- Open Access
The association between angiotensin II type 1 receptor A1166C gene polymorphism and the risk of essential hypertension: a meta-analysis
Egyptian Journal of Medical Human Genetics volume 20, Article number: 14 (2019)
Since first reported having the association with essential hypertension, angiotensin II type 1 receptor (AT1R) A1166C was globally investigated worldwide. However, controversy was found. Furthermore, previous meta-analyses did not adequate to clarify the precise correlation due to some limitations. Therefore, we aimed to perform a meta-analysis concerning the association between AT1R A1166C single-nucleotide polymorphism (SNP) and the risk of essential hypertension with eliminating the limitations of previous studies.
A meta-analysis was conducted from February to March 2019. Some information related to sample size of hypertension and control groups and genotype frequencies of hypertension and control groups were extracted from each study. Data were analyzed using fixed or random effect model to determine the overall correlation.
A total of 45 papers consisting of 11911 cases and 1340 controls were enrolled for the study. Our overall analysis showed that C allele and AC genotype of AT1R A1166C was associated with 1.18-fold and 1.15-fold respectively increased risk of essential hypertension, while the decreased risk of essential hypertension was observed in A allele and AA genotype. In sub-group analysis, increased risk of essential hypertension was found in C allele, AC genotype, and CC genotype of both Asian population and PCR-RFLP sub-groups, while decreased risk was observed in A allele and AA genotype.
Our meta-analysis reveals that AT1R A1166C remains a valuable SNP having an association with the risk of essential hypertension.
Hypertension remains a serious health problem causing a high-cost expenditure because of its fatal complications, such as heart failure , stroke , and renal disease . Recently, various genetic mapping studies including gene-gene, gene-disease, and gene-environment interaction are believed to have a promising prospect for maintaining future treatment and prevention of the disease. In the context of hypertension, studies have focused on the polymorphism of genes in renin-angiotensin-aldosterone system (RAAS), the main pathway playing a pivotal role in the development of hypertension. Briefly, angiotensinogen is cleaved by renin into angiotensin I, and angiotensin I is converted into angiotensin II by angiotensin-converting enzyme (ACE) . Of those precursors, angiotensin II is defined as the most potent vasoconstrictor. To trigger the adverse effects in hypertension, angiotensin II is mediated by angiotensin II type I receptor (AT1R) .
During this time, several studies have identified some AT1R single-nucleotide polymorphisms (SNPs), such as G2228A, C1424G, C521T , C573T, and A1166C . Of those, studies reporting G2228A, C1424G, C521T; and C573T were limited, while A1166C, the substitution of cytosine for adenosine at position 1166 in the 3′ untranslated region of the human AT1R gene , was extensively investigated and proven to have a close correlation with AT1R activity in circulation . Since first reported in the Caucasian population that this SNP had a significant association with essential hypertension , A1166C was widely investigated worldwide. However, the results were inconclusive. The controversy was observed among the reports. Moreover, previous meta-analyses in this context were not adequate to determine the real correlation because of some limitations. Therefore, our present study aimed to perform a meta-analysis concerning the correlation between AT1R A1166C gene polymorphism and the risk of essential hypertension. Our present study might clarify the better association in this topic.
A meta-analysis was performed from February to March 2019 to clarify the association between AT1R A1166C gene polymorphism and the risk of hypertension in the general population. To achieve our purpose, papers published in PubMed, Embase, Cochrane, and Web of science were searched and identified in accordance with eligibility criteria, and they were analyzed to determine the pooled odds ratio (OR) and 95% confidence interval (95%CI) using fixed or random effect model. The design of our present study was adapted from our previous meta-analyses [11,12,13,14,15].
Papers were included in our analysis if they met the following inclusion criteria, such as (1) papers with the following designs: retrospective; prospective; cross-sectional, and randomized controlled trials (RCTs); (2) English publication language; (3) available full text; (4) evaluating the correlation between AT1R A1166C gene polymorphism and the risk of essential hypertension (essential hypertension was assessed using standard criteria formulated by the Joint National Committee VII); and (5) having required data for calculation of OR95%CI, while articles were excluded if the following criteria were found: (1) obvious irrelevance title and or abstract, (2) review, (3) non-standard data presentation, (4) evaluating secondary hypertension; (5) unavailable full text, and (6) deviation from Hardy-Weinberg equilibrium (χ2 < 3.84 was considered in Hardy–Weinberg equilibrium) . Newcastle-Ottawa scale was used to evaluate the quality of each study .
Search strategy and data extraction
A comprehensive searching with English publication language was performed in PubMed, Embase, Cochrane, and Web of science up to 10 March 2019 to collect the papers evaluating the association between AT1R A1166C gene polymorphism and the risk of essential hypertension. For searching the papers, we used the combination of the following keywords: (AT1R A1166C or angiotensin II type 1 receptor A1166C) and (essential hypertension). If we found studies using the same data, only studies with larger sample size were included in our analysis. Moreover, for data extraction, information related to (1) name of first author, (2) year of publication, (3) country of origin, (4) genotyping method, (5) sample size of hypertension and control groups, and (6) genotype frequencies and percents of hypertension and control groups were extracted from each study.
