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Gene Reports 16 (2019) 100421

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Gene Reports
journal homepage: www.elsevier.com/locate/genrep

The genes polymorphism of angiotensinogen (AGT) M235T and AGT T174M T


in patients with essential hypertension: A meta-analysis
⁎ ⁎
Jonny Karunia Fajara, , Budi Susetio Pikirb, , Erdo Puncak Sidartac, Putu Nina Berlinda Sakac,
Rizal Rahmanda Akbard, Fredo Tamarae, Ema Dianita Mayasarie, Atma Gunawane,f,

Teuku Heriansyahg,
a
Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia
b
Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60115, Indonesia
c
Brawijaya Cardiovascular Research Center, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
d
Department of Emergency, Wava Husada Hospital, Malang 65163, Indonesia
e
Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
f
Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
g
Department of Cardiology and Vascular Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Elevated level of angiotensinogen (AGT), a major precursor in the hypertension pathogenesis, is
Hypertension governed by the single nucleotide polymorphisms (SNPs) of AGT M235T and AGT T174M. However, during this
Angiotensinogen time, inconsistency in this context was discovered.
AGT M235T Objectives: To perform a meta-analysis regarding the correlation between the risk of essential hypertension and
AGT T174M
the polymorphisms of AGT M235T and AGT T174M.
Methods: A meta-analysis was conducted during January to February 2019. Information related to: author name
and year, country of origin, disease end point, sample size of case and control, and genotype frequency of case
and control were extracted from each study. To determine the correlation and effect estimates, data were as-
sessed using fixed or random effect model.
Results: A total of 41 papers regarding AGT M235T and 21 papers regarding AGT T174M was enrolled for meta-
analysis. Our results found that, overall, increasing the risk of essential hypertension was observed in T allele of
AGT M235T (OR95%CI = 1.15 [1.00–1.32], p = 0.0450). While, decreasing the risk was found in M allele
(OR95%CI = 0.87 [0.76–1.00], p = 0.0450) and MM genotype (OR95%CI = 0.81 [0.66–0.99], p = 0.0360). For
AGT T174M, M allele (OR95%CI = 1.17 [1.01–1.36], p = 0.0310) and TM genotype (OR95%CI = 1.18
[1.05–1.33], p = 0.0050) were associated with increasing the risk of essential hypertension, and decreasing the
risk was observed in T allele (OR95%CI = 0.85 [0.74–0.99], p = 0.0310) and TT genotype (OR95%CI = 0.83
[0.71–0.96], p = 0.0140). Moreover, the association was also observed in genotyping method and Asian po-
pulation sub-groups. In addition, our effect estimation revealed that AGT T174M gene polymorphism had
stronger correlation with the risk of essential hypertension than AGT M235T.
Conclusions: Our meta-analysis reveals that AGT T174M and AGT M235T are associated with the risk of essential
hypertension.

1. Introduction (Murphy et al., 2009), stroke (White, 2009), heart failure (Gaddam
et al., 2009), and renal disease (Tylicki and Rutkowski, 2003) are
Several life-threatening diseases such as myocardial infarction widely known as the complications of hypertension. These

Abbreviations: ACE, angiotensin-converting enzyme; AGT, angiotensinogen; CI, confidence interval; CMA, Comprehensive Meta-Analysis; HT, hypertension; HWE,
Hardy-Weinberg equilibrium; M235T, methionine at position 235 replaced by threonine; OR, odd ratio; PCR, polymerase chain reaction; PCR-RFLP, PCR - restriction
fragment length polymorphism; RAAS, renin-angiotensin aldosterone system; RCT, randomized-controlled trials; T174M, threonine at position 174 replaced by
methionine

Corresponding authors.
E-mail addresses: gembyok@gmail.com (J.K. Fajar), bsp49@fk.unair.ac.id (B.S. Pikir), teuku_hery@unsyiah.ac.id (T. Heriansyah).

https://doi.org/10.1016/j.genrep.2019.100421
Received 18 February 2019; Received in revised form 23 April 2019; Accepted 13 May 2019
Available online 17 May 2019
2452-0144/ © 2019 Elsevier Inc. All rights reserved.
J.K. Fajar, et al. Gene Reports 16 (2019) 100421

complications had been reported to cause high morbidity and mortality 2.3. Search strategy and data extraction
(Román et al., 2001). Moreover, total cost expenditure for treating
hypertension and hypertension-related conditions were reported rela- We performed a comprehensive searching in PubMed and Embase
tively high and gradually increased in the last two decades (Wang et al., up to 10 February 2019 to collect the articles concerning the association
2017). Therefore, it was revealed that prevention of hypertension might between the risk of hypertension and the genes polymorphism of AGT
alleviate the economic burden (Zhang et al., 2017). This phenomenon is M235T and or AGT T174M. In searching the papers, we restricted the
likened to “an egg at the tip of a horn”. For this reason, a compre- publication language in English, and we used the combination of the
hensive understanding regarding hypertension pathogenesis especially following key words: (hypertension) and (angiotensin gene M235T or
in genetic level is crucial for future treatment and prevention. AGT M235T) and (angiotensin gene T174M or AGT T174M). If we
The most important pathological mechanism in hypertension is found studies using the same data, only studies with larger sample size
renin-angiotensin cascade. Of those, angiotensinogen (AGT) is known were included in our analysis. For data extraction, information related
as the major precursor having fundamental role to cause hypertension to: (1) name of first author; (2) year of publication; (3) country of
and hypertension-related conditions. Briefly, AGT is cleaved by renin origin, (4) genotyping method, (5) sample size of hypertension and
into angiotensin I, and angiotensin I is converted into angiotensin II by control groups, and (6) genotype frequencies and percent of hy-
angiotensin-converting enzyme (ACE). Angiotensin II plays a pivotal pertension and control groups were extracted from each study. Data
role to cause hypertension and hypertension-related conditions through extraction was conducted by three independent authors (JKF, BSP, TH)
various pathways (Lu et al., 2016). Some studies revealed that in- to prevent errors in data extraction.
creasing AGT level in circulation had been associated with elevated
level of angiotensin II and hypertension (Umemura et al., 1997; 2.4. Covariates and sub-group analysis
Kooffreh and Anumudu, 2013). Moreover, altered plasma level of AGT
was proven to be impressed by the single nucleotide polymorphisms To perform a comprehensive analysis, the correlation and effect
(SNP) in exon 2 of AGT gene, and the SNPs in exon 2 widely in- estimates were determined in all genetic (alleles and genotypes) models
vestigated are AGT M235T (methionine at position 235 replaced by of both AGT M235T and T174M. For AGT M235T, the genetic models
threonine) and AGT T174M (threonine at position 174 replaced by were M vs. T; T vs. M; MM vs. MT + TT; MT vs. MM + TT; and TT vs.
methionine) (Miller and Scholey, 2004). Until now, some studies have MM + MT. While, for AGT T174M, the genetic models were T vs. M; M
reported the correlation between the risk of hypertension and the genes vs. T; TT vs. TM + MM; TM vs. TT + MM; and MM vs. TT + TM.
polymorphism of AGT M235T and AGT T174M. However, conflicting Moreover, we also performed sub-group analysis of all genetic models
results were observed. Furthermore, several meta-analyses in this con- according to continent and genotyping method sub-groups. For con-
text during this time also are not strong enough to make a conclusion tinent sub-group analysis, data were differentiated based on regional
because of small sample size, heterogeneity, study bias, nontransparent origin (Europe; America; Asia; Africa; and Australia). While, for geno-
data, and data discrepancy (Kunz et al., 1997; Zhu et al., 2012; Ji et al., typing method sub-group, we distinguished data based on method used
2010; Gu et al., 2012; Pereira et al., 2008; Liao et al., 2014). for gene identification, either using polymerase chain reaction (PCR) or
Our present study aimed to perform a meta-analysis regarding the polymerase chain reaction-restriction fragment length polymorphism
association between the risk of essential hypertension and the genes (PCR-RFLP).
polymorphism of AGT M235T and AGT T174M using a larger sample
size and eliminating the limitation factors of previous studies. Our re- 2.5. Statistical analysis
sults might clarify better association between the genes polymorphism
(AGT M235T and AGT T174M) and the risk of essential hypertension. The calculation of pooled OR and 95%CI was used to estimate the
association between the risk of hypertension and the genes poly-
2. Methods morphism of AGT M235T and or AGT T174M. The significance of
pooled ORs was determined using Z test (p < 0.05 was considered
2.1. Study design statistically significant), and for evaluating the heterogeneity, we per-
formed a Q test. If heterogeneity existed (p < 0.10), a random effect
We performed a meta-analysis during January to February 2019 to model was used. Otherwise, we used a fixed effect model. Moreover, for
evaluate the association between the risk of hypertension and the genes assessing publication bias, an Egger's test was used (p < 0.05 was
polymorphism of AGT M235T and AGT T174M. In effort to gain this considered statistically significant). All data were analyzed using
purpose, several papers from PubMed and Embase evaluating the cor- Comprehensive Meta-Analysis (CMA, New Jersey, USA) version 2.1 and
relation between the risk of hypertension and the genes polymorphism Review Manager (Revman Cochrane, London, UK) version 5.3. To
of AGT M2350T and or AGT T174M were enrolled to calculate a pooled prevent analysis errors, statistical analysis was performed by three in-
odd ratio (OR) and 95% confidence interval (CI) using fixed or random dependent authors (JKF, BSP, TH).
effect model. The meta-analysis design of this study was adapted from
our previous meta-analyses (Fajar, 2017; Fajar, 2016; Fajar et al., 2018; 3. Results
Rohman et al., 2018; Fajar et al., 2019).
3.1. Eligible studies
2.2. Eligibility criteria
As described in Fig. 1, a total of 62 papers consisting of 41 papers
Studies with the following criteria: (1) retrospective studies; (2) regarding AGT M235T and 21 papers regarding AGT T174M was in-
prospective studies; (3) cross-sectional studies; (4) randomized-con- cluded in our meta-analysis. This amount of papers was retrieved from
trolled trials (RCTs); (5) controlled before and-after studies; (6) cross- searching in PubMed and Embase, and excluded according to the
over studies; (7) evaluating the correlation between the risk of hy- eligibility criteria. In PubMed and Embase, we found 779 papers con-
pertension and the genes polymorphism of AGT M235T and or AGT sisting of 617 papers concerning AGT M235T and 162 papers con-
T174M; and (8) having required data for calculation of OR95%CI were cerning AGT T174M. The exclusion process was as follows: a total of
included in the study. While, articles with the following criteria: (1) 640 papers was excluded because of irrelevant title and or abstract;
obvious irrelevance title and or abstract, (2) family-based study, review eight papers were excluded because of review; 24 papers were excluded
and or commentary, (3) incomplete and or ungeneralized data were because of not providing sufficient data for calculation of OR95%CI; 39
excluded. papers were excluded because full-texts were not found; and six papers

