In Silico Analysis of Human AGTR1 Gene and Precision Medicine Among Hypertensive Population

  • Praveen P. Balgir
  • Jaspreet Kaur


Renin-angiotensin-aldosterone system (RAAS) is the most important regulator of blood pressure to maintain homeostasis and vascular tone. The effect is mediated by four primary genes: angiotensinogen (AGT), renin (REN), angiotensin-I-converting enzyme (ACE), and angiotensin II receptor, subtype I (AGTRI). To study the role of AGTR1 gene polymorphisms influencing pharmacogenetics of hypertension was carried out by in silico analysis. This work helps in predicting functional biological variables, viz., genetic polymorphisms, which act as markers to predict individual’s response to drugs. Knowledge of pharmacogenetics helps in optimization of therapeutic strategies, based on the individualization of pharmacological treatment. This study is an attempt to predict possible structure-activity relationship effect of nsSNPs. These were analyzed using SIFT and PolyPhen-2. It is hypothesized that these variations have the potential to result in differential drug response and were further investigated by subsequent empirical approach as no population data is available for many of these SNPs. AGTR1 nsSNP rs12721226 (A163T) resulting in change from alanine to threonine at position 163 in AGTRI protein was investigated. The analysis included 300 clinically diagnosed hypertensive patients with/without associated metabolic disorders and 100 normal healthy subjects with their informed consent. Study has been approved by institutional clinical ethical committee vide No. ICEC/4/2011.



This work was supported by grant from the DBT-Punjabi University Interdisciplinary Life Science Programme for advanced research and education (DBT-IPLS Project) No. BT/PR-4548/INF/22/146/2012


  1. Arsenault J, Lehoux J, Lanthier L, Cabana J et al (2010) A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity. Pharmacogenet Genomics 20(6):377–388CrossRefPubMedGoogle Scholar
  2. Banday AA, Siddiqui AH, Menezes MM, Hussain T (2005) Insulin treatment enhances AT1 receptor function in OK cells. Am J Physiol Ren Physiol 288:F1213–F1219CrossRefGoogle Scholar
  3. Bozkurt O, de Boer A, Grobbee DE, de Leeuw PW et al (2009) Variation in Renin-Angiotensin system and salt-sensitivity genes and the risk of diabetes mellitus associated with the use of thiazide diuretics. Am J Hypertens 22(5):545–551CrossRefPubMedGoogle Scholar
  4. Chen Q, Yu CQ, Tang X, Chen DF et al (2011) Interactions of renin-angiotensin system gene polymorphisms and antihypertensive effect of benazepril in Chinese population. Pharmacogenomics 12(5):735–743CrossRefPubMedGoogle Scholar
  5. de Denus S, Zakrzewski-Jakubiak M, Dubé MP, Bélanger F et al (2008) Effects of AGTR1 A1166C gene polymorphism in patients with heart failure treated with candesartan. Ann Pharmacother 42(7):925–932CrossRefPubMedGoogle Scholar
  6. Furuta H, Guo D, Inagami T (1992) Molecular cloning and sequencing of the gene encoding human angiotensin II type 1 receptor. Biochem Biophys Res Commun 183:8–13CrossRefPubMedGoogle Scholar
  7. Guo DF, Furuta H, Mizukoshi M, Inagami T (1994) The genomic organization of human angiotensin II type 1 receptor. Biochem Biophys Res Commun 200:313–319CrossRefPubMedGoogle Scholar
  8. Jiang S, Hsu YH, Venners SA, Zhang Y et al (2011) Interactive effect of angiotensin II type 1 receptor (AGT1R) polymorphisms and plasma irbesartan concentration on antihypertensive therapeutic responses to irbesartan. J Hypertens 29(5):890–895CrossRefPubMedGoogle Scholar
  9. Johnson MM, Houck J, Chen C (2005) Screening for deleterious non-synonymous single-nucleotide polymorphisms in genes involved in steroid hormone metabolism and response. Cancer Epidemiol Biomark Prev 14(5):1326–1329CrossRefGoogle Scholar
  10. Le MT, Vanderheyden PM, Szaszak M, Hunyady L et al (2003) Peptide and nonpeptide antagonist interaction with constitutively active human AT1 receptors. Biochem Pharmacol 65:1329–1338CrossRefPubMedGoogle Scholar
  11. Lee JK, Wu CK, Tsai CT, Lin LY et al (2013) Genetic variation-optimized treatment benefit of angiotensin-converting enzyme inhibitors in patients with stable coronary artery disease: a 12-year follow-up study. Pharmacogenet Genomics 23(4):181–189CrossRefPubMedGoogle Scholar
  12. Ma Q and Lu AY (2011) Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev 63:437–459CrossRefPubMedGoogle Scholar
  13. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31(13):3812–3814CrossRefPubMedPubMedCentralGoogle Scholar
  14. Nickenig G, Ostergren J, Struijker-Boudier H (2006) Clinical evidence for the cardiovascular benefits of angiotensin receptor blockers. J Renin-Angiotensin-Aldosterone Syst 7(Suppl 1):S1–S7CrossRefPubMedGoogle Scholar
  15. Noda K, Saad Y, Kinoshita A, Boyle TP et al (1995) Tetrazole and carboxylate groups of angiotensin receptor antagonists bind to the same subsite by different mechanisms. J Biol Chem 270:2284–2289CrossRefPubMedGoogle Scholar
  16. Oemrawsingh RM, Akkerhuis KM, Van Vark LC et al (2016) Individualized Angiotensin-Converting Enzyme (ACE)-inhibitor therapy in stable coronary artery disease based on clinical and pharmacogenetic determinants: the Perindopril Genetic (PERGENE) risk model. Pharmacogenet Genomics 23(4):181–189Google Scholar
  17. Polimanti R, Iorio A, Piacentini S, Manfellotto D, Fuciarelli M (2014) Human pharmacogenomic variation of antihypertensive drugs: from population genetics to personalized medicine. Pharmacogenomics 15(2):157–167CrossRefPubMedGoogle Scholar
  18. Spiering W, Kroon AA, Fuss-Lejeune MJ, de Leeuw PW (2005) Genetic contribution to the acute effects of angiotensin II type 1 receptor blockade. J Hypertens 23(4):753–758CrossRefPubMedGoogle Scholar
  19. Suonsyrjä T, Hannila-Handelberg T, Fodstad H et al (2009) Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study. Am J Hypertens 22(2):169–175CrossRefPubMedGoogle Scholar
  20. Weir MR (2007) Effects of renin-angiotensin system inhibition on end-organ protection: can we do better? Clin Ther 29(9):1803–1824CrossRefPubMedGoogle Scholar
  21. Yamano Y, Ohyama K, Kikyo M, Sano T et al (1995) Mutagenesis and the molecular modeling of the rat angiotensin II receptor (AT1). J Biol Chem 270:14024–14030CrossRefPubMedGoogle Scholar
  22. Zhu Y, Hoffman A, Wu X, Zhang H et al (2008) Correlating observed odds ratios from lung cancer case-control studies to SNP functional scores predicted by bioinformatic tools. Mutat Res 639(1–2):80–88CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Praveen P. Balgir
    • 1
  • Jaspreet Kaur
    • 1
  1. 1.Department of BiotechnologyPunjabi UniversityPatialaIndia

Personalised recommendations