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. 2015 Aug 15;8(8):12914–12920.

Angiotensinogen polymorphism and ischemic stroke risk

Huan Bao 1, Jun-Jie Hao 1, Yu-Mei Yang 1, Xia-Hong Xu 1, Yue Wang 1, Lian Zuo 1, Jing Lu 1, Jing Zhang 1, Yue Zhang 1, Si-Yi Xu 1, Xuan Wang 1, Ying Li 1, Gang Li 1
PMCID: PMC4612893  PMID: 26550208

Abstract

The angiotensinogen M235T polymorphism was associated with ischemic stroke risk. However, the results were controversial. Thus, a meta-analysis was conducted. NCBI, Medline, Web of Science and Embase databases were systematically searched. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. There was a significant association between angiotensinogen M235T polymorphism and ischemic stroke risk (OR = 1.69; 95% CI, 1.35-2.11; P < 0.001). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with ischemic stroke in Asian (OR = 1.85; 95% CI, 1.45-2.35; P < 0.001). In the age subgroup, we found that angiotensinogen M235T polymorphism could increase both early-onset ischemic stroke risk (OR = 1.88; 95% CI, 1.33-2.43; P < 0.001) and late-onset ischemic stroke risk (OR = 1.20; 95% CI, 1.01-1.39; P = 0.04). This meta-analysis suggested that angiotensinogen M235T polymorphism was associated with ischemic stroke.

Keywords: Ischemic stroke, angiotensinogen, meta-analysis, genetic

Introduction

Stroke is the fourth leading cause of death in the United States. One in 6 people worldwide will have a stroke during their lifetime and one third of the survivors will experience a recurrence [1,2]. In the past 4 decades, the incidence rates of stroke decreased by 42% in the economically developed nations, while they increased in the developing countries [3]. Recently, some genetic variants, such as single nucleotide polymorphisms (SNPs) of several genes, are shown to be associated with an increased risk of ischemic stroke [4], suggesting that genetic factors may play an important role in ischemic stroke development.

The renin-angiotensin-aldosterone system (RAAS) plays a major role in maintaining salt-water balance and controlling blood pressure [5]. Angiotensinogen is an upstream member of the RAAS encoded by the AGT gene on chromosome 1. It is primarily synthesized in the liver and then cleaved by renin from the kidney to form angiotensin I. Angiotensin I is further cleaved by the angiotensin-converting enzyme (ACE) to form the biologically active form called angiotensin II. Didion et al. found that acetylcholine-induced relaxation of carotid artery is impaired selectively in mice made hypertensive by expression of human renin and human angiotensinogen [6]. Maeda et al. suggested that in angiotensinogen-knockout mice the more efficient collateral blood supply delays ischemic injury despite the lower blood pressure [7].

The human angiotensinogen gene is located on chromosome 1q42-43. Some studies investigated the association between the angiotensinogen M235T polymorphism and susceptibility of ischemic stroke [8-28]. However, the results were controversial and inconsistent. In this meta-analysis, we evaluated the correlation between angiotensinogen M235T polymorphism and ischemic stroke risk.

Methods

Publication search

Relevant studies were systematically searched by using the NCBI, Medline, Web of Science and Embase databases (The last retrieval date was Dec 1, 2014, using the search terms: ‘‘ischemic stroke” and “angiotensinogen” and “polymorphism”). All searched studies were retrieved and only published studies with full-text articles were included. When more than publications with duplicate samples, only the newest study was used in this research.

Inclusion and exclusion criteria

The following inclusion criteria were used: (1) evaluate the association between angiotensinogen M235T polymorphism and ischemic stroke risk; (2) a case-control or cohort design; (3) sufficient data should have been provided in order to calculate odds ratios (OR) and 95% confidence interval (CI). Studies were excluded if any of the following conditions applied: (1) not relevant to angiotensinogen or ischemic stroke; (2) only case population; (3) studies were repeated or publications overlapped.