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J.K. Fajar, et al. Gene Reports 16 (2019) 100421

Fig. 1. A flowchart for eligibility process in our study.

were excluded because of secondary hypertension. Details of studies (Fig. 4A) was observed in M allele (OR95%CI = 1.37 [1.18–1.59],
included in our analysis are described in Table 1 for AGT M235T and p < 0.0001), and protective affects were observed in T allele
Table 2 for AGT T174M. (OR95%CI = 0.73 [0.63–0.85], p < 0.0001) and TT genotype
(OR95%CI = 0.71 [0.59–0.85], p < 0.0001). For continent sub-group,
3.2. Data synthesis the association between AGT T174M gene polymorphism and essential
hypertension was only found in Asia sub-group. Our findings showed
For the association between AGT M235T gene polymorphism and that decreasing the risk of essential hypertension was observed in T
the risk of hypertension, a total of 41 papers consisting of 10,446 cases allele (OR95%CI = 0.79 [0.71–0.88], p < 0.0001) and TT genotype
and 9802 controls was enrolled for our analysis. Overall, our analysis (OR95%CI = 0.77 [0.68–0.88], p < 0.0001). On the contrary, in-
found that decreasing the risk of essential hypertension was observed in creasing the risk of essential hypertension was found in M allele
M allele (OR95%CI = 0.87 [0.76–1.00], p = 0.0450) and MM genotype (OR95%CI = 1.27 [1.14–1.42], p < 0.0001) and TM genotype
(OR95%CI = 0.81 [0.66–0.99], p = 0.0360) of AGT M235T. On the (OR95%CI = 1.25 [1.05–1.49], p = 0.0140). See Fig. 4B & C. While,
contrary, increasing the risk of essential hypertension was found in T we failed to confirm the correlation in Europe and Africa sub-groups.
allele (OR95%CI = 1.15 [1.00–1.32], p = 0.0450) of AGT M235T The summary of the correlation between AGT T174M gene poly-
(Fig. 2A). For genotyping method sub-group, our results revealed that morphism and the risk of essential hypertension is described in Table 4.
MM genotype was correlated with 0.75-fold decreasing the risk of es-
sential hypertension (OR95%CI = 0.75 [0.57–0.97], p = 0.0310). See 3.3. Source of heterogeneity
Fig. 2B. For continent sub-group, we failed to show the correlation
between hypertension and AGT M235T gene polymorphism in Europe, For AGT M235T, overall, evidence for heterogeneity was observed
America, Africa, Asia, and Australia continents. We summarize the in all alleles and genotypes of AGT M235T. Therefore, random effect
correlation between AGT M235T gene polymorphism and the risk of model was used to evaluate the correlation. For genotyping method
essential hypertension in Table 3. sub-group, both in PCR and PCR-RFLP sub groups, random effect model
Totally, we found 21 papers consisting of 3819 cases and 3460 was used to assess the data because all alleles and genotypes had evi-
controls evaluating the association between AGT T174M gene poly- dence for heterogeneity. Other evidences of heterogeneity for continent
morphism and the risk of hypertension. On the whole, M allele sub-group are described in Table 3.
(OR95%CI = 1.17 [1.01–1.36], p = 0.0310) and TM genotype For AGT T174M, on the whole, evidence for heterogeneity was
(OR95%CI = 1.18 [1.05–1.33], p = 0.0050) were associated with in- observed in T and M alleles and TT genotype, and therefore data were
creasing the risk of hypertension. See Fig. 3. While, T allele analyzed using random effect model. While, other genotypes (TM and
(OR95%CI = 0.85 [0.74–0.99], p = 0.0310) and TT genotype TT) were analyzed using fixed effect model because we found no het-
(OR95%CI = 0.83 [0.71–0.96], p = 0.0140) were proven to have pro- erogeneity. In PCR genotyping method sub-group, all data were as-
tective effects against hypertension. For PCR genotyping method sub- sessed using fixed effect model because we found no heterogeneity.
group, we showed that increasing the risk of essential hypertension While, in PCR-RFLP genotyping method, all alleles were evaluated

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Table 1
Baseline characteristics of studies concerning AGT M235T gene polymorphism in hypertensive subjects included in the meta-analysis.
Author name & year HT Control Country Continent Genotyping