The association between AT1R A1166C gene polymorphism and the risk of hypertension was determined using Z test and the calculation of OR and 95%CI. This calculation model, whether using fixed or random effect model, was confirmed by a Q test. If the p value was less than 0.10, a random effect model was used, while a fixed effect model was used if the p value was more than 0.10. Moreover, to evaluate publication bias, we used an Egger’s test (p < 0.05 was considered statistically significant). All data were analyzed using Review Manager (RevMan; Cochrane, London, UK) version 5.3 and Comprehensive Meta-Analysis (CMA, NJ, USA) version 2.1.
Results and discussion
A total of 45 papers evaluating the association between AT1R A1166C gene polymorphism and the risk of essential hypertension was enrolled for our analysis. These papers were searched in PubMed, Embase, Cochrane, and Web of Science. In initial searching, totally, we found 579 papers. Of those, 484 papers were excluded because of irrelevance title and or abstract. Further exclusions were as follows: 12 papers were excluded because of review, six papers were excluded because data were not presented in standard format, 18 papers were excluded because full texts were not found, and 14 papers were excluded because they were not presented in Hardy-Weinberg equilibrium. Detail of exclusion process in our study is presented in Fig. 1, and baseline characteristics of our study are described in Table 1.
A total of 45 papers consisting of 11,911 cases and 1340 controls was included in our analysis. The cumulative genotype percentage in case for AA, AC, and CC was 73.69%, 22.47%, and 3.85%, respectively, while in the control group, the percentage was 77.65%, 19.51%, and 2.84% for AA, AC, and CC, respectively. Overall, our analysis found that A allele (OR95%CI = 0.88 [0.75–0.97], p = 0.0130) and AA genotype (OR95%CI = 0.82 [0.71–0.94], p = 0.0050) were associated with decreased risk of essential hypertension, while C allele (OR95%CI = 1.18 [1.04–1.34], p = 0.0130) and AC genotype (OR95%CI = 1.15 [1.04− 1.28], p = 0.0060) were found to increase the odds of having essential hypertension (Figs. 2 and 3).
To establish a comprehensive analysis, we also performed a sub-group analysis according to the continent of origin and genotyping method. Continent sub-group analysis consisted of Europe, America, Asia, and Africa sub-groups, while genotyping method consisted of polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) sub-groups. In the America continent sub-group analysis, the genotype percentage in patients with essential hypertension was 63.73%, 31.64%, and 4.63% for AA, AC, and CC, respectively. In the control group, the percentage was 67.39, 27.03, and 5.59% for AA, AC, and CC, respectively. In the Europe continent sub-group, the genotype percentage in patients with essential hypertension for AA, AC, and CC was 60.00%, 33.54%, and 6.46%, respectively, while the genotype percentage in the control group was 62.61%, 31.85%, and 5.54% for AA, AC, and CC, respectively. In the Asia sub-group analysis, the genotype percentage for AA, AC, and CC in patients with essential hypertension was 80.75%, 16.74%, and 2.51%, respectively, while in the control group, the percentage was 83.55%, 14.93%, and 1.52% for AA, AC, and CC, respectively. In the Africa continent sub-group, the percentage was 83.49%, 14.11%, and 2.40% for AA, AC, and CC, respectively, in patients with essential hypertension. In the control group, the genotype percentage for AA, AC, and CC was 84.33%, 13.18%, and 2.49%, respectively. Our results found no association between AT1R A1166C gene polymorphism and the risk of essential hypertension in the Europe, America, and Africa continent sub-groups, while in the Asia sub-group, the increased risk of essential hypertension was found in C allele (OR95%CI = 1.27 [1.04–1.55], p = 0.0190) (Fig. 4a), AC genotype (OR95%CI = 1.19 [1.01–1.41], p = 0.0410) (Fig. 4b), and CC genotype (OR95%CI = 1.81 [1.38–2.36], p < 0.0001) (Fig. 4c).
In genotyping method sub-group, the genotype percentage for the PCR sub-group was 72.24%, 24.32%, and 3.45% for AA, AC, and CC respectively in patients with essential hypertension, while in the control group, the percentage for AA, AC, and CC was 77.01%, 20.10%, and 2.89%, respectively. In the PCR-RFLP sub-group, the percentage in the essential hypertension group was 74.90%, 20.92%, and 4.18% for AA, AC, and CC, respectively. In the control group, the genotype percentage for AA, AC, and CC was 78.42%, 18.80%, and 2.78%, respectively. Our cumulative calculation found that the correlation was found in the PCR-RFLP sub-group. Our results found that A allele (OR95% CI = 0.77 [0.61–0.96], p = 0.0190) and AA genotype (OR95% CI = 0.74 [0.58–0.95], p = 0.0160) were associated with decreased risk of essential hypertension, while increased odds of having essential hypertension was found in C allele (OR95% CI = 1.31 [1.05–1.63], p = 0.0190), AC genotype (OR95% CI = 1.20 [1.01–1.43], p = 0.0430), and CC genotype (OR95%CI = 1.53 [1.02–2.28], p = 0.0390) (Fig. 5a, b). We summarize the correlation between AT1R A1166C gene polymorphism and the risk of essential hypertension in Table 2.
