Contribution of AGTR 1 Promoter Region Polymorphism to the Progression and Outcome of Sepsis in Patients with Various Comorbidities

Blood pressure dysregulation and circulatory failure are major contributors to the progression of sepsis and especially septic shock. One of the genes affecting the vascular endothelium and arteriolar tone is the angiotensin II receptor 1 gene (AGTR1). The AGTR1 rs275651 single-nucleotide polymorphism is associated with the development of angina, high altitude pulmonary edema, and hypertension. The significance of the AGTR1 rs275651 polymorphism in sepsis, particularly in patients with significant comorbidity, has not been studied previously.
The aim of the study was to determine the impact of AGTR1 functional polymorphism on sepsis outcome in patients with various comorbidities, including cardiovascular disease and type 2 diabetes mellitus.
Material and methods. A prospective study included 144 ICU patients of two clinical hospitals in Moscow, aged 18-75 years with clinical signs of sepsis (Sepsis-3, 2016).
Results. In the group of patients with cardiovascular diseases, carriers of the TT AGTR1 rs275651 genotype had a lower mortality rate compared with carriers of the A allele (25 deaths out of 33 versus 16 out of 16, respectively, P=0.041, Fisher's exact test; P=0.0019, log-rank test). In the group of patients with diabetes mellitus (n=62), we also found significant differences in sepsis outcome based on the AGTR1 rs275651 genotype variant. The subgroup of TT AGTR1 rs275651 genotype carriers demonstrated significantly lower mortality compared with TA, AA genotypes carriers (27 deaths out of 41 and 20 out of 21, respectively, P=0.012, Fisher's exact test; OR=10.37; 95% CI: 1.26 to 85.5; P<0.0001, log-rank test).
Conclusion. We found an association of the functional polymorphism AGTR1 -777 T>A (rs275651) with sepsis outcome in ICU patients with high-value baseline comorbidity: carriers of the more common TT genotype had lower mortality compared to carriers of the minor A allele.

1. Cavaillon Zh. New Approaches to Treat Sepsis: Animal Models «Do Not Work» (Review). Obshchaya Reanimatologiya=General Reanimatology. 2018; 14 (3): 46-53 [In Russ.]. DOI: 10.15360/1813-9779-20183-46-53

2. Moroz V.V., Smelaya T.V., Golubev A.M., Salnikova L.E. Genetics and Medicine of Critical Conditions: from Theory to Practice. General Reanimatology. 2012; 8 (4): 5. [In Russ.] DOI: 10.15360/1813-97792012-4-5

3. Pisarev V.M., Chumachenko A.G., Filev A.D., Ershova E.S., Kostyuk S.V., Veiko N.N., Grigoriev E.K., Elysina E.V., Cherpakov R.A., Tutelyan A.V. Combination of DNA Molecular Biomarkers in the Prediction of Critical Illness Outcome. Obshchaya Reanimatologiya=General Reanimatology. 2019; 15 (3): 31-47[In Russ.]. DOI: 10.15360/1813-97792019-3-31-47

4. Pisarev V.M., Chumachenko A.G., Turin I.N., Cherpakov R.A., Elisina E.V., Grigoriev E.K., Aleksandrov I.A., Tutelyan A.V. Prognostic Value of a Genetic Polymorphism in Promotor Region of AQP5 in Sepsis Depends on the Source of Infection. Obshchaya Reanimatologiya=General Reanimatology. 2020; 16 (3): 16-33 [In Russ.]. DOI: 10.15360/18139779-2020-3-16-33

5. Nakada T.-A., Takahashi W., Nakada E., Shimada T., Russell J.A., Walley K. R. Genetic Polymorphisms in Sepsisrdiovascular Disease: Do Similar Risk Genes Suggest Similar Drug Targets? Chest. 2019; 155 (6): 1260-1271. DOI: 10.1016/j.chest.2019.01.003

6. Bronkhorst M.W.G.A., Patka P., Van Lieshout E.M.M. Effects of Sequence Variations in Innate Immune Response Genes on Infectious Outcome in Trauma Patients: A Comprehensive Review. Shock. 2015; 44 (5): 390-396. DOI: 10.1097/SHK.0000000000000450

7. Qian X., Guo D., Zhou H., Qiu J., Wang J., Shen C., Guo Z., Xu Y., Dong C. Interactions Between PPARG and AGTR1 Gene Polymorphisms on the Risk of Hypertension in Chinese Han Population. Genet Test Mol Biomarkers. 2018; 22 (2): 90-97. DOI: 10.1089/gtmb.2017.0141