MM MT TT N MM MT TT N

Agachan et al., 2003 32 20 48 100 23 2 49 74 Turkey Europe PCR


Barbalić et al., 2006 34 52 21 107 36 56 30 122 Croatia Europe PCR
Bennett et al., 1993 26 55 11 92 32 50 12 94 Australia Australia PCR
Cheng et al., 2012 27 108 165 300 15 66 69 150 China Asia PCR-RFLP
Chiang et al., 1997 90 11 1 102 33 16 0 49 China Asia PCR-RFLP
Davis et al., 2002 27 37 22 86 41 63 16 120 Australia Australia PCR
Fang et al., 2010 7 50 121 178 8 72 176 256 China Asia PCR
Fardella et al., 1998 9 33 22 64 11 37 14 62 Chile America PCR-RFLP
Fernández-Llama et al., 1998 23 31 21 75 21 33 21 75 Spain Europe PCR-RFLP
Freitas et al., 2007 26 35 30 91 64 43 7 114 Brasil America PCR-RFLP
Ghazali et al., 2008 7 66 127 200 7 55 136 198 Malaysia Asia PCR-RFLP
Glavnik and Petrovic, 2007 96 201 116 413 85 198 121 404 Slovenia Europe PCR
Hingorani et al., 1996 76 107 40 223 58 91 38 187 England Europe PCR-RFLP
Iso et al., 2000 10 72 147 229 9 63 157 229 Japan Asia PCR
Iwai et al., 1994 1 21 60 82 1 11 71 83 Japan Asia PCR-RFLP
Karthikeyan et al., 2013 31 30 193 254 42 98 114 254 India Asia PCR
Khin-Snadar et al., 2018 2 45 25 72 17 48 7 72 Myanmar Asia PCR-RFLP
Kiema et al., 1996 69 121 62 252 72 161 65 298 Finland Europe PCR-RFLP
Kim et al., 2015 138 230 116 484 52 120 91 263 Korea Asia PCR-RFLP
Kishimoto et al., 2001 9 65 127 201 7 66 128 201 Japan Asia PCR
Kooffreh et al., 2013 4 67 541 612 2 52 642 696 Nigeria Africa PCR-RFLP
Mohana et al., 2012 70 110 99 279 53 84 63 200 India Asia PCR-RFLP
Mondorf et al., 1998 41 45 26 112 53 53 18 124 Germany Europe PCR-RFLP
Morise et al., 1995 5 23 52 80 5 32 63 100 Japan Asia PCR-RFLP
Nair et al., 2003 15 60 84 159 11 40 80 131 India Asia PCR-RFLP
Nakamura et al., 2007 76 661 1612 2349 175 640 1424 2239 Japan Asia PCR
Nejatizadeh et al., 2008 74 197 178 449 104 198 57 359 India Asia PCR-RFLP
Niu et al., 2016 61 160 0 221 84 152 6 242 China Asia PCR-RFLP
Patnaik et al., 2015 17 90 99 206 23 84 127 234 India Asia PCR-RFLP
Procopciuc et al., 2002 7 20 11 38 7 10 4 21 Romania Europe PCR-RFLP
Rodríguez-Pérez et al., 2000 57 123 57 237 68 119 54 241 Spain Europe PCR
Say et al., 2005 33 46 22 101 59 18 10 87 Malaysia Asia PCR-RFLP
Shamaa et al., 2015 12 18 53 83 41 14 5 60 Egypt Africa PCR-RFLP
Singh et al., 2014 13 81 117 211 30 78 103 211 India Asia PCR-RFLP
Srivastava et al., 2012 112 120 18 250 154 90 6 250 India Asia PCR-RFLP
Tchelougou et al., 2015 3 24 177 204 2 29 171 202 Burkina Faso Africa PCR
Vasků et al., 2002 52 90 31 173 50 98 50 198 Czech Europe PCR-RFLP
Williams et al., 2004 0 18 92 110 0 6 43 49 Ghana Africa PCR-RFLP
Wu et al., 2004 18 115 320 453 5 89 231 325 Taiwan Asia PCR
Ying et al., 2010 14 104 125 243 14 88 156 258 China Asia PCR-RFLP
Yuan et al., 2009 6 77 188 271 4 68 198 270 China Asia PCR-RFLP

Notes, AGT, angiotensinogen; HT, hypertension; PCR, polymerase chain reaction; PCR-RFLP, PCR - restriction fragment length polymorphism.

using random effect model, and all genotypes were assessed using fixed polymorphism was associated with the risk of hypertension (Chiang
effect model. We summarize other evidences of heterogeneity in et al., 1997; Freitas et al., 2007; Karthikeyan et al., 2013; Khin-Snadar
Table 4. et al., 2018; Kim et al., 2015; Kooffreh et al., 2013; Nakamura et al.,
2007; Nejatizadeh et al., 2008; Say et al., 2005; Shamaa et al., 2015;
3.4. Potential publication bias Singh et al., 2014; Srivastava et al., 2012). Interestingly, a study by
Shamaa et al. (2015) showed the highest impact. This impact might be
For AGT M235T, overall, we found no publication bias. In geno- governed by a complex and multifactoral relationship. Previous studies
typing method sub-group analysis, we also found no evidence of pub- revealed that the prevalence of hypertension in Egypt was high and
lication bias. While, in continent sub-group analysis, we found pub- reported to increase with age. Approximately > 50% of Egyptian in-
lication bias in Europe (MM vs. MT + TT), America (MT vs. MM + TT), dividuals older than 60 years suffered from hypertension (Ibrahim,
and Australia (M vs. T; T vs. M; MM vs. MT + TT) sub-groups. We 1997; Ibrahim and Damasceno, 2012). This high number might be
summarize Egger test of AGT M235T in Table 3. triggered by several factors. A study reported that Egyptian individuals
For AGT T174M, overall, publication bias was not found. In geno- had low awareness rates regarding hypertension (Ibrahim et al., 1995).
typing method sub-group, publication bias was observed in MM geno- Moreover, > 60% of Egyptian individuals with hypertension were re-
type of both PCR and PCR-RFLP sub-groups. In continent sub-group, ported having other cardiovascular risk factors (Khalil, 1996). How-
publication bias was found in MM genotype of Asia sub-group and all ever, further studies are required to investigate the precise role of AGT
genetic models of Africa and Europe sub-group. Egger test of AGT M235T in Egyptian individuals with hypertension. Furthermore, of the
T174M is summarized in Table 4. collected papers, 29 other studies failed to confirm the correlation
(Agachan et al., 2003; Barbalić et al., 2006; Bennett et al., 1993; Cheng
4. Discussion et al., 2012; Davis et al., 2002; Fang et al., 2010; Fardella et al., 1998;
Fernández-Llama et al., 1998; Ghazali et al., 2008; Glavnik and
A total of 41 papers evaluating the association between AGT M235T Petrovic, 2007; Hingorani et al., 1996; Iso et al., 2000; Iwai et al., 1994;
gene polymorphism and the risk of hypertension was evaluated for Kiema et al., 1996; Kishimoto et al., 2001; Mohana et al., 2012;
meta-analysis. Of those, 12 papers showed that AGT M235T gene Mondorf et al., 1998; Morise et al., 1995; Nair et al., 2003; Niu et al.,

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Table 2
Baseline characteristics of studies concerning AGT T174M gene polymorphism in hypertensive subjects included in the meta-analysis.
Author name & year HT Control Country Continent Genotyping

TT TM MM N TT TM MM N

Agachan et al., 2003 80 17 0 97 75 8 0 83 Turkey Europe PCR


Amrani et al., 2014 116 37 27 180 95 33 42 170 Algeria Africa PCR-RFLP
Barbalić et al., 2006 75 27 7 109 82 34 3 119 Croatia Europe PCR
Basak et al., 2008 62 22 0 84 38 13 1 52 Turkey Europe PCR-RFLP
Chiang et al., 1997 83 17 2 102 40 8 1 49 China Asia PCR-RFLP
Fang et al., 2010 146 25 7 178 209 37 10 256 China Asia PCR
Fernández-Llama et al., 1998 62 11 2 75 64 9 2 75 Spain Europe PCR-RFLP
Iso et al., 2000 177 50 2 229 198 31 0 229 Japan Asia PCR
Iwai et al., 1994 60 21 1 82 71 11 1 83 Japan Asia PCR-RFLP
Jiang et al., 2009 126 85 9 220 167 63 5 235 China Asia PCR
Karthikeyan et al., 2013 62 121 71 254 76 130 48 254 India Asia PCR
Mohana et al., 2012 189 87 3 279 151 44 5 200 India Asia PCR-RFLP
Morise et al., 1995 61 18 1 80 89 11 0 100 Japan Asia PCR-RFLP
Nair et al., 2003 104 29 1 134 102 27 2 131 India Asia PCR-RFLP
Nejatizadeh et al., 2008 378 67 5 450 291 61 6 358 India Asia PCR-RFLP
Patnaik et al., 2015 156 45 4 205 180 43 1 224 India Asia PCR-RFLP
Sato et al., 2000 145 31 4 180 155 38 2 195 Japan Asia PCR-RFLP
Vasků et al., 2002 142 44 3 189 147 50 4 201 Czech Europe PCR-RFLP
Williams et al., 2004 106 2 0 108 47 2 0 49 Ghana Africa PCR-RFLP
Yang et al., 2015 243 64 6 313 106 21 3 130 Taiwan Asia PCR
Yuan et al., 2009 227 44 0 271 235 32 0 267 China Asia PCR-RFLP

Notes, AGT, angiotensinogen; HT, hypertension; PCR, polymerase chain reaction; PCR-RFLP, PCR - restriction fragment length polymorphism.