Source of heterogeneity and publication bias
Overall, evidence for heterogeneity was observed in all alleles and genotypes of AT1R A1166C gene polymorphism (p < 0.10). Therefore, a random effect model was used to evaluate the correlation. In the continent sub-group, no heterogeneity (p > 0.10) was observed in AC genotype of the America and Africa sub-groups and CC genotype of the America, Asia, and Africa sub-groups. Therefore, data were assessed using fixed effect model, while other models were assessed using random effect model. In genotyping method sub-group, fixed effect model was used to evaluate AA, AC, and CC genotype of the PCR sub-group because we found no evidence of heterogeneity, while we found heterogeneity in other genetic models in the both PCR and PCR-RFLP sub-groups, and therefore, we used random effect model. For publication bias, our Egger’s test showed that the bias was only found in AC genotype of the PCR sub-groups (p < 0.0500). The summary of heterogeneity and potential publication bias is provided in Table 2.
The main pathway having crucial responsibility for the development of essential hypertension is RAAS . One of the RAAS precursors, angiotensin II, plays a pivotal role to trigger adverse effects in hypertension through AT1R . Until now, A1166C is one of AT1R genes widely reported. However, of the reports, inconsistency was found. Our present study aimed to perform a meta-analysis concerning the association between AT1R A1166C gene polymorphism and the risk of essential hypertension.
We collected 45 papers investigating the association between AT1R A1166C gene polymorphism and the risk of essential hypertension. Of those, 14 studies [9, 18, 21,22,23, 27, 32, 39, 45,46,47, 50, 58, 61] showed that AT1R A1166C gene polymorphism was associated with the risk of essential hypertension, while 31 other studies [19, 20, 24,25,26, 28,29,30,31, 33,34,35,36,37,38, 40,41,42,43,44, 48, 49, 51,52,53,54,55,56,57, 59, 60] failed to confirm the correlation. Our pooled calculation found that A allele and AA genotype of AT1R A1166C gene polymorphism were associated with a decreased risk of essential hypertension, while C allele and AC genotype were 1.18-fold and 1.15-fold, respectively, associated with increased odds of essential hypertension. During this time, there were three meta-analysis studies [64,65,66] evaluating the association between AT1R A1166C gene polymorphism and the risk of essential hypertension. Overall, our results were consistent with previous studies. However, some limitations of those previous studies were found, such as data discrepancy, unavailable full texts, and deviation from Hardy-Weinberg equilibrium (Table 3). Data discrepancy means that irrelevant data was found between data presented in the meta-analysis and the original papers. In previous studies [65, 66], we found irrelevant genotype frequency between data presented in meta-analyses and in original papers. This limitation often occurs in data collection without checking for validity, and it is considered as fatal analysis error having a crucial impact on study bias. Moreover, we also found unavailable full texts. Because of this limitation, data were not presented transparently. As a result, we could not confirm the validity of the data. Furthermore, papers with deviation from Hardy-Weinberg equilibrium were also found in the previous meta-analyses. Hardy-Weinberg equilibrium is defined as the basis of population genetics . The distribution of genetics in population should not deviate from Hardy-Weinberg law. If the deviation has occurred, the distribution of gene in population will be misleading whatever method is used . Therefore, these limitations might be considered as fatal limitations, and these fatal limitations might drive to false-positive findings. Because of these limitations, these previous studies might be considered having low evidence to confer the overall association. In our study, all full texts were available and data were presented transparently and in accordance with Hardy-Weinberg equilibrium. Therefore, our study might clarify better correlation between AT1R A1166C gene polymorphism and the risk of essential hypertension.
Theoretically, it has been globally known that RAAS is a group of pathways involving several precursors that act together to regulate blood pressure by maintaining the vascular tone and the balance of sodium and water . Of all RAAS precursors, angiotensin II is considered as a potent vasoconstrictor . Some literatures reveal that the effects of angiotensin II to cause vasoconstriction occur through its receptors, such as AT1R, AT2R, AT3R, and AT4R [63, 69, 70]. However, correlated to blood pressure maintaining, AT1R was reported to have more dominant role than other angiotensin receptors in governing the effects of angiotensin II. This receptor is expressed in a variety of organs and plays a crucial role in maintaining blood pressure homeostasis . Some studies have reported AT1R gene polymorphism such as G2228A, C1424G, C521T , C573T, and A1166C . However, A1166C was the widest of AT1R genes reported. A1166C is located at the 5′ end of the 3′ untranslated region of the gene . This location is a non-coding region of AT1R, and it is linked to disequilibrium with a nearby mutation that may affect AT1R messenger ribonucleic acid (mRNA) stability . In essential hypertension, the C allele of A1166C was revealed to have a pivotal role for influencing AT1R activities through affecting mRNA stability and transcription or alternatively be linked to other SNPs . A study found that C allele of AT1R A1166C was associated with increased risk of hypertension through interrupting the ability of microRNA-155 to attenuate translation and resulting in augmented AT1R expression . Another study also found that C allele of AT1R A1166C was associated with higher expression of AT1R gene and elevated plasma level of AT1R . Moreover, a study found that C allele of A1166C was observed higher in subjects with increased AT1R protein expression and decreased miR-155 expression. Elevated blood pressure is positively correlated with increased AT1R protein expression and negatively related to miR-155 expression . On other hand, gene-gene interaction study also supported our perspectives. They found that AT1R A1166C was linked to ACE I/D , and our previous study also revealed that ACE I/D gene polymorphism was correlated with hypertension . In addition, AT1R A1166C gene polymorphism was also investigated in patients with hypertension-related condition, such as coronary artery disease and heart failure. In coronary artery disease, previous meta-analysis found that increased risk of coronary artery disease was observed in C allele , while in the case of heart failure, it was reported that the presence of C allele was associated with elevated levels of oxidative stress markers in heart failure patients such as protein carbonyl and myeloperoxidase . This pathway might explain our results showing that C allele of AT1R A1166C gene polymorphism was associated with increased odds of having essential hypertension. However, further studies are required to clarify the precise mechanism how AT1R A1166C gene polymorphism affects essential hypertension.
Moreover, in the continent sub-group analysis, the correlation was observed only in the Asian population. We revealed that the increased risk of essential hypertension was observed in C allele, AC genotype, and CC genotype. Although it was difficult to explain the precise mechanism concerning A1166C gene polymorphism in the Asian population, however, our results might be supported by previous study. They found that this SNP was proven over-represented particularly in the Asian population . However, they also failed to confirm the exact mechanism. Until now, it still becomes the paradigm that should be clarified whether the mechanism occurs through gene-gene interaction or gene-environment interaction or other genetic interaction models.
In the genotyping method, our results found the correlation in the PCR-RFLP sub-group. We showed that A allele and AA genotype were significantly associated with decreased risk of essential hypertension, while C allele, AC genotype, and CC genotype were associated with increased risk of essential hypertension. Since discovered, PCR-RFLP was widely used for genotyping in various SNPs. Although both genotyping methods were proven having the same efficacy , however, PCR-RFLP was reported providing an easy typing scheme of isolates . In a study with larger sample size, this method may provide an easy method in data interpretation. Therefore, genotyping methods may govern the final results. This explanation may be a benchmark for the result of our study showing that the correlation was found only in the PCR-RFLP sub-group.
Although our results suggested that AT1R A1166C gene polymorphism was associated with the risk of essential hypertension, however, at present time, it is not possible to recommend this gene as a biomarker or as risk stratification in hypertensive patients. Moreover, although our study seemed having more complex design than previous meta-analyses, our study also had some crucial limitations that should be clarified in future studies. Therefore, further studies with more complex design involving gene-gene or gene-disease or gene-environment interaction may be required to clarify the better correlation.
Our study had several crucial limitations. First, some factors which might have a pivotal impact on essential hypertension such as age, physical inactivity, and body mass index  were not analyzed. Second, in the sub-group analysis, false-positive findings might occur because of the small sample size. Third, most of the studies included in our analysis were cross-sectional. Further analysis including only RCT studies may be required to reach a higher level of evidence. Fourth, the proportion of studies in each continent was not equal, and therefore, this might drive to analysis bias.
Our study reveals that A allele and AA genotype of AT1R A1166C gene polymorphism are associated with a protective effect against essential hypertension, while C allele and AC genotype of AT1R A1166C are correlated with the increased risk of essential hypertension. Our results may contribute to better understanding concerning gene-disease interaction between AT1R gene polymorphism and the risk of essential hypertension.
Availability of data and materials
The data and material will be available with the corresponding author upon reasonable request.
95% confidence interval
The substitution of cytosine for adenosine at position 1166
Angiotensin II type I receptor
Messenger ribonucleic acid
Polymerase chain reaction
PCR-restriction fragment length polymorphism
Randomized controlled trial
Gaddam KK, Verma A, Thompson M, Amin R, Ventura H (2009) Hypertension and cardiac failure in its various forms. Med Clin North Am 93(3):665–680
White WB (2009) Defining the problem of treating the patient with hypertension and arthritis pain. Am J Med 122(5 Suppl):S3–S9
Tylicki L, Rutkowski B (2003) Hypertensive nephropathy: pathogenesis, diagnosis and treatment. Pol Merkur Lekarski 14(80):168–173
Lu H, Cassis LA, Kooi CW, Daugherty A (2016) Structure and functions of angiotensinogen. Hypertens Res 39(7):492–500
Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM (2013) Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 19(10):1110–1120
Zhang X, Erdmann J, Regitz-Zagrosek V, Kürzinger S, Hense HW, Schunkert H (2000) Evaluation of three polymorphisms in the promoter region of the angiotensin II type I receptor gene. J Hypertens 18(3):267–272
Chaves FJ, Pascual JM, Rovira E, Armengod ME, Redon J (2001) Angiotensin II AT1 receptor gene polymorphism and microalbuminuria in essential hypertension. Am J Hypertens. 14(4 Pt 1):364–370
Zivković M, Stanković A, Alavantić D (2005) AT1 receptor A1166C and AT2 receptor -1332A/G gene polymorphisms: efficient genotyping by single-tube PCR. J Clin Lab Anal 19(2):84–86
Chandra S, Narang R, Sreenivas V, Bhatia J, Saluja D, Srivastava K (2014) Association of angiotensin II type 1 receptor (A1166C) gene polymorphism and its increased expression in essential hypertension: a case-control study. PLoS One 9(7):e101502
Bonnardeaux A, Davies E, Jeunemaitre X, Féry I, Charru A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F (1994) Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 24(1):63–69
Fajar JK, Heriansyah T, Rohman MS (2018) The predictors of no reflow phenomenon after percutaneous coronary intervention in patients with ST elevation myocardial infarction: a meta-analysis. Indian Heart J 70(Suppl 3):S406–S418
Fajar JK, Mahendra AI, Tamara F, Mahdi BA, Heriansyah T, Rohman MS (2018) The association between complete blood count and the risk of coronary heart disease. Turkiye Klinikleri J Med Sci. https://doi.org/10.5336/medsci.2018-61970
Fajar JK, Pikir BS, Sidarta EP, Saka PNB, Akbar RR, Tamara F, Mayasari ED, Gunawan A, Heriansyah T (2019) The genes polymorphism of angiotensinogen (AGT) M235 T and AGT T174 M in patients with essential hypertension: A meta-analysis. Gene Reports 16:100421
Rohman MS, Fajar JK, Kuncahyo BH, Yunita L, Sidarta EP, Saka PNB, Heriansyah T, Widodo N (2018) Angiotensin-converting enzyme (ACE) I/D and bradykinin B2 receptor T/C genes polymorphism in patients with ACE inhibitors-related cough. Egypt J Med Hum Genet 19(4):307–313
Fajar JK (2017) The β fibrinogen gene G-455A polymorphism in Asian subjects with coronary heart disease: a meta analysis. Egypt J Med Hum Genet 18(1):19–28
Rodriguez S, Gaunt TR, Day IN (2009) Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169(4):505–514
Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605
Agachan B, Isbir T, Yilmaz H, Akoglu E (2003) Angiotensin converting enzyme I/D, angiotensinogen T174 M-M235 T and angiotensin II type 1 receptor A1166C gene polymorphisms in Turkish hypertensive patients. Exp Mol Med 35(6):545–549
Ashavaid TF, Shalia KK, Nair KG, Dalal JJ (2000) ACE and AT1R gene polymorphisms and hypertension in Indian population. J Clin Lab Anal 14(5):230–237
Bautista LE, Vargas CI, Oróstegui M, Gamarra G (2008) Population-based case-control study of renin-angiotensin system genes polymorphisms and hypertension among Hispanics. Hypertens Res 31(3):401–408
Bayramoglu A, Kurt H, Gunes HV, Ata N, Birdane A, Dikmen M, Ustuner MC, Colak E, Degirmenci I (2015) Angiotensin II type 1 receptor (AT1) gene A1166C is associated with the risk of hypertension. Genet Test Mol Biomarkers 19(1):14–17
Castellano M, Muiesan ML, Beschi M, Rizzoni D, Cinelli A, Salvetti M, Pasini G, Porteri E, Bettoni G, Zulli R, Agabiti-Rosei E. Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. Hypertension 1996; 28(6): 1076 - 1080.
Dzida G, Sobstyl J, Puzniak A, Golon P, Mosiewicz J, Hanzlik J (2001) Polymorphisms of angiotensin-converting enzyme and angiotensin II receptor type 1 genes in essential hypertension in a Polish population. Med Sci Monit 7(6):1236–1241
El-Banawy BRN, Mohammed A (2015) Angiotensin II type 1 receptor (A1166C) gene polymorphism in Egyptian adult hemodialysis patients. Alexandria J Med 2015(51):339–345
Farrag W, Eid M, El-Shazly S, Abdallah M (2011) Angiotensin II type 1 receptor gene polymorphism and telomere shortening in essential hypertension. Mol Cell Biochem 351(1-2):13–18
Filigheddu F, Argiolas G, Bulla E, Troffa C, Bulla P, Fadda S, Zaninello R, Degortes S, Frau F, Pitzoi S, Glorioso N (2008) Clinical variables, not RAAS polymorphisms, predict blood pressure response to ACE inhibitors in Sardinians. Pharmacogenomics 9(10):1419–1427
Freitas SR, Cabello PH, Moura-Neto RS, Dolinsky LC, Lima AB, Barros M, Bittencourt I, Cordovil IL (2007) Analysis of renin-angiotensin-aldosterone system gene polymorphisms in resistant hypertension. Braz J Med Biol Res 40(3):309–316
Hannila-Handelberg T, Kontula KK, Paukku K, Lehtonen JY, Virtamo J, Tikkanen I, Hiltunen TP (2010) Common genetic variations of the renin-angiotensin-aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension. J Hypertens 28(4):771–779
Jiang X, Sheng H, Li J, Xun P, Cheng Y, Huang J, Xiao H, Zhan Y (2009) Association between renin-angiotensin system gene polymorphism and essential hypertension: a community-based study. J Hum Hypertens 23(3):176–181
Jinmin L, Jianmin L, Shuqin Z, Xueqiu L, Shuyi T (2013) The polymorphism of angiotensin-receptor gene A1166C in familial hypertension and its distribution in the Han Yellow race of China. Saudi Med J 34(10):1007–1012
Kato N, Sugiyama T, Morita H, Kurihara H, Furukawa T, Isshiki T, Sato T, Yamori Y, Yazaki Y (2000) Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese. J Hypertens 18(8):1025–1032
Kim HK, Lee H, Kwon JT, Kim HJ (2015) A polymorphism in AGT and AGTR1 gene is associated with lead-related high blood pressure. J Renin Angiotensin Aldosterone Syst 16(4):712–719
Kooffreh ME, Anumudu CI, Duke R, Okpako EC, Kumar PL (2013) Angiotensin II type 1 receptor A1166C gene polymorphism and essential hypertension in Calabar and Uyo cities. Nigeria. Indian J Hum Genet 19(2):213–218
Kretowski A, McFann K, Hokanson JE, Maahs D, Kinney G, Snell-Bergeon JK, Wadwa RP, Eckel RH, Ogden L, Garg S, Li J, Cheng S, Erlich HA, Rewers M (2007) Polymorphisms of the renin-angiotensin system genes predict progression of subclinical coronary atherosclerosis. Diabetes 56(3):863–871
Kurbanova D, Eliseyeva M (2010) Genetic background of left ventricular hypertrophy in Uzbek hypertensive men. Turk Kardiyol Dern Ars 38(7):466–472
Lapierre AV, Arce ME, Lopez JR, Ciuffo GM (2006) Angiotensin II type 1 receptor A1166C gene polymorphism and essential hypertension in San Luis. Biocell 30(3):447–455
Lesage S, Velho G, Vionnet N, Chatelain N, Demenais F, Passa P, Soubrier F, Froguel P (1997) Genetic studies of the renin-angiotensin system in arterial hypertension associated with non-insulin-dependent diabetes mellitus. J Hypertens 15(6):601–606
Liu Y, Zhuoma C, Shan G, Cui C, Hou S, Qin W, Cai D, Gesang L, Xiao Z, Pingcuo Z, Zheng H, Wu Z, Zhou W, Qiu C (2002) A1166C polymorphism of the angiotensin II type 1 receptor gene and essential hypertension in Han. Tibetan and Yi populations. Hypertens Res 25(4):515–521
Lozinsky S (2016) The association of A1166C gene polymorphism of angiotensin receptors with the parameters of central pulse wave in normotensive persons and patients with hypertension. Folia Cardiologica 11(3):180–185
Mehri S, Mahjoub S, Finsterer J, Zaroui A, Mechmeche R, Baudin B, Hammami M (2011) The CC genotype of the angiotensin II type I receptor gene independently associates with acute myocardial infarction in a Tunisian population. J Renin Angiotensin Aldosterone Syst 12(4):595–600
Morisawa T, Kishimoto Y, Kitano M, Kawasaki H, Hasegawa J (2001) Influence of angiotensin II type 1 receptor polymorphism on hypertension in patients with hypercholesterolemia. Clin Chim Acta 304(1-2):91–97
Nie SJ, Wen-ru T, Bi-feng C, Jin L, Wen Z, Sheng-jun L, Wei-wei L, Hai-jing Y, Chun-jie X (2010) Haplotype-based case-control study of the human AGTR1 gene and essential hypertension in Han Chinese subjects. Clin Biochem 43(3):253–258