Data extraction

The following data were recorded from each article: first author, years of publication, ethnicity of participants, age, numbers of cases and controls, and genotype numbers of angiotensinogen M235T polymorphism. The data were extracted by two of the authors independently. Discrepancies between these two authors were resolved by discussion.

Statistical analysis

The strength of association between angiotensinogen M235T polymorphism and ischemic stroke risk was assessed by calculating OR with 95% CI. A statistical test for heterogeneity was performed based on the Q statistic. The P > 0.10 of the Q-test indicated a lack of heterogeneity among studies. The random effects model was used to calculate the pooled ORs. A goodness-of-fit χ2 test was used to check whether the frequencies of genotypes deviate from the Hardy-Weinberg equilibrium (HWE). Stratified analysis was performed by ethnicity and age. Cumulative meta-analysis was conducted. The one-way sensitivity analyses were performed to assess the stability of the results, namely, a single study in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs. Potential publication bias was examined by Egger’s test. All statistical tests were performed with the software STATA version 11.0 (Stata Corporation, College station, TX, USA). A P value < 0.05 was considered statistically significant.

Results

Study characteristics

As shown in Figure 1, 21 studies met the inclusion criteria and were included in the final analysis [8-28]. Only 4 case-control study included Caucasians; while 17 studies were performed in Asian population. Only 2 studies were not in HWE. The characteristics of included studies summarized in Table 1.

Figure 1.

Figure 1

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Flow chart of included studies for this metaanalysis.

Table 1.

Characteristics of the studies

No. of case No. of control Case Control
First author Year Ethnicity Age HWE MM MT TT MM MT TT
Nakata 1997 Asian 66 55 61 Yes 7 18 30 3 31 27
Guan 1 2000 Asian 60 55 82 Yes 5 16 34 10 37 35
Guan 2 2000 Asian 60 102 82 Yes 12 37 53 10 37 35
Wei 2000 Asian 67 87 257 Yes 8 32 48 14 81 162
Sethi 2001 Caucasian 74 489 7975 Yes 362 423 139 2779 3886 1310
Zhang 2001 Asian 68 75 48 Yes 6 21 48 8 22 18
Zhang 2002 Asian 70 119 82 Yes 7 55 57 10 37 35
Joshua 2003 Caucasian 65 116 717 Yes 31 55 30 215 349 153
Brenner 2005 Caucasian 69 459 459 Yes 164 221 74 158 223 78
Zhang 2005 Asian 60 135 150 Yes 8 50 77 26 60 64
Um 2005 Asian 57 211 319 No 2 35 174 5 108 206
Li 2005 Asian 65 75 48 Yes 6 21 48 8 22 18
Niu 2006 Asian 43 89 58 Yes 3 19 40 5 21 32
Lalouschek 2007 Asian 64 450 817 Yes 139 213 98 232 410 175
Cui 2008 Asian 65 114 76 Yes 2 37 75 3 37 36
He 2008 Asian 66 77 98 Yes 3 25 49 12 52 34
Yue 2008 Asian 62 82 82 No 11 27 44 31 22 29
Saidi 2009 Caucasian 60 329 444 Yes 122 149 58 235 172 37
Du 2010 Asian 63 664 716 Yes 8 15 59 11 35 49
Sun 2010 Asian 65 180 130 Yes 7 59 114 16 69 45
Zhang 2010 Asian 65 334 193 Yes 227 91 16 147 40 6
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HWE, Hardy-Weinberg equilibrium.

Results of meta-analysis

There was a significant association between angiotensinogen M235T polymorphism and ischemic stroke risk (OR = 1.69; 95% CI, 1.35-2.11; P < 0.001; Figure 2). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with ischemic stroke in Asian (OR = 1.85; 95% CI, 1.45-2.35; P < 0.001). In the age subgroup, we found that angiotensinogen M235T polymorphism could increase both early-onset ischemic stroke risk (OR = 1.88; 95% CI, 1.33-2.43; P < 0.001) and late-onset ischemic stroke risk (OR = 1.20; 95% CI, 1.01-1.39; P = 0.04). Table 2 listed the results of the meta-analysis.

Figure 2.

Figure 2

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Meta-analyses of the angiotensinogen M235T polymorphism and ischemic stroke risk.

Table 2.

Results of this meta-analysis

No. of study OR (95% CI) P I2 (%)
Overall 21 1.69 (1.35-2.11) < 0.001 77
Asian 17 1.85 (1.45-2.35) < 0.001 68
Caucasian 4 1.23 (0.82-1.83) 0.32 82
Early-onset 14 1.88 (1.33-2.43) < 0.001 32
Late-onset 7 1.20 (1.01-1.39) 0.04 25
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As shown in Figure 3, the results showed that the pooled ORs tended to be stable. Statistically similar results were obtained after sequentially excluding each study and the corresponding pooled ORs were not materially altered (Figure 4), suggesting stability and liability of this meta-analysis.

Figure 3.

Figure 3

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Cumulative meta-analysis of associations between the angiotensinogen M235T polymorphism and ischemic stroke risk.

Figure 4.

Figure 4

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Sensitivity analysis for the angiotensinogen M235T polymorphism and ischemic stroke risk.

Egger’s test was used to provide statistical evidence of funnel plot symmetry (Figure 5) and did not detect evidence of publication bias (P = 0.11).

Figure 5.

Figure 5

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Funnel plot between the angiotensinogen M235T polymorphism and ischemic stroke risk.

Discussion

Many studies indicated that genetic factors played important roles in the development of ischemic stroke. Cui found that MTHFR C677T mutation increased the risk of ischemic stroke in adults, especially in large-artery atherosclerosis [29]. Türkanoğlu Özçelik et al. suggested that NOS3 genetic polymorphisms are the risk of development of ischemic stroke the Turkish Population [30]. van Goor et al. indicated that PAI-1 4G/5G polymorphism is a strong risk factor for ischemic stroke [31]. Furthermore, Han and coworkers suggested that both rs1711503 and rs2479408 of PCSK9 genes were associated with cerebral ischemic stroke in the Han population of China [32].

This meta-analysis of 21 studies evaluated the association between angiotensinogen M235T polymorphism and ischemic stroke risk. The results indicated that angiotensinogen M235T polymorphism was a risk factor for ischemic stroke. In the stratified analysis by ethnicity, this polymorphism was significantly associated with ischemic stroke in Asians. However, no significant association between this polymorphism and ischemic stroke risk in Caucasian was found. In the age subgroup, we found that this polymorphism could increase both early-onset ischemic stroke risk and late-onset ischemic stroke risk. This result suggested that angiotensinogen M235T polymorphism might play important roles in the development of early-onset ischemic stroke risk and late-onset ischemic stroke.

Angiotensinogen M235T polymorphism was also associated with some disease risks. Mao et al. found that angiotensinogen M235T polymorphism might be a protective factor against the Henoch-Schönlein purpura risk in adult [33]. Wang et al. suggested that M235T polymorphism in the angiotensinogen gene might be related to the increased risk of atrial fibrillation in Asians [34]. Jiang et al. found that angiotensinogen M235T polymorphism is a low-penetrant risk factor for the development of heart failure among Asians [35].

Our meta-analysis had some limitations. First, the numbers of published studies were not sufficient for a comprehensive analysis, particularly for Africans. Second, other than M235T polymorphism, there are other variants in the angiotensinogen gene. We did not carry out meta-analysis on these polymorphisms due to limited data. Third, lacking of the original data of the eligible studies limited the evaluation of the effects of the gene-gene interactions in ischemic stroke.

In conclusion, this meta-analysis suggested that angiotensinogen M235T polymorphism is significantly asso ciated with the risk of ischemic stroke.

Disclosure of conflict of interest

None.

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