2016; Patnaik et al., 2015; Procopciuc et al., 2002; Rodríguez-Pérez significant correlation with the risk of hypertension (Karthikeyan et al.,
et al., 2000; Tchelougou et al., 2015; Vasků et al., 2002; Williams et al., 2013; Iso et al., 2000; Morise et al., 1995; Amrani et al., 2014; Jiang
2004; Wu et al., 2004; Ying et al., 2010; Yuan et al., 2009). Our pooled et al., 2009). While, other studies showed otherwise (Chiang et al.,
calculation found that M allele (OR95%CI = 0.87 [0.76–1.00], 1997; Nejatizadeh et al., 2008; Agachan et al., 2003; Barbalić et al.,
p = 0.0450) and MM genotype (OR95%CI = 0.81 [0.66–0.99], 2006; Fang et al., 2010; Fernández-Llama et al., 1998; Iwai et al., 1994;
p = 0.0360) of AGT M235T gene polymorphism were associated with Mohana et al., 2012; Nair et al., 2003; Patnaik et al., 2015; Vasků et al.,
decreasing the risk of essential hypertension. While, increasing the risk 2002; Williams et al., 2004; Yuan et al., 2009; Basak et al., 2008; Sato
of essential hypertension was observed in T allele (OR95%CI = 1.15 et al., 2000; Yang et al., 2015). Our combination data found that M
[1.00–1.32], p = 0.0450). In sub-group analysis, although we found no allele (OR95%CI = 1.17 [1.01–1.36], p = 0.0310) and TM genotype
association in continent sub-group, however, the correlation was found (OR95%CI = 1.18 [1.05–1.33], p = 0.0050) were associated with in-
in genotyping method sub-group. We found that MM genotype creasing the risk of essential hypertension, and T allele
(OR95%CI = 0.75 [0.57–0.97], p = 0.0310) was associated with 0.75- (OR95%CI = 0.85 [0.74–0.99], p = 0.0310) and TT genotype
fold decreasing the risk of essential hypertension in PCR-RFLP sub- (OR95%CI = 0.83 [0.71–0.96], p = 0.0140) had a significant correla-
group. See Fig. 2B. tion with decreasing the risk of essential hypertension. See Fig. 3. In
Previous meta-analyses had reported the correlation in this context. sub-group analysis, we revealed that the correlation between AGT
They revealed that AGT M235T gene polymorphism was associated T174M gene polymorphism and the risk of essential hypertension was
with the risk of essential hypertension. Our results were consistent with found in PCR (Fig. 4A) and Asia population sub-groups (Fig. 4B & C).
those previous studies (Kunz et al., 1997; Zhu et al., 2012; Ji et al., Our results were consistent with Gu et al. (2012) and Pereira et al.
2010). However, we found several limitations in those previous studies. (2008), but contrast with Liao et al. (2014). Because those previous
First, their studies had small sample size. Compared to our meta-ana- studies had several important limitations (Table 5) including small
lysis, we had larger sample size. Second, data discrepancy was found. sample size, uneven data presentation, Hardy-Weinberg deviation, and
Data discrepancy means that there is a difference between the data unavailable full-texts; further studies with larger sample size and well
presented at meta-analysis and the data at the original papers. Data and transparent presented data may be required. Compared to previous
discrepancy often occurs in the analysis of larger sample size without studies, our meta-analysis had larger sample size and more transparent
being accompanied by accuracy. Data discrepancy is a serious limita- data presentation. Therefore, our present study might establish better
tion and has great potency to trigger publication bias. To prevent data association.
discrepancy, in our present meta-analysis, data extraction and analysis The role of AGT in the pathogenesis of hypertension has been widely
were performed by three independent authors (JKF, BSP, TH). Third, known. AGT affecting hypertension occurs through sodium homeostasis
full-texts were not found, and therefore data validation could not be and the regulation of fluid volume (Guyton, 1991; Lalouel et al., 2001).
confirmed. In our study, all papers included in our study were available These pathological mechanisms are mediated by angiotensin II. In the
online. Fourth, Hardy-Weinberg equilibrium was not evaluated. Hardy- renin-angiotensin cascade, AGT is cleaved into angiotensin I by renin,
Weinberg equilibrium is the basic law of genetic in population. and angiotensin I is cleaved by ACE into angiotensin II (Lu et al., 2016).
Therefore, if this basic principle was not evaluated, whatever method In the cellular level, the activity of angiotensin II is governed by its
used might not demonstrate a valid correlation in the context of genetic receptors, such as AT1 and AT2 receptors (Crowley et al., 2006).
in population. Because of these comparisons, our study might confirm However, the impact of angiotensin II to cause blood pressure elevation
better correlation than previous meta-analyses. We summarize the is dominantly mediated by AT1 receptors. These receptors are ex-
limitations of previous studies in Table 5. pressed in the variety of organs and play a crucial role in maintaining
Concerning the correlation between AGT T174M gene poly- blood pressure homeostasis (Crowley et al., 2004). Of this pathological
morphism and the risk of hypertension, we collected 21 papers. Of pathway, it is inferred that AGT has a fundamental role in the patho-
those, five papers showed that AGT T174M gene polymorphism had a genesis and development of hypertension. Previous studies had shown

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Fig. 2. Forestplot of AGT M235T gene polymorphism in subjects with essential hypertension [A). T vs. M] and in PCR-RFLP sub group [B). MM vs. MT + TT].
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J.K. Fajar, et al. Gene Reports 16 (2019) 100421

Table 3
Summary of meta-analysis regarding the association between AGT M235T gene polymorphism and the risk of hypertension.
No. Alleles & genotypes Parameters All Genotyping method Continent

PCR PCR-RFLP Europe America Africa Asia Australia

1. M vs. T OR 0.87 0.92 0.84 1.05 0.47 0.63 0.89 0.81


95%CI 0.76–1.00 0.78–1.10 0.69–1.02 0.95–1.15 0.20–1.10 0.16–2.43 0.75–1.06 0.61–1.08
p 0.0450 0.3770 0.0850 0.3380 0.0800 0.5010 0.1880 0.1510
pH < 0.0001 < 0.0001 < 0.0001 0.2010 0.0090 < 0.0001 < 0.0001 0.4860
pE 0.3960 0.2740 0.4850 0.0940 0.5700 1.3430 0.3740 < 0.0001
2. T vs. M OR 1.15 1.08 1.19 0.96 2.14 1.59 1.12 1.23
95%CI 1.00–1.32 0.91–1.29 0.98–1.45 0.87–1.05 0.91–5.03 0.41–6.16 0.95–1.33 0.93–1.64
p 0.0450 0.3770 0.0850 0.3380 0.0800 0.5010 0.1880 0.1510
pH < 0.0001 < 0.0001 < 0.0001 0.2010 0.0090 < 0.0001 < 0.0001 0.4860
pE 0.3960 0.2740 0.4850 0.0940 0.5700 1.3430 0.3740 < 0.0001
3. MM vs. MT + TT OR 0.81 0.93 0.75 1.05 0.45 0.58 0.81 0.82
95%CI 0.66–0.99 0.69–1.25 0.57–0.97 0.91–1.22 0.19–1.05 0.056.65 0.62–1.07 0.54–1.26
p 0.0360 0.6070 0.0310 0.5140 0.0650 0.6650 0.1400 0.3750
pH < 0.0001 < 0.0001 < 0.0001 0.7100 0.1220 < 0.0001 < 0.0001 0.7420
pE 0.5190 0.4220 0.5850 < 0.0001 0.4780 2.0120 0.5470 < 0.0001
4. MT vs. MM + TT OR 1.03 0.92 1.09 1.00 0.90 1.21 1.02 0.93
95%CI 0.91–1.16 0.73–1.16 0.94–1.25 0.87–1.14 0.58–1.39 0.92–1.61 0.86–1.22 0.62–1.39
p 0.6850 0.4760 0.2580 0.9600 0.6250 0.1790 0.8080 0.7340
pH < 0.0001 < 0.0001 < 0.0001 0.2440 0.4340 0.2620 < 0.0001 0.1140
pE 0.3040 0.3470 0.2840 0.1190 < 0.0001 0.1840 0.3660 0.3560
5. TT vs. MM + MT OR 1.19 1.11 1.26 0.93 3.62 1.70 1.16 1.57
95%CI 0.99–1.41 0.87–1.41 0.97–1.63 0.80–1.09 0.89–14.73 0.52–5.53 0.93–1.45 0.90–2.73
p 0.0580 0.4020 0.0840 0.3760 0.0720 0.3760 0.1920 0.1100
pH < 0.0001 < 0.0001 < 0.0001 0.1360 0.0180 < 0.0001 < 0.0001 0.1270
pE 0.4820 0.3730 0.5990 0.1860 0.9180 1.1360 0.4700 0.4690

Notes, AGT, angiotensinogen; OR, odd ratio; pH, p heterogeneity; pE, p Egger test; PCR, polymerase chain reaction; PCR-RFLP, PCR - restriction fragment length
polymorphism.

that elevated plasma level of AGT was significantly associated with intake was reported higher in Asian population (Teo et al., 2014;
increasing the rate of angiotensin II formation (Bohlender et al., 2000) Firestone et al., 2017). This suggested that M allele of AGT T174M had
and blood pressure (Umemura et al., 1997; Kooffreh and Anumudu, a crucial role in Asian subjects with hypertension, as reported in our
2013). Moreover, the functional expression of AGT is impressed by results, through sodium intake. However, studies are required to clarify
SNPs in exon 2 of AGT gene (Cardoso et al., 2011), and SNPs located in the proper mechanism of M allele of AGT T174M in hypertension.
exon 2 are AGT M235T and AGT T174M. Both of those genes variants In genotyping method sub-group analysis, the correlation between
had been reported to correlate with plasma AGT levels (Miller and AGT M235T and essential hypertension was found in PCR-RFLP sub-
Scholey, 2004). Previous study revealed that T allele of AGT M235T group. While, for AGT T174M, the correlation was observed in PCR sub-
was associated with elevated plasma level of AGT (Jeunemaitre et al., group. This suggested that genotyping method for identifying both of
1992). Moreover, other genes in AGT gene including A-6C, A-20C, and two SNPs is independent, and lack of gene-gene interaction. This was an
G-217A, proven to have a crucial role in hypertension, had been re- intricate circumstance and arduous to elucidate. Although PCR-RFLP
ported to be implicated by the regulation of T allele of AGT M235T was considered better in data interpretation (Tanahashi et al., 2000),
(Zhu et al., 2012). Furthermore, T allele of AGT M235T was associated however, both of those methods were proven having same-related
with extended function of A-6C gene (Inoue et al., 1997), and A-6C gene outcome (Ben Abda et al., 2011). Therefore, further investigations may
polymorphism had been shown to correlate with increasing plasma be required to elucidate the role of those genotyping method in AGT
level of AGT (Hunt et al., 1998). On other hand, a study also showed genes polymorphism, especially related to gene-gene interaction.
that altered AGT level was not only impressed by AGT M235T, but also Our study had several important limitations. First, several factors
M allele of AGT T174M (Balam-Ortiz et al., 2011). This explanation having pivotal role in the pathogenesis and development of hyperten-
may be a benchmark for our study showing that T allele of AGT M235T sion such as age, body weight, physical activity, tobacco use, salt in-
and M allele of AGT T174M had a significant association with essential take, and family history of hypertension, stroke, and or cardiovascular
hypertension. In addition, although it is still a debate concerning which disease (Islam et al., 2015) were not controlled for and included in our
genes have more dominant role affecting AGT level and activity in the study. Second, small sample size in sub-group analysis may drive to
circulation, our results revealed that AGT T174M had more dominant false positive findings even when combined. Third, the proportion of
role than AGT M235T in patients with essential hypertension. However, published papers included in our study was not equal in each continent,
further studies are required to elucidate the exact mechanism how AGT and therefore, this factor may contribute to heterogeneity and study
T174M and AGT M235T affect hypertension. bias. Fourth, most of papers included in our study were cross-sectional.
Our findings, in sub-group analysis, also showed that M allele and Further meta-analysis including higher study designs may be required
TM genotype of AGT T174M was correlated with increasing the risk of to reach a higher level of evidence. Because of these limitation factors,
essential hypertension in Asian population. See Fig. 4B & C. Although it further studies eliminating these limitations may be required to clarify
is proposed that, in the correlation theory, “where there is sugar, there the better association between the risk of hypertension and the genes
are bound to be ants”; because of lack evidence of gene-environment polymorphism of AGT M235T and AGT T174M.
interaction reports regarding this topic, it is difficult to explain the
precise correlation theory of this context. However, studies revealed 5. Conclusions
that urinary sodium excretion and sodium intake, one of hypertension
risk factors (Ha, 2014), were observed higher in patients with M allele Our meta-analysis reveals that M allele and TM genotype of AGT
of AGT T174M (Iso et al., 2000; Yamagishi et al., 2004), and sodium T174M and T allele of AGT M235T are associated with increasing the

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J.K. Fajar, et al. Gene Reports 16 (2019) 100421

Fig. 3. Forestplot of the association between AGT T174M gene polymorphism and the risk of hypertension [A). M vs. T; B). TM vs. TT + MM].

risk of essential hypertension. Our effect estimation shows that M allele Funding source
and TM genotype of AGT T174M have higher effect in essential hy-
pertension than T allele of AGT M235T. Our findings suggest that ge- There is no funding in our study.
netic is the important risk factor for the development of essential hy-
pertension. Our study may support to better comprehension regarding Financial disclosure
the role of AGT M235T and AGT T174M genes polymorphism in pa-
tients with essential hypertension. There is no financial disclosure.

8
J.K. Fajar, et al. Gene Reports 16 (2019) 100421

Fig. 4. Forestplot of the association between AGT T174M gene polymorphism and the risk of essential hypertension in PCR sub-group [A). M vs. T] and Asian
population sub-group [B). M vs. T; C) TM vs. TT + MM].

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J.K. Fajar, et al. Gene Reports 16 (2019) 100421

Table 4
Summary of meta-analysis regarding the association between AGT T174M gene polymorphism and the risk of hypertension.
No. Alleles & genotypes Parameters All Genotyping method Continent

PCR PCR-RFLP Europe Africa Asia

1. T vs. M OR 0.85 0.73 0.94 0.95 1.57 0.79


95%CI 0.74–0.99 0.63–0.85 0.78–1.13 0.73–1.22 1.14–2.16 0.71–0.88
p 0.0310 < 0.0001 0.5080 0.6620 0.0060 < 0.0001
pH 0.0080 0.3600 0.0410 0.6090 0.7220 0.1090
pE 0.2220 0.0650 0.2220 < 0.0001 < 0.0001 0.1530
2. M vs. T OR 1.17 1.37 1.06 1.06 0.64 1.27
95%CI 1.01–1.36 1.18–1.59 0.89–1.28 0.82–1.37 0.46–0.88 1.14–1.42
p 0.0310 < 0.0001 0.5080 0.6620 0.0060 < 0.0001
pH 0.0080 0.3600 0.0410 0.6090 0.7220 0.1090
pE 0.2220 0.0650 0.2220 < 0.0001 < 0.0001 0.1530
3. TT vs. TM + MM OR 0.83 0.71 0.93 0.96 1.46 0.77
95%CI 0.71–0.96 0.59–0.85 0.80–1.07 0.72–1.27 0.96–2.22 0.68–0.88
p 0.0140 < 0.0001 0.3100 0.7520 0.0770 < 0.0001
pH 0.0490 0.2840 0.1210 0.6310 0.6610 0.1050
pE 0.2040 0.1220 0.1930 < 0.0001 < 0.0001 0.1790
4. TM vs. TT + MM OR 1.18 1.24 1.15 1.02 1.01 1.25
95%CI 1.05–1.33 0.94–1.64 0.99–1.34 0.76–1.37 0.61–1.68 1.05–1.49
p 0.0050 0.1240 0.0740 0.8850 0.9570 0.0140
pH 0.1300 0.0520 0.3430 0.5490 0.3990 0.0570
pE 0.1660 0.2640 0.0990 < 0.0001 < 0.0001 0.2100
5. MM vs. TT + TM OR 1.11 1.60 0.68 1.22 0.54 1.39
95%CI 0.86–1.43 1.14–2.24 0.46–1.00 0.51–2.91 0.31–0.92 1.02–1.89
p 0.4370 0.0070 0.0530 0.6580 0.0240 0.0380
pH 0.2180 0.7110 0.7310 0.4300 1.0000 0.6680
pE 0.3000 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001

Notes, AGT, angiotensinogen; OR, odd ratio; pH, p heterogeneity; pE, p Egger test; PCR, polymerase chain reaction; PCR-RFLP, PCR - restriction fragment length
polymorphism.

Table 5
Summary of the limitations in previous study.
Author & year SNP Case setting Number of studies Limitations

Ji et al., 2010 AGT M235T & ACE I/D EHT 39 The sample was only from Chinese Han population.
36 references were not available for full-text.
Data discrepancy was found.
Kunz et al., 1997 AGT M235T EHT 11 The sample was only from Caucasians
HWE was not evaluated.
Zhu et al., 2012 AGT M235T & ACE I/D PIH 22 The sample was only from Chinese Han population.
20 references were not available for full-text.
Gu et al., 2012 AGT T174M EHT 17 The sample was only from Chinese Han population.
13 references were not available for full-text.
Liao et al., 2014 AGT T174M EHT 9 Small sample size.
Pereira et al., 2008 AGT T174M; AGT M235T; G217A; A-20C; EHT 26 Studies with HWE deviation were included.
A-6C. Too many genes were evaluated, and therefore detailed analysis was not
carried out.

Note, SNP, single nucleotide polymorphism; EHT, essential hypertension; PIH, pregnancy-induced hypertension; AGT, angiotensinogen; ACE, angiotensin-converting
enzyme; HWE, Hardy-Weinberg equilibrium.