8. Smyth L. J., Cañadas-Garre M., Cappa R.C., Maxwell A.P., McKnight A.J. Genetic associations between genes in the renin-angiotensin-aldosterone system and renal disease: a systematic review and metaanalysis. BMJ Open. 2019; 9 (4): e026777. DOI: 10.1136/bmjopen-2018-026777

9. Rivard K., Grandy S. A., Douillette A., Paradis P., Nemer M., Allen B.G., Fiset C. Overexpression of type 1 angiotensin II receptors impairs excitation-contraction coupling in the mouse heart. Am J Physiol Heart Circ Physiol. 2011; 301 (5): H2018-27. DOI: 10.1152/ajpheart.01092.2010

10. Dimitrijevic I., Ekelund U., Edvinsson M-L., Edvinsson L. Increased expression of endothelin ET (B) and angiotensin AT (1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome. Heart Vessels. 2009; 24 (6): 393-398. DOI: 10.1007/s00380-008-1136-8

11. Ghafil F.A., Mohammad B.I., Al-Janabi H. S., Hadi N.R., Al-Aubaidy H.A. Genetic Polymorphism of Angiotensin II Type 1 Receptors and Their Effect on the Clinical Outcome of Captopril Treatment in Arab Iraqi Patients with Acute Coronary Syndrome (Mid Euphrates). Indian J Clin Biochem. 2021; 36 (1): 81-87. DOI: 10.1007/s12291-019-00860-x

12. Jin T., Ren Y.,Zhu X., Li X., Ouyang Y., He X., Zhang Z., Zhang Y. Kang L., Yuan D. Angiotensin II receptor 1 gene variants are associated with high-altitude pulmonary edema risk. Oncotarget. 2016; 7 (47): 77117-77123.DOI: 10.18632/oncotarget.12489

13. Martmez-Rodriguez N., Posadas-Romero C., Cardoso G., Perez-Rodriguez J. M., Perez-Hernandez N., Vallejo M., Vargas-Alarcon G. Association of angiotensin II type 1-receptor gene polymorphisms with the risk of developing hypertension in Mexican individuals. J Renin Angiotensin Aldosterone Syst. 2012; 13 (1): 133-140. DOI: 10.1177/1470320311419175

14. Mottl A.K., Shoham D.A., North K. E. Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: a HuGE review. Genet Med. 2008; 10 (8): 560-574. DOI: 10.1097/gim.0b013e3181809613

15. Jain S., Prater A., Pandey V., Rana A., Puri N., Kumar A. A haplotype of Angiotensin receptor type 1 associated with human hypertension increases blood pressure in transgenic mice. Journal of biological chemistry. 2013; 288 (52): 37048-37056. DOI: 10.1074/jbc.M113.520023. Epub 2013 Nov 7

16. Bucher M., Ittner K-P., Hobbhahn J., Taeger K., Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension 2001; 38: 177-182. DOI: 10.1161/01.hyp.38.2.177

17. Zhuang Y., Niu F., Liu D., Sun J., Zhang X., Zhang J., Guom S. Association between AGTR1 A1166C polymorphism and the susceptibility to diabetic nephropathy: Evidence from a meta-analysis. Medicine (Baltimore). 2018; 97 (41): e07689. DOI: 10.1097/MD.0000000000007689

18. Shah V.N., Cheema B.S., Sharma R., Khullar M., Kohli H. S., Ahluwalia T. S., Mohan V., Bhansali A. ACACe gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes. Mol Cell Biochem. 2013; 372 (1-2): 191-198. DOI: 10.1007/s11010-012-1460-2. Epub 2012 Oct 19

19. Smelaya T.V., Kuzovlev A.N., Moroz V.V., Golubev A.M., Belopolskaya O.B., Salnikova L.E. Search for Common Molecular Genetic Markers of Nosocomial Pneumonia and Acute Respiratory Distress Syndrome. Obshchaya Reanimatologiya=General Reanimatology. 2015; 11 (3): 24-38. [In Russ.]. DOI: 10.15360/1813-9779-2015-3-24-38

20. Sun Y., Liao Y., Yuan Y., Feng L., Ma S., Wei F., Wang M., Zhu F. Influence of autoantibodies against АП receptor and AGTR1 polymorphisms on candesartan-based antihypertensive regimen. Journal of the American Society of Hypertension, 2014; 8 (1): 21-27. DOI: 10.1016/j.jash.2013.08.002

21. Padro-MiquelA., A., Alía-Ramos P, Gonzalez-Alvarez M. T., Navarro-Moreno M. A. Survival in type 2 diabetic patients in dialysis and the number of risk alleles in polymorphisms of the renin-angiotensin system genes. Clin Biochem. 2009; 42 (1-2): 5-11. DOI: 10.1016/j.clinbioc-hem.2008.10.011.2009 Jan; 42 (1-2): 5-11

22. Narkevich A.N., Vinogradov K.A. Methods for determining the minimum required sample size in medical research. Sotsialniye aspekty zdorovya. 2019; 65 (6): 10 [In Russ.]. DOI: 10.21045/2071-5021-201965-6-10

23. Likhvantsev V.V., Yadgarov M.Ya., Berikashvili L.B., Kazantseva K.K., Kuzovlev A.N. Determination of the sample size. Anestesiol. i reanimatol. 2020; 6: 77-87 [In Russ.] DOI: 10.17116/anaesthesiology202006177

24. Tiwari S., Pratyush D.D., Gahlot A., Surya K Singh S.K. Sepsis in diabetes: А bad duo. Diabetes Metab Syndr. 2011; 5 (4): 222-227. DOI: 10.1016/j.dsx.2012.02.026. Epub 2012 Apr 4;

25. Doerschug K.C., Delsing A.S., Schmidt G.A., Ashare A. Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis. Crit Care. 2010; 14: R24-32. DOI: 10.1186/cc8887

26. Ganter M.T., Cohen M.J., Brohi K., Chesebro B. B., Staudenmayer K. L., Rahn P, Christiaans S. C., Bir N. D., Pittet J.-F. Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann. Surg. 2008; 247: 320-326. DOI 10.1097/SLA.0b013e318162d616

27. Sander C.S., Chang H., Salzmann S., Müller C.S.L., Ekanayake-Mudiyanselage S., Elsner P., Thiele J.J. Photoaging is associated with protein oxidation in human skin in vivo. J Invest Dermatol. 2002; 118 (4): 618-625. DOI: 10.1046/j.1523-1747.2002.01708.x

28. Bissell B.D., Browder K., McKenzie M., Flannery A.H. А Blast From the Past: Revival of Aпgiotensin II for Vasodilatory Shock. Ann Pharmacother. 2018; 52 (9): 920-927. DOI: 10.1177/1060028018767899

29. Russell J.A. Vasopressor therapy in critically ill patients with shock. Intensive Care Med. 2019; 45 (11): 1503-1517. DOI: 10.1007/s00134-019-05801-z

30. Russell J.A., Gordon A.C., Williams M.D., Boyd J.H., Walley K.R., Kissoon N. Vasopressor Therapy in the Intensive Care Unit. Semin Respir Crit Care Med. 2021; 42 (1): 59-77. DOI: 10.1055/s-0040-1710320. Epub 2020 А^ 20. PMID: 32820475

31. Senatore F., Jagadeesh G., Rose M., Pillai V.C., Hariharan S., Liu Q., McDowell T.Y., Sapru M.K., Southworth M.R., Stockbridge N. FDA Approval of Aпgiotensin II for the Treatment of Hypotension in Adults with Distributive Shock. Am J Cardiovasc Drugs. 2019; 19 (1): 11-20. DOI: 10.1007/s40256-018-0297-9

32. Jadhav A.P, Sadaka F.G. Angiotensin II in septic shock. Аш J Emerg Med. 2019; 37 (6): 1169-1174. DOI: 10.1016/j.ajem.2019.03.026. Epub 2019 Mar 19

33. Bellomo R., Forni L.G., Busse L.W., McCurdy M.T., Ham K.R., Boldt D.W., Hastbacka J., Khanna A.K., Albertson T.E., Tumlin J., Storey K., Handisides D., Tidmarsh G.F., Chawla L.S., Ostermann M. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. А Clinical Trial. Am J Respir Crit Care Med. 2020; 202 (9): 1253-1261. DOI: 10.1164/rccm.201911-2172OC

34. Schmidt C., Hocherl K., Kurt B., Moritz S., Kurtz A., Bucher M. Blockade of multiple but not single cytokines abrogates downregulation of angiotensin II type-I receptors and anticipates septic shock. Cytokine. 2010; 49 (1): 30-38. DOI: 10.1016/j.cyto.2009.10.006

35. Zhang W., Chen X., Huang L., Zhou L. N., Wu G., Chen Y. Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosi. Exp. Ther. Med. 2014; 7 (5): 1342-1348. DOI: 10.3892/etm.2014.1566

36. Antonucci E., Gleeson P.J., Annoni F., Agosta S., Orlando S., Taccone F. S., Velissaris D., Scolletta S. Angiotensin II in Refractory Septic Shock. Shock. 2017; 47 (5): 560-566. DOI: 10.1097/SHK.0000000000000807

37. Kochkin A.A., Yavorovskiy A.G., