Skip to main content

Advertisement

SpringerLink
Log in

AGT rs699 and AGTR1 rs5186 gene variants are associated with cardiovascular-related phenotypes in atherosclerotic peripheral arterial obstructive disease

  • Original Article
  • Published:
Irish Journal of Medical Science (1971 -) Aims and scope Submit manuscript

Abstract

Background

Peripheral arterial diseases (PAD) refer to the arterial diseases other than coronary arteries and the aorta. Atherosclerosis is the major cause of PAD. Renin angiotensin aldosterone system (RAAS)-related genes were associated with cardiovascular diseases. Angiotensin II is the pro-inflammatory, proliferative and vasoconstrictor effector of RAAS in the vascular system.

Aims

In this study, we aimed to investigate whether the effects of the angiotensinogen (AGT) rs699 (M268T), angiotensin-converting enzyme (ACE) I/D (rs1799752), angiotensin II receptor type 1 (AGTR1) (A1166C) rs5186, and angiotensin II receptor type 2 (AGTR2) rs35474657 variants were associated with PAD etiology due to atherosclerotic involvement of aorta-iliac and femoro-popliteal artery occlusions.

Methods

AGT rs699, AGTR1 rs5186, ACE I/D (rs1799752), AGTR2 rs35474657 gene variants were determined by real-time polymerase chain reaction (RT-PCR) in 63 PAD patients (33 femoro-popliteal, 30 aorta-iliac) and 70 healthy controls.

Results

Although there was no significant relationship in the genotype frequencies of AGT rs699, AGTR1 rs5186, ACE I/D (rs1799752), and AGTR2 rs35474657 variants between PAD and control groups (p > 0.05), AGT rs699 TT genotype was significantly associated with fasting glucose (p = 0.023) in PAD patients. Besides, CC genotype of rs699 was significantly related with HDL-cholesterol levels (p = 0.020) in PAD group. Furthermore, AGTR1 rs5186 CC genotype carriers demonstrated significantly higher LDL-cholesterol (p = 0.034) and triglycerides levels (p = 0.007).

Conclusions

This report is the first to show an association between RAAS-related gene variants and their relation with the biochemical characteristics of PAD and suggests that RAAS-associated gene variants may have significant roles in cardiovascular related phenotypes of PAD patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Aboyans V, Ricco JB, MEL B et al (2018) 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Documentcovering atherosclerotic disease of extracranial carotid and vertebral,mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 39(9):763–816

    PubMed  Google Scholar 

  2. Pipinos II, Judge AR, Selsby JT, Zhu Z, Swanson SA, Nella AA, Dodd SL (2007) The myopathy of peripheral arterial occlusive disease: part 1. Functional and histomorphological changes and evidence for mitochondrial dysfunction. Vasc Endovasc Surg 41:481–489

    Google Scholar 

  3. Grenon SM, Chong K, Alley H, Nosova E, Gasper W, Hiramoto J, Boscardin WJ, Owens CD (2014) Walking disability in patients with peripheral artery disease is associated with arterial endothelial function. J Vasc Surg 59:1025–1034

    PubMed  PubMed Central  Google Scholar 

  4. Aiello A, Anichini R, Brocco E et al (2014) Treatment of peripheral arterial disease in diabetes: a consensus of the Italian societies of diabetes (SID, AMD), radiology (SIRM) and vascular endovascular surgery (SICVE). Nutr Metab Cardiovasc Dis 24(4):355–369

    CAS  PubMed  Google Scholar 

  5. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott M, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH (2013) Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 382:1329–1340

    PubMed  Google Scholar 

  6. Basgoz BB, Cintosun U, Tasci İ (2017) Peripheral arterial disease and heart. Turkiye Klinikleri J Cardiol-Special Topics 10(3):173–177

    Google Scholar 

  7. Neri Serneri GG, Boddi M, Modesti PA, Coppo M, Cecioni I, Toscano T, Papa ML, Bandinelli M, Lisi GF, Chiavarelli M (2004) Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component. Circ Res 94(12):1630–1637

    CAS  PubMed  Google Scholar 

  8. George AJ, Thomas WG, Hannan RD (2010) The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 10:745–759

    CAS  PubMed  Google Scholar 

  9. Yin G, Yan C, Berk BC (2003) Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35:780–783

    CAS  PubMed  Google Scholar 

  10. Sobczuk P, Szczylik C, Porta C, Czarnecka AM (2017) Renin angiotensin system deregulation as renal cancer risk factor. Oncol Lett 14(5):5059–5068