Authors' contributions Angiotensinogen gene T174M polymorphism and essential hypertension in a sample
of Algerian population: case control study. J. Med. Sci. 14 (4).
Balam-Ortiz, E., Esquivel-Villarreal, A., Alfaro-Ruiz, L., Carrillo, K., Elizalde, A., Gil, T.,
Idea/concept: BSP; JKF. Design: BSP; JKF. Control/supervision: Urushihara, M., Kobori, H., Jimenez-Sanchez, G., 2011. Variants and haplotypes in
BSP; AG; TH. Data collection/processing: BSP; JKF; EPS; PNBS; RRA; angiotensinogen gene are associated with plasmatic angiotensinogen level in Mexican
FT; EDM. Extraction/Analysis/interpretation: JKF; BSP; TH. Literature population. Am J Med Sci 342 (3), 205–211.
Barbalić, M., Skarić-Jurić, T., Cambien, F., Barbaux, S., Poirier, O., Turek, S., Vrhovski-
review: JKF; EPS; PNBS; RRA; FT; EDM. Writing the article: JKF. Hebrang, D., Cubrilo-Turek, M., Rudan, I., Rudan, P., Narancić, N.S., 2006. Gene
Critical review: BSP; AG; TH. polymorphisms of the renin-angiotensin system and early development of hy-
pertension. Am. J. Hypertens. 19 (8), 837–842.
Basak, A.A., Sipahi, T., Ustundag, S., Ozgen, Z., Budak, M., Sen, S., Sener, S., 2008.
Declaration of Competing Interest Association of angiotensinogen T174M and M235T gene variants with development
of hypertension in Turkish subjects of Trakya region. Biotechnol. Biotechnol. Equip.
There is no conflict of interest. 22 (4), 984–989.
Ben Abda, I., de Monbrison, F., Bousslimi, N., Aoun, K., Bouratbine, A., Picot, S., 2011.
Advantages and limits of real-time PCR assay and PCR-restriction fragment length
References polymorphism for the identification of cutaneous Leishmania species in Tunisia.
Trans. R. Soc. Trop. Med. Hyg. 105 (1), 17–22.
Agachan, B., Isbir, T., Yilmaz, H., Akoglu, E., 2003. Angiotensin converting enzyme I/D, Bennett, C.L., Schrader, A.P., Morris, B.J., 1993. Cross-sectional analysis of Met235→Thr
angiotensinogen T174M-M235T and angiotensin II type 1 receptor A1166C gene variant of angiotensinogen gene in severe, familial hypertension. Biochem. Biophys.
polymorphisms in Turkish hypertensive patients. Exp. Mol. Med. 35 (6), 545–549. Res. Commun. 197 (2), 833–839.
Amrani, A., Bendieb, F.M.T., Hamed, M.B.B., 2014. Relationship between Bohlender, J., Ménard, J., Ganten, D., Luft, F.C., 2000. Angiotensinogen concentrations
and renin clearance: implications for blood pressure regulation. Hypertension 35 (3),

