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Abstract

Objective:

The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI), but previous studies have been inconsistent. The present study aimed at assessing the association of M235T polymorphism in the AGT gene with MI using a meta-analysis.

Methods:

We retrieved literature in Google Scholar, PubMed, Cochrane Library and the China National Knowledge Infrastructure database (January 1990–December 2011) for the relevant studies on the AGT polymorphism M235T and risk of MI. Statistical analyses were carried out using Stata 10.0 for combining all the relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Begg’s test was used to measure publication bias.

Results:

A total of 21 case-control studies containing 5887 patients and 6164 controls were enrolled into this meta-analysis. Overall, significant association was found between the AGT gene M235T polymorphism and risk of MI in the subgroup analysis for TT vs MT in Asians (OR 1.47, 95% CI: 1.01–2.12; p = 0.04). No associations were detected between AGT M235T and the risk of MI in total population and Caucasians.

Conclusions:

This meta-analysis demonstrated that the AGT M235T polymorphism could be a prediction marker for risk of MI in Asians. Conclusive evidence on the effects of the variants in MI should be addressed in further studies.

Keywords

Angiotensinogen polymorphism meta-analysis myocardial infarction

Introduction

Coronary artery disease (CAD) arises as a complex-trait disease that includes myocardial infarction (MI) and coronary atherosclerosis; the role of genetic and environmental risk factors promotes the development of the disorder. The classic risk factors include family history, body mass index, smoking habits, hypertension, diabetes mellitus and serum lipid levels. In addition, genetic factors also play important roles in the pathogenesis of CAD. It has been estimated that approximately 50% of the variability of the major risk factors for CAD is determined by genetics.¹

Over the past few years, the role of the renin-angiotensin-aldosterone system (RAAS) in the development of MI has generated much interest across the world. The investigations were expanded to implicate that the RAAS in a variety of physiologic processes may play a significant role in the initiation and progression of atherosclerosis.² To date, more and more studies show that the angiotensinogen (AGT, the components of RAAS) gene M235T polymorphism is closely associated with MI among different populations. The AGT M235T single nucleotide polymorphism (SNP) is a methionine (Met) to threonine (Thr) amino acid substitution at codon 235, designated the M and T alleles, respectively. However, published results have been inconsistent.^3,4 To help clarify the inconsistent findings, with the publication of several more recent studies we conducted this meta-analysis of the M235T polymorphism in the AGT gene and risk of MI. This meta-analysis includes 21 studies with a total of 5887 MI cases and 6164 controls.

Materials and methods

Literature and search strategy

All studies published before December 2011 on MI and the AGT M235T polymorphism were sought by computer-based searches of Google Scholar, PubMed, Cochrane Library and the China National Knowledge Infrastructure (CNKI) database. The search strategy in identifying all possible studies involved the use of the following keywords: angiotensinogen (or AGT), myocardial infarction (or MI), coronary heart disease (or CHD), coronary artery disease (or CAD), ischemic heart disease and M235T polymorphism. The search was conducted without restrictions on languages. Hand searches of bibliographies, scientific meeting abstracts, and related journals were also performed.

Inclusion criteria and data extraction

All relevant data from the studies were independently reviewed and extracted by two experienced cardiologists; disputed data were resolved by discussion or adjudicated by a third reviewer. The inclusion criteria were: had original data from case-control studies; cases in the control group were patients without MI or healthy adults from the same area who were matched for gender and age, and diagnosis of MI according to the World Health Organization criteria on the basis of presence of at least two of the following three findings: characteristic chest pain, elevated cardiac-enzyme levels, and electrocardiographic results consistent with a MI. If duplicate publications were encountered, the study with the smaller data was excluded. For incomplete information, the investigators contacted the author via email for more details.

Statistical methods

Deviation from the Hardy–Weinberg equilibrium (HWE) for distribution of the allele frequencies was analyzed by χ² test in control groups. The association between the AGT M235T polymorphism and risk of MI was estimated by calculating pooled odds ratio (OR) and 95% confidence interval (CI) under a co-dominant model (TT vs MM, TT vs MT), dominant model (MM+MT vs TT), and recessive model (TT+MT vs MM), respectively. The significance of the pooled OR was determined by Z test. P < 0.05 was considered statistically significant. Q test and I² test were performed to probe whether the variation was due to heterogeneity or sampling error (chance). I² ranges from 0 to 100%. A value of 0% indicates no observed heterogeneity, and larger values reflect increasing heterogeneity, with 25% regarded as low, 50% as moderate, and 75% as severe heterogeneity. When the effects were assumed to be homogeneous (p > 0.1, I² < 50%), the fixed-effects model was more appropriate. Otherwise, the random-effects model was used. To evaluate ethnicity-specific effects, subgroup analyses were performed for assessment of heterogeneity. Other potentially relevant subgroups (such as age) could not be investigated because individual participant data were not available in this meta-analysis. Begg’s test was used to measure publication bias. Sensitivity analysis was performed through random-effects model values compared to the fixed effect to ensure the stability of the findings. All analyses were carried out with Stata software version 10.0 (StataCorp LP; College Station, TX, USA).

