, there was significant between-study heterogeneity for M235T variant. The variables including sex frequency, mean age, study design, region and sample size were introduced into meta-regression analysis. However, non-significant confounders were found, suggesting that other unknown factors might confound the association between M235T variant and CHD risk.

In conclusion, the result indicated the significant associations of two AGT polymorphisms (M235T, T174M) with CHD risk in the Chinese population. However, further studies considering gene-gene and gene-environment interactions should be conducted to investigate the associations.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

O’Toole

Conklin

Bhatnagar

. Environmental risk factors for heart disease. Rev Environ Health 2008; 23: 167–202.

Wang

Staessen

. Genetic polymorphism in the renin-angiotensin system: relevance for susceptibility to cardiovascular disease. Eur J Pharmacol 2000; 410: 289–302.

Zintzaras

Raman

Kitsios

. Angiotensin-converting enzyme insertion/deletion gene polymorphic variant as a marker of coronary artery disease: a meta-analysis. Arch Intern Med 2008; 168: 1077–1089.

Zhou

Wei

. Meta-analysis of the association between the insertion/deletion polymorphism in ACE gene and coronary heart disease among the Chinese population. J Renin Angiotensin Aldosterone Syst 2012; 13: 296–304; Epub ahead of print 25 January 2012.

Zafarmand

van der Schouw

Grobbee

. The M235T polymorphism in the AGT gene and CHD risk: evidence of a Hardy-Weinberg equilibrium violation and publication bias in a meta-analysis. PLoS One 2008; 3: e2533.

. Quantitative assessment of the effect of angiotensinogen gene polymorphisms on the risk of coronary heart disease. Circulation 2007; 116: 1356–1366.

DerSimonian

Laird

. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

Mantel

Haenszel

. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719–748.

Egger

Davey Smith

Schneider

. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

10.

Wang

. Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese. Hum Genet 1997; 100: 210–214.

11.

Chen

Zhang

Fan

. A molecular variant of angiotensionogen gene is associated with myocardial infarction in Chinese. Chinese Journal of Genetics 1998; 3: 133–135.

12.

Sheu

Lee

Jeng

. Angiotensinogen gene polymorphism is associated with insulin resistance in nondiabetic men with or without coronary heart disease. Am Heart J 1998; 136: 125–131.

13.

Xie

Zhang

. Association between gene polymorphism of rennin-angiotensin system and coronary heart disease. Acta Nanjing Med Univ 2001; 21: 488–492.

14.

Zhu

Yang

. Polymorphisms in three renin-angiotensin system genes and coronary heart disease. Jiangsu Med J 2002; 28: 745–746.

15.

Zhu

Pan

. Effects of angiotensinogen and apolipoprotein E gene polymorphisms on coronary heart disease. Acta Nantong Med Univ 2003; 23: 394–395.

16.

Pan

Zhang

. Association between angiotensinogen gene polymorphism and severity of coronary artery stenosis. Journal of Medical Forum 2004; 25: 12–14.

17.

Lin

Wang

Xia

. Journal of Dalian Medical University 2005, 27: 329–332.

18.

Ren

Jia

. Relationship between angiotensinogen gene M235T polymorphism and coronary heart disease. J Shanxi Med Univ 2005; 36: 439–442.

19.

Liang

Dong

Yang

. Research of ACE, angiotensinogen and endothelial nitric oxide synthase (eNOS) gene polymorphisms in predisposition to CHD with chip technology. Hebei Medicine 2006; 12: 403–406.

20.

Tsai

Hwang

Ritchie

. Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. Atherosclerosis 2007; 195: 172–180.

21.

Niu

Luo

Peng

. Relationship between rennin-angiotensin system gene polymorphism and ischemic chronic heart failure. Journal of Sun Yat-Sen University (Medical Sciences) 2008; 29: 168–172.

22.

Zhu

Wang

. Association between the gene polymorphism of angiotensinogen-converting enzyme and coronary artery disease. Chin J Arterioscler 2010; 18: 405–408.

23.

Peng

Luo

. Relationship between rennin-angiotensin system gene polymorphism and ischemic chronic heart failure in aged coronary artery disease patient. Chinese Circulation Journal 2011; 26: 93–96.

24.

Liu

Jin

Jiang

. Correlation between T174M and M235T polymorphism of angiotensinogen gene and coronary heart disease. J Diagn Concepts Pract 2002; 1: 231–233.

25.

Ning

Zhang

Shen

. Association between AGT gene T174M polymorphism and myocardial infarction among Chinese elderly population. Chinese Journal of Gerontology 2005; 25: 1347–1349.

26.

Zhang

Ning

. Polymorphism of angiotensinogen gene is associated with myocardial infarction in Chinese Han population. J Fourth Mil Med Univ 2005; 26: 729–731.

27.

Sun

Yang

. Association of the angiotensin converting enzyme I/D and angiotensinogen T174M gene polymorphism with acute myocardial infarction. Chin J Arterioscler 2006; 14: 697–700.

28.

Deng

Huang

Liu

. Association between insulin resistance of coronary heart disease and angiotensinogen gene M235T polymorphism. Chinese Journal of Medical Genetics 2001; 18: 415–416.

29.

Jia

Guo

Yang

. Association between gene polymorphisms of rennin-angiotensin system and coronary heart disease. Chin J Arterioscler 2008; 16: 981–985.

30.

Wang

Cheng

. Relationship between angiotensin-converting enzyme and angiotensinogen gene polymorphism and coronary artery disease. Journal of Nanchang University (Medical Science) 2010; 50: 8–11.

31.

Zhang

Wang

. The research of apolipoprotein B, E and angiotensinogen gene polymorphisms in predisposition to CHD. China Modern Doctor 2011; 49: 4–6.

32.

Lanz

Pereira

Lemos

. Angiotensinogen M235T polymorphism is associated with coronary artery disease severity. Clin Chim Acta 2005; 362: 176–181.

33.

Rodríguez-Pérez

Rodríguez-Esparragón

Hernández-Perera

. Association of angiotensinogen M235T and A(-6)G gene polymorphisms with coronary heart disease with independence of essential hypertension: the PROCAGENE study. Prospective Cardiac Gene. J Am Coll Cardiol 2001; 37: 1536–1542.

AGT gene polymorphisms (M235T,T174M) are associated with coronary heart disease in a Chinese population

Abstract

Objective:

Methods:

Results:

Conclusions:

Keywords

Introduction

Materials and methods

Literature and search strategy

Inclusion criteria and data extraction

Statistical analysis

Results

Characteristics of the studies

Meta-analysis results

Sensitivity analysis

Publication bias

Discussion

Footnotes

Conflict of interest

Funding

References