10
J.K. Fajar, et al. Gene Reports 16 (2019) 100421

780–786. Iso, H., Harada, S., Shimamoto, T., Sato, S., Kitamura, A., Sankai, T., Tanigawa, T., Iida,
Cardoso, C.C., Cabrini, D.A., May, M., Bhagat, C.S., Eleno, N., Cayla, C., Walther, T., M., Komachi, Y., 2000. Angiotensinogen T174M and M235T variants, sodium intake
Bader, M., 2011. Functional expression of angiotensinogen depends on splicing en- and hypertension among non-drinking, lean Japanese men and women. J. Hypertens.
hancers in exon 2. Mol. Cell. Endocrinol. 332 (1-2), 228–233. 18 (9), 1197–1206.
Cheng, J.L., Wang, A.L., Wan, J., 2012. Association between the M235T polymorphism of Iwai, N., Ohmichi, N., Nakamura, Y., Mitsunami, K., Kinoshita, M., 1994. Molecular
the AGT gene and cytokines in patients with hypertension. Exp. Ther. Med. 3 (3), variants of the angiotensinogen gene and hypertension in a Japanese population.
509–512. Hypertens. Res. 17 (2), 117–121.
Chiang, F.T., Hsu, K.L., Tseng, C.D., Hsiao, W.H., Lo, H.M., Chern, T.H., Tseng, Y.Z., 1997. Jeunemaitre, X., Soubrier, F., Kotelevtsev, Y.V., Lifton, R.P., Williams, C.S., Charru, A.,
Molecular variant M235T of the angiotensinogen gene is associated with essential Hunt, S.C., Hopkins, P.N., Williams, R.R., Lalouel, J.M., Corvol, P., 1992. Molecular
hypertension in Taiwanese. J. Hypertens. 15 (6), 607–611. basis of human hypertension: role of angiotensinogen. Cell 71, 169–180.
Crowley, S.D., Tharaux, P.L., Audoly, L.P., Coffman, T.M., 2004. Exploring type I an- Ji, L.D., Zhang, L.N., Shen, P., Wang, P., Zhang, Y.M., Xing, W.H., Xu, J., 2010.
giotensin (AT1) receptor functions through gene targeting. Acta Physiol. Scand. 181 Association of angiotensinogen gene M235T and angiotensin-converting enzyme
(4), 561–570. gene I/D polymorphisms with essential hypertension in Han Chinese population: a
Crowley, S.D., Gurley, S.B., Herrera, M.J., Ruiz, P., Griffiths, R., Kumar, A.P., Kim, H.S., meta-analysis. J. Hypertens. 28 (3), 419–428.
Smithies, O., Le, T.H., Coffman, T.M., 2006. Angiotensin II causes hypertension and Jiang, X., Sheng, H., Li, J., Xun, P., Cheng, Y., Huang, J., Xiao, H., Zhan, Y., 2009.
cardiac hypertrophy through its receptors in the kidney. Proc. Natl. Acad. Sci. U. S. A. Association between renin-angiotensin system gene polymorphism and essential
103 (47), 17985–17990. hypertension: a community-based study. J. Hum. Hypertens. 23 (3), 176–181.
Davis, D., Liyou, N., Lockwood, D., Johnson, A., 2002. Angiotensinogen genotype, plasma Karthikeyan, M., Shridevi, V., Rose, R., Anandan, B., Singh, K.D., Shanmugasundaram, S.,
protein and mRNA concentration in isolated systolic hypertension. Clin. Genet. 61 Mohan, D., Ramesh, A., Jayaraman, G., 2013. Angiotensin gene polymorphisms
(5), 363–368. (T174M and M235T) are significantly associated with the hypertensive patients of
Fajar, J.K., 2016. The association of ectonucleotide pyrophosphatase/phosphodiesterase Tamil Nadu, South India. Int. J. Hum. Genet. 13 (4), 201–207.
1 (ENPP1) K121Q gene polymorphism with the risk of type 2 diabetes mellitus in Khalil, H.H., 1996. Hypertension in elderly Egyptians. East Mediterr. Health J. 2 (2),
European, American, and African populations: a meta-analysis. J. Health Sci. 6 (2), 206–210.
76–86. Khin-Snadar, O.O., Sein, K.W., Han, S., Tun, H.N., 2018. Association between angio-
Fajar, J.K., 2017. The β fibrinogen gene G-455A polymorphism in Asian subjects with tensinogen Gene M235T polymorphism and plasma angiotensinogen level in essential
coronary heart disease: a meta analysis. Egypt J. Med. Hum. Genet. 18 (1), 19–28. hypertension. EC Cardiology 5 (3), 82–89.
Fajar, J.K., Heriansyah, T., Rohman, M.S., 2018. The predictors of no reflow phenomenon Kiema TR, Kauma H, Rantala AO, Lilja M, Reunanen A, Kesäniemi YA, Savolainen MJ.
after percutaneous coronary intervention in patients with ST elevation myocardial Variation at the angiotensin-converting enzyme gene and angiotensinogen gene loci
infarction: a meta-analysis. Indian Heart J. 70 (Suppl. 3), S406–S418. in relation to blood pressure. Hypertension 1996; 28(6): 1070 - 1075.
Fajar, J.K., Mahendra, A.I., Tamara, F., Mahdi, B.A., Heriansyah, T., Rohman, M.S., 2019. Kim, H.K., Lee, H., Kwon, J.T., Kim, H.J., 2015. A polymorphism in AGT and AGTR1 gene
The association between complete blood count and the risk of coronary heart disease. is associated with lead-related high blood pressure. J. Renin-Angiotensin-Aldosterone
Turkiye Klinikleri J. Med. Sci. 39 (1), 56–64. Syst. 16 (4), 712–719.
Fang, Y.J., Deng, H.B., Thomas, G.N., Tzang, C.H., Li, C.X., Xu, Z.L., Yang, M., Tomlinson, Kishimoto, T., Suyama, A., Osaki, Y., Miyamoto, T., Igarashi, A., Okamoto, M., Kurosawa,
B., 2010. Linkage of angiotensinogen gene polymorphisms with hypertension in a Y., Fukumoto, S.A., 2001. Molecular variant of the angiotensinogen gene and hy-
sibling study of Hong Kong Chinese. J. Hypertens. 28 (6), 1203–1209. pertension in a case-control study in Japanese. Yonago Acta medica 44, 79–83.
Fardella, C.E., Claverie, X., Vignolo, P., Montero, J., Villarroel, L., 1998. T235 variant of Kooffreh, M.E., Anumudu, C.I., 2013. Increased plasma angiotensinogen levels and its
the angiotensinogen gene and blood pressure in the Chilean population. J. Hypertens. association with the M235T gene polymorphism and hypertension in Calabar and
16 (6), 829–833. Uyo cities, Nigeria. Asian Int. J. Biomed. Pharm. Sci. 03 (26), 15–18.
Fernández-Llama, P., Poch, E., Oriola, J., Botey, A., Rivera, F., Revert, L., 1998. Kooffreh, M.E., Anumudu, C.I., Akpan, E.E., Ikpeme, E.V., Kumar, P.L., 2013. A study of
Angiotensinogen gene M235T and T174M polymorphisms in essential hypertension: the M235T variant of the angiotensinogen gene and hypertension in a sample po-
relation with target organ damage. Am. J. Hypertens. 11 (4 Pt 1), 439–444. pulation of Calabar and Uyo, Nigeria. Egypt J. Med. Human Genet. 14, 13–19.
Firestone, M.J., Beasley, J.M., Kwon, S.C., Ahn, J., Trinh-Shevrin, C., Yi, S.S., 2017. Asian Kunz, R., Kreutz, R., Beige, J., Distler, A., Sharma, A.M., 1997. Association between the
American dietary sources of sodium and salt behaviors compared with other racial/ angiotensinogen 235T-variant and essential hypertension in whites: a systematic
ethnic groups, NHANES, 2011–2012. Ethn. Dis. 27 (3), 241–248. review and methodological appraisal. Hypertension 30 (6), 1331–1337.
Freitas, S.R., Cabello, P.H., Moura-Neto, R.S., Dolinsky, L.C., Lima, A.B., Barros, M., Lalouel, J.M., Rohrwasser, A., Terreros, D., Morgan, T., Ward, K., 2001. Angiotensinogen
Bittencourt, I., Cordovil, I.L., 2007. Analysis of renin-angiotensin-aldosterone system in essential hypertension: from genetics to nephrology. J. Am. Soc. Nephrol. 12 (3),
gene polymorphisms in resistant hypertension. Braz. J. Med. Biol. Res. 40 (3), 606–615.
309–316. Liao, X., Yang, Z., Peng, D., Dai, H., Lei, Y., Zhao, Q., Han, Y., Wang, W., 2014.
Gaddam, K.K., Verma, A., Thompson, M., Amin, R., Ventura, H., 2009. Hypertension and Association of T174M polymorphism of angiotensinogen gene with essential hy-
cardiac failure in its various forms. Med. Clin. North Am. 93 (3), 665–680. pertension: a meta-analysis. Genet. Mol. Biol. 37 (3), 473–479.
Ghazali, D.M., Rehman, A., Rahman, A.R., 2008. Candidate gene polymorphisms and Lu, H., Cassis, L.A., Kooi, C.W., Daugherty, A., 2016. Structure and functions of angio-
their association with hypertension in Malays. Clin. Chim. Acta 388 (1-2), 46–50. tensinogen. Hypertens. Res. 39 (7), 492–500.
Glavnik, N., Petrovic, D., 2007. M235T polymorphism of the angiotensinogen gene and Miller, J.A., Scholey, J.W., 2004. The impact of renin-angiotensin system polymorphisms
insertion/deletion polymorphism of the angiotensin-1 converting enzyme gene in on physiological and pathophysiological processes in humans. Curr. Opin. Nephrol.
essential arterial hypertension in Caucasians. Folia Biol. (Praha) 53 (2), 69–70. Hypertens. 13 (1), 101–106.
Gu, W., Liu, Y., Wang, Z., Liu, K., Lou, Y., Niu, Q., Wang, H., Liu, J., Wen, S., 2012. Mohana, V.U., Swapna, N., Surender, R.S., Vishnupriya, S., Padma, T., 2012. Gender-
Association between the angiotensinogen gene T174M polymorphism and hy- related association of AGT gene variants (M235T and T174M) with essential hy-
pertension risk in the Chinese population: a meta-analysis. Hypertens. Res. 35 (1), pertension—a case-control study. Clin. Exp. Hypertens. 34 (1), 38–44.
70–76. Mondorf, U.F., Russ, A., Wiesemann, A., Herrero, M., Oremek, G., Lenz, T., 1998.
Guyton, A.C., 1991. Blood pressure control—special role of the kidneys and body fluids. Contribution of angiotensin I converting enzyme gene polymorphism and angio-
Science. 252 (5014), 1813–1816. tensinogen gene polymorphism to blood pressure regulation in essential hyperten-
Ha, S.K., 2014. Dietary salt intake and hypertension. Electrolyte Blood Press 12 (1), 7–18. sion. Am. J. Hypertens. 11 (2), 174–183.
Hingorani, A.D., Sharma, P., Jia, H., Hopper, R., Brown, M.J., 1996. Blood pressure and Morise, T., Takeuchi, Y., Takeda, R., 1995. Rapid detection and prevalence of the variants
the M235T polymorphism of the angiotensinogen gene. Hypertension 28 (5), of the angiotensinogen gene in patients with essential hypertension. J. Intern. Med.
907–911. 237 (2), 175–180.
Hunt, S.C., Cook, N.R., Oberman, A., Cutler, J.A., Hennekens, C.H., Allender, P.S., Murphy, B.P., Stanton, T., Dunn, F.G., 2009. Hypertension and myocardial ischemia.
Walker, W.G., Whelton, P.K., Williams, R.R., 1998. Angiotensinogen genotype, so- Med. Clin. North Am. 93 (3), 681–695.
dium reduction, weight loss, and prevention of hypertension: trials of hypertension Nair, K.G., Shalia, K.K., Ashavaid, T.F., Dalal, J.J., 2003. Coronary heart disease, hy-
prevention, phase II. Hypertension 32 (3), 393–401. pertension, and angiotensinogen gene variants in Indian population. J. Clin. Lab.
Ibrahim, M.M., 1997. Hypertension surveys in the developing world. Lessons from the Anal. 17 (5), 141–146.
Egyptian National Hypertension Project (NHP). J. Hum. Hypertens. 11 (11), Nakamura, Y., Tabara, Y., Miki, T., Tamaki, S., Kita, Y., Okamura, T., Ueshima, H., 2007.
709–726. Both angiotensinogen M235T and alpha-adducin G460W polymorphisms are asso-
Ibrahim, M.M., Damasceno, A., 2012. Hypertension in developing countries. Lancet 380 ciated with hypertension in the Japanese population. J. Hum. Hypertens. 21 (3),
(9841), 611–619. 253–255.
Ibrahim MM, Rizk H, Appel LJ, el Aroussy W, Helmy S, Sharaf Y, Ashour Z, Kandil H, Nejatizadeh, A., Kumar, R., Stobdan, T., Goyal, A.K., Gupta, M., Javed, S., Pasha, M.Q.,
Roccella E, Whelton PK. Hypertension prevalence, awareness, treatment, and control 2008. Significance of angiotensinogen gene haplotypes and genotypes combinations
in Egypt. Results from the Egyptian National Hypertension Project (NHP). NHP in hypertension. J. Hypertens. 26 (6), 1094–1101.
Investigative Team. Hypertension 1995; 26(6Pt1): 886 - 890. Niu, S., Zhang, B., Zhang, K., Zhu, P., Li, J., Sun, Y., He, N., Zhang, M., Gao, Z., Li, X.,
Inoue, I., Nakajima, T., Williams, C.S., Quackenbush, J., Puryear, R., Powers, M., Cheng, Simayi, A., Ge, J., Cong, M., Zhou, W., Qiu, C., 2016. Synergistic effects of gene
T., Ludwig, E.H., Sharma, A.M., Hata, A., Jeunemaitre, X., Lalouel, J.M., 1997. A polymorphisms of the renin-angiotensin-aldosterone system on essential hyperten-
nucleotide substitution in the promoter of human angiotensinogen is associated with sion in Kazakhs in Xinjiang. Clin. Exp. Hypertens. 38 (1), 63–70.
essential hypertension and affects basal transcription in vitro. J. Clin. Invest. 99 (7), Patnaik, M., Pati, P., Swain, S.N., Mohapatra, M.K., Dwibedi, B., Kar, S.K., Ranjit, M.,
1786–1797. 2015. Gender specific association of angiotensinogen gene polymorphisms with es-
Islam, S.M., Mainuddin, A., Islam, M.S., Karim, M.A., Mou, S.Z., Arefin, S., Chowdhury, sential hypertension. Int. J. Food Nutritional Sci. 4 (1), 182–194.
K.N., 2015. Prevalence of risk factors for hypertension: A cross-sectional study in an Pereira, T.V., Nunes, A.C., Rudnicki, M., Yamada, Y., Pereira, A.C., Krieger, J.E., 2008.
urban area of Bangladesh. Glob. Cardiol. Sci. Pract. 2015 (4), 43. Meta-analysis of the association of 4 angiotensinogen polymorphisms with essential