Onna M, Kroon AA, Houben AJ, Koster D, Zeegers MP, Henskens LH, Plat AW, Stoffers HE, de Leeuw PW (2004) Genetic risk of atherosclerotic renal artery disease: the candidate gene approach in a renal angiography cohort. Hypertension 44(4):448–453
Ono K, Mannami T, Baba S, Yasui N, Ogihara T, Iwai N (2003) Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res 26(2):131–134
Parchwani DN, Patel DD, Rawtani J, Yadav D (2018) Analysis of association of angiotensin II type 1 receptor gene A1166C gene polymorphism with essential hypertension. Indian J Clin Biochem 33(1):53–60
Patnaik M, Pati P, Swain SN, Mohapatra MK, Dwibedi B, Kar SK, Ranjit M (2014) Aldosterone synthase C-344 T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha. India. J Genet 93(3):799–808
Saab YB, Gard PR, Overall AD (2011) The association of hypertension with renin-angiotensin system gene polymorphisms in the Lebanese population. J Renin Angiotensin Aldosterone Syst 12(4):588–594
Schmidt S, Beige J, Walla-Friedel M, Michel MC, Sharma AM, Ritz E (1997) A polymorphism in the gene for the angiotensin II type 1 receptor is not associated with hypertension. J Hypertens 15(12 Pt 1):1385–1388
Shahin DS, Irshaid YM, Saleh AA (2014) The A(1166)C polymorphism of the AT1R gene is associated with an early onset of hypertension and high waist circumference in Jordanian males attending the Jordan University Hospital. Clin Exp Hypertens 36(5):333–339
Shamaa MM, Fouad H, Haroun M, Shamaa LA (2016) Angiotensin II type 1 receptor (A1166C) gene polymorphism and essential hypertension in Egyptian population. Egyptian Heart J 68(3):165–169
Soualmia H, Ayadi I, Kallel A, Jemaa R, Feki M, Sanhaji H, Kaabachi N (2014) Angiotensin II receptor gene A1166C variant and hypertension in Tunisian population. Int J Sci Basic Applied Res 16(2):86–96
Stanković A, Zivkovic M, Glisić S, Alavantić D (2003) Angiotensin II type 1 receptor gene polymorphism and essential hypertension in Serbian population. Clin Chim Acta 327(1-2):181–185
Szombathy T, Szalai C, Katalin B, Palicz T, Romics L (1998) Csa´sza´r A. Association of angiotensin II type 1 receptor polymorphism with resistant essential hypertension. Clinica Chimica Acta 269(1998):91–100
Takami S, Katsuya T, Rakugi H, Sato N, Nakata Y, Kamitani A, Miki T, Higaki J, Ogihara T (1998) Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension. Am J Hypertens 11(3 Pt 1):316–321
Tchelougou D, Kologo JK, Karou SD, Yaméogo VN, Bisseye C, Djigma FW, Ouermi D, Compaoré TR, Assih M, Pietra V, Zabsonré P, Simpore J (2015) Renin-Angiotensin System Genes Polymorphisms and Essential Hypertension in Burkina Faso. West Africa. Int J Hypertens 2015:979631
Thomas GN, Young RP, Tomlinson B, Woo KS, Sanderson JE, Critchley JA (2000) Renin-angiotensin-aldosterone system gene polymorphisms and hypertension in Hong Kong Chinese. Clin Exp Hypertens 22(1):87–97
Tiret L, Blanc H, Ruidavets JB, Arveiler D, Luc G, Jeunemaitre X, Tichet J, Mallet C, Poirier O, Plouin PF, Cambien F (1998) Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. Projet d’Etude des Gènes de l’Hypertension Artérielle Sévère à modérée Essentielle. J Hypertens 16(1):37–44
Tong J, Wang Y, Yuan J, Yang J, Wang Z, Zheng Y, Chai F, Li X (2017) Effect of interaction between noise and A1166C site of AT1R gene polymorphism on essential hypertension in an iron and steel enterprise workers. J Occup Environ Med 59(4):412–416
Tsai CT, Fallin D, Chiang FT, Hwang JJ, Lai LP, Hsu KL, Tseng CD, Liau CS, Tseng YZ (2003) Angiotensinogen gene haplotype and hypertension: interaction with ACE gene I allele. Hypertension 41(1):9–15
van den Born BJ, van Montfrans GA, Uitterlinden AG, Zwinderman AH, Koopmans RP (2007) The M235 T polymorphism in the angiotensinogen gene is associated with the risk of malignant hypertension in white patients. J Hypertens 25(11):2227–2233
Zhu S, Meng QH (2006) Association of angiotensin II type 1 receptor gene polymorphism with carotid atherosclerosis. Clin Chem Lab Med 44(3):282–284
Yim HE, Yoo KH (2008) Renin-angiotensin system - considerations for hypertension and kidney. Electrolyte Blood Press 6(1):42–50
Singh KD, Karnik SS (2016) Angiotensin receptors: structure, function, signaling and clinical applications. J Cell Signal 1(2)