Results

Characteristics of the included studies

A total of 21 eligible studies concerning the association between AGT M235T and risk of MI were identified for this meta-analysis (Figure 1 and Table 1). These studies involved 5887 patients and 6164 controls, containing the population studies of 14 Caucasians^5–18 and seven Asians.^19–25 The frequency distributions of genotypes in the controls were consistent with HWE in all studies. Of the 21 case-control studies, eight used population-based controls,^{5,7–9,11,15,17,22} and 13 used hospital-based controls.^{6,10,12–14,16,18–21,23–25} In the subgroup analyses, five studies with males in a Caucasian population were included in gender-specific groups.^5–7,12,13 All studies used polymerase chain reaction (PCR)/restriction fragment length polymorphism with restriction enzymes (ThtIII I) for genotyping. Furthermore, the PCR primer sequence was checked in the GenBank database (http://www.ncbi.nlm.nih.gov/genbank/) to guarantee that the chosen genes were the target genes.

Figure 1.

Flow diagram of the study search and selection process.

Table 1.

Study selection and subject characteristics included in the meta-analysis.

First author	Area	Total cases	Total controls	Genotypes for cases			Genotypes for controls			Frequency of T allele	Test for HWE
				MM	MT	TT	MM	MT	TT		χ²	p
Tiret⁵	France	630	741	229	301	100	258	372	111	0.40	1.51	0.22
Kamitani¹⁹	Japan	103	103	6	31	66	10	41	52	0.70	0.21	0.65
Chen²⁰	China	57	76	4	13	40	13	31	32	0.63	1.28	0.26
Frossard²¹	United Arab Emirates	40	61	14	18	8	16	26	19	0.52	1.29	0.26
Winkelmann⁶	Germany	122	92	38	54	30	28	53	11	0.41	3.42	0.06
Batalla⁷	Spain	220	200	69	99	52	64	96	40	0.44	0.14	0.71
Ermis⁸	Turkey	102	114	32	48	22	39	59	16	0.40	0.71	0.40
Bis⁹	USA	208	717	71	98	39	215	349	153	0.46	0.26	0.61
Ranjith²²	India	195	300	24	80	91	29	127	144	0.69	0.01	0.90
Araujo¹⁰	Brazil	110	104	46	52	12	43	51	10	0.34	0.85	0.36
Ren²³	China	47	70	2	10	35	13	26	31	0.47	0.21	0.65
Ko²⁴	China	150	337	4	22	124	4	54	279	0.91	0.56	0.45
Xie²⁵	China	48	86	3	12	33	11	30	45	0.70	2.58	0.11
Mehri¹¹	Tunisia	123	144	29	53	41	53	61	30	0.42	2.46	0.12
Fernández-Arcás¹²	Spain	212	180	59	121	32	34	97	49	0.54	1.31	0.25
Gardemann¹³	Germany	1058	1192	319	582	157	385	585	222	0.43	7.30	0.99
Hooper¹⁴	USA	100	100	4	29	67	2	31	67	0.83	0.54	0.46
Fomicheva¹⁵	Russia	198	152	63	85	50	43	75	34	0.47	0.01	0.91
Olivieri¹⁶	Italy	247	157	63	124	60	54	76	27	0.41	0.01	0.98
Renner¹⁷	Austria	1370	733	431	675	264	236	360	137	0.43	0.00	0.99
Tobin¹⁸	England	547	505	212	252	83	197	226	82	0.39	1.58	0.21

HWE: Hardy–Weinberg equilibrium.

Meta-analysis results

The meta-analysis results and the heterogeneity test are shown in Table 2. In the stratified analysis by ethnicity, significant associations were observed in the co-dominant model (TT vs MT) of Asians with the random-effects model (OR: 1.47, 95% CI: 1.01–2.12, p = 0.55, Figures 2 and 3). However, such associations were not found in other comparisons of overall populations and Caucasians between AGT M235T and the risk of MI. Sensitivity analysis was performed by comparing the results of fixed- and random-effects models, and the result for the fixed-effects model were not materially altered in the co-dominant model (TT vs MT) of Asians (OR: 1.35, 95% CI: 1.07–1.69, p = 0.04), indicating the result of the meta-analysis was statistically significant.

Table 2.

Summary ORs and 95% CI of AGT M235T polymorphism and MI risk.