11
J.K. Fajar, et al. Gene Reports 16 (2019) 100421

hypertension: a role beyond M235T? Hypertension 51 (3), 778–783. patients. Singap. Med. J. 55 (12), 652–655.
Procopciuc, L., Popescu, T., Jebeleanu, G., Pop, D., Zdrenghea, D., 2002. Essential arterial Tylicki, L., Rutkowski, B., 2003. Hypertensive nephropathy: pathogenesis, diagnosis and
hypertension and polymorphism of angiotensinogen M235T gene. J. Cell. Mol. Med. treatment. Pol Merkur Lekarski 14 (80), 168–173.
6 (2), 245–250. Umemura, S., Nyui, N., Tamura, K., Hibi, K., Yamaguchi, S., Nakamaru, M., Ishigami, T.,
Rodríguez-Pérez, J.C., Rodríguez-Esparragón, F.J., Hernández-Perera, O., Fiuza-Pérez, Yabana, M., Kihara, M., Inoue, S., Ishii, M., 1997. Plasma angiotensinogen con-
M.D., Anabitarte-Prieto, A., Losada-Cabrera, A., 2000. Effects of the angiotensinogen centrations in obese patients. Am. J. Hypertens. 10 (6), 629–633.
gene M235T and A(−6)G variants on blood pressure and other vascular risk factors Vasků, A., Soucek, M., Tschöplová, S., Stejskalová, A., 2002. An association of BMI with A
in a Spanish population. J. Hum. Hypertens. 14 (12), 789–793. (−6) G, M235T and T174M polymorphisms in angiotensinogen gene in essential
Rohman, M.S., Fajar, J.K., Kuncahyo, B.H., Yunita, L., Sidarta, E.P., Saka, P.N.B., hypertension. J. Hum. Hypertens. 16 (6), 427–430.
Heriansyah, T., Widodo, N., 2018. Angiotensin-converting enzyme (ACE) I/D and Wang G, Zhou X, Zhuo X, Zhang P. Annual total medical expenditures associated with
bradykinin B2 receptor T/C genes polymorphism in patients with ACE inhibitors- hypertension by diabetes status in U.S. adults. Am J Prev Med 2017; 53(6S2): S182 -
related cough. Egypt J. Med. Hum. Genet. 19 (4), 307–313. S189.
Román, O., Cuevas, G., Badilla, M., Valenzuela, M.A., Cumsille, F., Valverde, L., González, White, W.B., 2009. Defining the problem of treating the patient with hypertension and
A., Pulgar, M., Pino, C., 2001. Risk factors for morbidity and mortality in patients arthritis pain. Am. J. Med. 122 (5 Suppl), S3–S9.
with essential hypertension, followed for 25 years. Rev. Med. Chil. 129 (11), Williams, S.M., Ritchie, M.D., Phillips 3rd, J.A., Dawson, E., Prince, M., Dzhura, E., Willis,
1253–1261. A., Semenya, A., Summar, M., White, B.C., Addy, J.H., Kpodonu, J., Wong, L.J.,
Sato, N., Katsuya, T., Nakagawa, T., Ishikawa, K., Fu, Y., Asai, T., Fukuda, M., Suzuki, F., Felder, R.A., Jose, P.A., Moore, J.H., 2004. Multilocus analysis of hypertension: a
Nakamura, Y., Higaki, J., Ogihara, T., 2000. Nine polymorphisms of angiotensinogen hierarchical approach. Hum. Hered. 57 (1), 28–38.
gene in the susceptibility to essential hypertension. Life Sci. 68 (3), 259–272. Wu, S.J., Chiang, F.T., Chen, W.J., Liu, P.H., Hsu, K.L., Hwang, J.J., Lai, L.P., Lin, J.L.,
Say, Y.H., Ling, K.H., Duraisamy, G., Isaac, S., Rosli, R., 2005. Angiotensinogen M235T Tseng, C.D., Tseng, Y.Z., 2004. Three single-nucleotide polymorphisms of the an-
gene variants and its association with essential hypertension and plasma renin ac- giotensinogen gene and susceptibility to hypertension: single locus genotype vs.
tivity in Malaysian subjects: a case control study. BMC Cardiovasc. Disord. 5 (1), 7. haplotype analysis. Physiol. Genomics 17 (2), 79–86.
Shamaa, M.M., Fouad, H., Haroun, M., Hassanein, M., Hay, M.A.A., 2015. Association Yamagishi, K., Iso, H., Tanigawa, T., Cui, R., Kudo, M., Shimamoto, T., 2004. High sodium
between the angiotensinogen (AGT) gene (M235T) polymorphism and essential hy- intake strengthens the association between angiotensinogen T174M polymorphism
pertension in Egyptian patients. Egypt Heart J. 67 (1), 1–5. and blood pressure levels among lean men and women: a community-based study.
Singh, K.D., Jajodia, A., Kaur, H., Kukreti, R., Karthikeyan, M., 2014. Gender specific Hypertens. Res. 27 (1), 53–60.
association of RAS gene polymorphism with essential hypertension: a case-control Yang CH, Lin YD, Wu SJ, Chuang LY, Chang HW. High order gene-gene interactions in
study. Biomed. Res. Int. 2014, 538053. eight single nucleotide polymorphisms of renin-angiotensin system genes for hy-
Srivastava, K., Chandra, S., Bhatia, J., Narang, R., Saluja, D., 2012. Association of an- pertension association study. Biomed. Res. Int. 2015; 2015: 454091.
giotensinogen (M235T) gene polymorphism with blood pressure lowering response to Ying, C.Q., Wang, Y.H., Wu, Z.L., Fang, M.W., Wang, J., Li, Y.S., Zhang, Y.H., Qiu, C.C.,
angiotensin converting enzyme inhibitor (enalapril). J. Pharm. Pharm. Sci. 15 (3), 2010. Association of the renin gene polymorphism, three angiotensinogen gene
399–406. polymorphisms and the haplotypes with essential hypertension in the Mongolian
Tanahashi, T., Kita, M., Kodama, T., Sawai, N., Yamaoka, Y., Mitsufuji, S., Katoh, F., population. Clin. Exp. Hypertens. 32 (5), 293–300.
Imanishi, J., 2000. Comparison of PCR-restriction fragment length polymorphism Yuan, J., Tang, W., Chun, Y., Ying, H., Yang, Y., Xiao, C., 2009. Angiotensinogen T174M
analysis and PCR-direct sequencing methods for differentiating Helicobacter pylori and M235T variants and hypertension in the Hani and Yi minority groups of China.
ureB gene variants. J. Clin. Microbiol. 38 (1), 165–169. Biochem. Genet. 47 (5-6), 344–350.
Tchelougou, D., Kologo, J.K., Karou, S.D., Yaméogo, V.N., Bisseye, C., Djigma, F.W., Zhang D, Wang G, Zhang P, Fang J, Ayala C. Medical expenditures associated with hy-
Ouermi, D., Compaoré, T.R., Assih, M., Pietra, V., Zabsonré, P., Simpore, J., 2015. pertension in the U.S., 2000–2013. Am J Prev Med 2017; 53(6S2): S164 - S171.
Renin-angiotensin system genes polymorphisms and essential hypertension in Zhu, M., Zhang, J., Nie, S., Yan, W., 2012. Associations of ACE I/D, AGT M235T gene
Burkina Faso, West Africa. Int. J. Hypertens. 2015, 979631. polymorphisms with pregnancy induced hypertension in Chinese population: a meta-
Teo, B.W., Bagchi, S., Xu, H., Toh, Q.C., Li, J., Lee, E.J., 2014. Dietary sodium intake in a analysis. J. Assist. Reprod. Genet. 29 (9), 921–932.
multiethnic Asian population of healthy participants and chronic kidney disease

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