Wang JL, Xue L, Hao PP, Xu F, Chen YG, Zhang Y (2010) Angiotensin II type 1 receptor gene A1166C polymorphism and essential hypertension in Chinese: a meta-analysis. J Renin Angiotensin Aldosterone Syst 11(2):127–135
Liu DX, Zhang YQ, Hu B, Zhang J, Zhao Q (2015) Association of AT1R polymorphism with hypertension risk: an update meta-analysis based on 28,952 subjects. J Renin Angiotensin Aldosterone Syst 16(4):898–909
Yang Y, Tian T, Lu J, He H, Xing K, Tian G (2017) A1166C polymorphism of the angiotensin II type 1 receptor gene contributes to hypertension susceptibility: evidence from a meta-analysis. Acta Cardiol 72(2):205–215
Namipashaki A, Razaghi-Moghadam Z, Ansari-Pour N (2015) The essentiality of reporting Hardy-Weinberg equilibrium calculations in population-based genetic association studies. Cell J 17(2):187–192
Matsuura M, Eguchi S (1990) Estimation of gene frequency and test for Hardy-Weinberg equilibrium in the HLA system. Environ Health Perspect 87:149–155
Zhang H, Han GW, Batyuk A, Ishchenko A, White KL, Patel N, Sadybekov A, Zamlynny B, Rudd MT, Hollenstein K, Tolstikova A, White TA, Hunter MS, Weierstall U, Liu W, Babaoglu K, Moore EL, Katz RD, Shipman JM, Garcia-Calvo M, Sharma S, Sheth P, Soisson SM, Stevens RC, Katritch V, Cherezov V (2017) Structural basis for selectivity and diversity in angiotensin II receptors. Nature 544(7650):327–332
Planes N, Digman MA, Vanderheyden PPML, Gratton E, Caballero-George C (2019) Number and brightness analysis to study spatio-temporal distribution of the angiotensin II AT1 and the endothelin-1 ETA receptors: influence of ligand binding. Biochim Biophys Acta Gen Subj
Crowley SD, Tharaux PL, Audoly LP, Coffman TM (2004) Exploring type I angiotensin (AT1) receptor functions through gene targeting. Acta Physiol Scand 181(4):561–570
Hulyam K, Aysegul B, Veysi GH, Demet O, Irfan D, Ertugrul C, Didem CT, Banu B, Miris D (2013) Frequency of angiotensin II type 1 receptor gene polymorphism in Turkish acute stroke patients. J Cell Mol Med 17(4):475–481
Martin MM, Buckenberger JA, Jiang J, Malana GE, Nuovo GJ, Chotani M, Feldman DS, Schmittgen TD, Elton TS (2007) The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA-155 binding. J Biol Chem 282(33):24262–24269
Ceolotto G, Papparella I, Bortoluzzi A, Strapazzon G, Ragazzo F, Bratti P, Fabricio AS, Squarcina E, Gion M, Palatini P, Semplicini A (2011) Interplay between miR-155, AT1R A1166C polymorphism, and AT1R expression in young untreated hypertensives. Am J Hypertens 24(2):241–246
Wang JG, Staessen JA (2000) Genetic polymorphisms in the renin-angiotensin system: relevance for susceptibility to cardiovascular disease. Eur J Pharmacol 410(2-3):289–302
Zhang K, Zhou B, Zhang L (2013) Association study of angiotensin II type 1 receptor: A1166C (rs5186) polymorphism with coronary heart disease using systematic meta-analysis. J Renin Angiotensin Aldosterone Syst 14(2):181–188
Cameron VA, Mocatta TJ, Pilbrow AP, Frampton CM, Troughton RW, Richards AM, Winterbourn CC (2006) Angiotensin type-1 receptor A1166C gene polymorphism correlates with oxidative stress levels in human heart failure. Hypertension 47(6):1155–1161
Wang WYS, Zee RYL, Morris BJ (1997) Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet 51:31–34
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 polymorphism for the identification of cutaneous Leishmania species in Tunisia. Trans R Soc Trop Med Hyg 105(1):17–22
Tanahashi T, Kita M, Kodama T, Sawai N, Yamaoka Y, Mitsufuji S, Katoh F, Imanishi J (2000) Comparison of PCR-restriction fragment length polymorphism analysis and PCR-direct sequencing methods for differentiating Helicobacter pylori ureB gene variants. J Clin Microbiol 38(1):165–169
Olack B, Wabwire-Mangen F, Smeeth L, Montgomery JM, Kiwanuka N, Breiman RF (2015) Risk factors of hypertension among adults aged 35-64 years living in an urban slum Nairobi, Kenya. BMC Public Health 15:1251
We thank Andri Tirta from Rumah Sakit Islam Aisyiyah Malang for providing the meta-analysis software.
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Fajar, J.K., Susanti, M., Pikir, B.S. et al. The association between angiotensin II type 1 receptor A1166C gene polymorphism and the risk of essential hypertension: a meta-analysis. Egypt J Med Hum Genet 20, 14 (2019) doi:10.1186/s43042-019-0016-3
- Angiotensin II type 1 receptor
- Single-nucleotide polymorphism