Subgroup	Genetic model	Sample size		Type of model	Test of heterogeneity		Test of association		Test of publication bias
		Case	Control		χ²	p	OR	95% CI	z	p
Overall	TT vs MM	5887	6164	Fixed	18.11	0.58	1.02	0.93–1.11	0.03	0.98
	TT vs MT			Random	49.43	0.00	1.11	0.90–1.37	1.18	0.24
	Dominant model			Random	114.38	0.00	1.16	0.91–1.47	0.94	0.35
	Recessive model			Random	59.81	0.00	1.18	0.99–1.41	2.39	0.02
Caucasians	TT vs MM	5247	5131	Random	30.47	0.00	1.06	0.86–1.30	0.77	0.44
	TT vs MT			Random	28.31	0.00	1.06	0.89–1.27	2.30	0.02
	Dominant model			Random	32.08	0.00	0.94	0.78–1.12	1.64	0.10
	Recessive model			Fixed	17.48	0.18	1.02	0.94–1.11	0.66	0.51
Caucasian males	TT vs MM	2242	2405	Random	13.07	0.01	0.92	0.64–1.32	0.73	0.46
	TT vs MT			Random	18.89	0.00	0.99	0.67–1.48	0.73	0.46
	Dominant model			Random	18.07	0.00	1.04	0.71–1.50	0.73	0.46
	Recessive model			Fixed	5.83	0.21	0.99	0.88–1.13	0.73	0.46
Asians	TT vs MM	640	1033	Random	18.41	0.00	1.49	0.71–3.12	1.50	0.13
	TT vs MT			Random	13.13	0.04	1.47	1.01–2.12	0.60	0.55
	Dominant model			Random	21.87	0.00	0.66	0.42–1.02	1.20	0.23
	Recessive model			Random	12.60	0.05	1.27	0.71–2.26	1.50	0.13

ORs: odds ratios; CI: confidence interval; ATG: angiotensinogen; MI: myocardial infarction.

Figure 2.

The association of M235T polymorphism with the risk for MI in Asians (TT vs. MT).

Figure 3.

Funnel plot of M235T polymorphism and susceptibility of MI in Asians (TT vs. MT).

Publication bias

Begg’s test and funnel plot were performed to assess the publication bias of the included studies. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry in all genetic models. The results suggest no evidence of publication biases (Table 2, Figure 3).

Discussion

For the past few years, there has been increasing evidence that gene–gene and gene–environment interaction play a vital role in the genetic studies of complex-trait diseases. AGT has been shown to play a vital role in affecting the cardiovascular system, and Kamitani et al.¹⁹ were the first to report that the AGT gene M235T polymorphism increased the risk of MI using a case-control study. The study included 103 patients who had MI and 103 control subjects, and all participants were Japanese. The TT genotype was more frequent in the MI group than in the control group (p < 0.05), and the M235T TT genotype is a predictor for MI. Later, several studies, but not all, confirmed the association of AGT M235T with increased risk for MI. However, based on a small number of samples, it is possible that the observed associations between the M235T polymorphism and increased MI risk reflect chance observations rather than true associations. To help clarify the inconsistent findings, several meta-analyses were produced, and the studies indicated that the M235T polymorphism was not associated with MI and the M235T polymorphism was related to an increased risk of CAD in the general population.^3,4,26 The result accords with a more recent study that the pathogenesis of MI and coronary atherosclerosis is due to different genetic variants.^27,28 Based on this conclusion, we conducted this meta-analysis to obtain a competitive result via combining more eligible studies, enlarging the sample size, and performing a subgroup analysis. No associations were detected between the AGT M235T polymorphism and MI risk in the overall population; the finding was consistent with those from the previous meta-analysis.^3,4,26 In the stratified analysis relating to ethnicity, our results indicated that the M235T polymorphism was associated with MI risk in Asians (OR: 1.47, 95% CI: 1.01–2.12), suggesting a possible role of ethnic differences in genetic backgrounds and the environment in which the participants lived.

The mechanism of how M235T polymorphism relates to risk of MI is still unclear. The M235T polymorphism of the human AGT gene has been recognized as being associated with a variation of serum AGT concentration,²⁹ with 235TT homozygotes having between 10% and 20% more plasma AGT than 235MM individuals.^30,31 AGT is the precursor of angiotensin and is cleaved into angiotensin I and II (Ang II). Ang II activates vascular cell apoptosis and increases the platelet-derived growth factor, contributing to vascular remodeling and cardiomyocyte loss in ischemia-reperfusion and MI.^32,33 This evidence suggested that the M235T polymorphism might play an important role in the development of MI.

Some limitations of this meta-analysis should be discussed. First, we partly used the random-effects model to calculate ORs, which may affect the precision of the result. Second, this meta-analysis was based primarily on unadjusted effect estimates; the confounding factors were not controlled. Last but not least, the potential function of the AGT gene polymorphism might be affected via gene-gene and gene-environment interactions.

In conclusion, our study indicates that the AGT M235T polymorphism was associated with risk of MI in Asians. Gene–gene and gene–environment interactions should be investigated in further studies.

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.

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The M235T polymorphism in the angiotensinogen gene and myocardial infarction risk: A meta-analysis

Abstract

Objective:

Methods:

Results:

Conclusions:

Keywords

Introduction

Materials and methods

Literature and search strategy

Inclusion criteria and data extraction

Statistical methods

Results

Characteristics of the included studies

Meta-analysis results

Publication bias

Discussion

Footnotes

Conflict of interest

Funding

References