    PubMed  PubMed Central  Google Scholar 

  11. Brand E, Chatelain N, Paillard F, Tiret L, Visvikis S, Lathrop M, Soubrier F, Demenais F (2002) Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis. Eur J Hum Genet 10(11):715–723

    CAS  PubMed  Google Scholar 

  12. Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A (2003) Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: a meta-analysis. Arterioscler Thromb Vasc Biol 23(7):1269–1275

    CAS  PubMed  Google Scholar 

  13. World Health Organization (1999) Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consult. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva: WHO Department of Noncommunicable Disease Surveillance:1–59

  14. https://www.omim.org/entry/106180. Last accessed 17-July-2019

  15. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/ deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang WY, Zee RY, Morris BJ (1997) Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet 51(1):31–34

    CAS  PubMed  Google Scholar 

  17. 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

    CAS  PubMed  Google Scholar 

  18. Jiang Z, Zhao W, Yu F, Xu G (2001) Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Chin Med J 114(12):1249–1251

    CAS  PubMed  Google Scholar 

  19. Ono K, Mannami T, Baba S et al (2003) Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res 26(2):131–134

    CAS  PubMed  Google Scholar 

  20. Han W, Sun N, Chen L et al (2017) Relationship of renin-angiotensin system polymorphisms with ambulatory and central blood pressure in patients with hypertension. J Clin Hypertens (Greenwich) 19(11):1081–1087

    CAS  Google Scholar 

  21. Hein L, Barsh GS, Pratt RE et al (1995) Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature 377(6551):744–747 Erratum in: nature 1996 mar 28;380(6572):366

    CAS  PubMed  Google Scholar 

  22. Schütz S, Le Moullec JM, Corvol P et al (1996) Early expression of all the components of the renin-angiotensin-system in human development. Am J Pathol 149:2067–2079

    PubMed  PubMed Central  Google Scholar 

  23. Nishimura H, Yerkes E, Hohenfellner K, Miyazaki Y, Ma J, Hunley TE, Yoshida H, Ichiki T, Threadgill D, Phillips JA 3rd, Hogan BM, Fogo A, Brock JW 3rd, Inagami T, Ichikawa I (1999) Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell 3(1):1–10

    CAS  PubMed  Google Scholar 

  24. Vervoort VS, Beachem MA, Edwards PS, Ladd S, Miller KE, de Mollerat X, Clarkson K, DuPont B, Schwartz CE, Stevenson RE, Boyd E, Srivastava AK (2002) AGTR2 mutations in X-linked mental retardation. Science 296(5577):2401–2403

    CAS  PubMed  Google Scholar 

  25. Piton A, Redin C, Mandel JL (2013) XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet 93(2):368–383 Erratum in: Am J Hum Genet 2013 Aug 8;93(2):406

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Miranda DM, Dos Santos AC Jr, Sarubi HC et al (2014) Association of angiotensin type 2 receptor gene polymorphisms with ureteropelvic junction obstruction in Brazilian patients. Nephrology (Carlton) 19(11):714–720

    CAS  Google Scholar 

  27. Deser SB, Bayoglu B, Besirli K, Cengiz M, Arapi B, Junusbekov Y, Dirican A, Arslan C (2016) Increased IL18 mRNA levels in peripheral artery disease and its association with triglyceride and LDL cholesterol levels: a pilot study. Heart Vessel 31(6):976–984

    Google Scholar 

  28. Hiatt WR (2001) Medical treatment of peripheral arterial disease and claudication. N Engl J Med 344:1608–1621

    CAS  PubMed  Google Scholar 

  29. Abd El-Aziz TA, Hussein YM, Mohamed RH et al (2012) Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease. Gene 498(2):270–275

    CAS  PubMed  Google Scholar 

  30. Jia EZ, Xu ZX, Guo CY, Li L, Gu Y, Zhu TB, Wang LS, Cao KJ, Ma WZ, Yang ZJ (2012) Renin-angiotensin-aldosterone system gene polymorphisms and coronary artery disease: detection of gene-gene and gene-environment interactions. Cell Physiol Biochem 29(3–4):443–452

    CAS  PubMed  Google Scholar 

  31. Xia MM, Wang M, Jiang H, Liu Y, Ma L, Lu C, Zhang W (2019) Association of angiotensin-converting enzyme insertion/deletion polymorphism with the risk of atherosclerosis. J Stroke Cerebrovasc Dis 28(6):1732–1743

    PubMed  Google Scholar 

  32. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell 71(1):169–180

    CAS  PubMed  Google Scholar 

  33. Su X, Lee L, Li X, Lv J, Hu Y, Zhan S, Cao W, Mei L, Tang YM, Wang D, Krauss RM, Taylor KD, Rotter JI, Yang H (2007) Association between angiotensinogen, angiotensin II receptor genes, and blood pressure response to an angiotensin-converting enzyme inhibitor. Circulation 115(6):725–732

    CAS  PubMed  Google Scholar 

  34. Imbalzano E, Vatrano M, Quartuccio S, di Stefano R, Aragona CO, Mamone F, D'Ascola A, Scuruchi M, Felice F, Trapani G, Alibrandi A, Ciconte VA, Ceravolo R, Saitta A, Mandraffino G (2017) Clinical impact of angiotensin I converting enzyme polymorphisms in subjects with resistant hypertension. Mol Cell Biochem 430(1–2):91–98

    CAS  PubMed  Google Scholar 

  35. 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. https://doi.org/10.1080/00015385.2017.1291211

    Article  PubMed  Google Scholar 

  36. Taute BM, Handschug K, Taute R, Seifert H, Gläser C, Podhaisky H (1998) Angiotensin-converting enzyme gene insertion/deletion polymorphism and peripheral arterial occlusive disease. Vasa 27(3):149–153

    CAS  PubMed  Google Scholar 

  37. Taute BM, Gläser C, Taute R, Podhaisky H (2002) Progression of atherosclerosis in patients with peripheral arterial disease as a function of angiotensin-converting enzyme gene insertion/deletion polymorphism. Angiology 53(4):375–382

    PubMed  Google Scholar 

  38. Li R, Nicklas B, Pahor M, Newman A, Sutton-Tyrrell K, Harris T, Lakatta E, Bauer DC, Ding J, Satterfield S, Kritchevsky SB (2007) Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the health, aging and body composition study. J Hum Hypertens 21(8):673–682

    CAS  PubMed  Google Scholar 

  39. Fatini C, Sticchi E, Sofi F, Said AA, Pratesi G, Pulli R, Pratesi C, Abbate R (2009) Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: role of ACE D/−240T haplotype. J Vasc Surg 50(6):1399–1404

    PubMed  Google Scholar 

  40. Scicchitano P, Cameli M, Maiello M et al (2014) Nutraceuticals and dyslipidaemia: beyond the common therapeutics. J Funct Foods 6:11–32

    CAS  Google Scholar 

  41. Paulis L, Foulquier S, Namsolleck P, Recarti C, Steckelings UM, Unger T (2016) Combined angiotensin receptor modulation in the management of cardio-metabolic disorders. Drugs 76(1):1–12

    CAS  PubMed  Google Scholar 

  42. Barrons RW, Woods JA (2016) The roles of ACE inhibitors in lower extremity peripheral artery disease. Am J Ther 23(1):e7–e15

    PubMed  Google Scholar 

Download references

Acknowledgments

The findings of this study were presented at the VII. International Congress of Molecular Medicine, Istanbul, Turkey, September 5-7, 2019.

Funding

This study was partly funded by the Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpasa (grant number 34151).

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Yerik Junusbekov & Caner Arslan

  2. Avrasya Hospital, Bestelsiz Mah. 101. Sokak. No: 107 Zeytinburnu, Istanbul, Turkey

    Yerik Junusbekov

  3. Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Burcu Bayoglu & Mujgan Cengiz

  4. Department of Biostatistics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Ahmet Dirican

  5. Private Medikar Hospital, Universite Mah, Sehit Ateşe Reşat Morali Bulvari No:7 Merkez, Karabuk, Turkey

    Caner Arslan

Authors
  1. Yerik Junusbekov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Burcu Bayoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mujgan Cengiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ahmet Dirican
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caner Arslan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Burcu Bayoglu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Junusbekov, Y., Bayoglu, B., Cengiz, M. et al. AGT rs699 and AGTR1 rs5186 gene variants are associated with cardiovascular-related phenotypes in atherosclerotic peripheral arterial obstructive disease. Ir J Med Sci 189, 885–894 (2020). https://doi.org/10.1007/s11845-019-02166-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11845-019-02166-6

Keywords

Search

Navigation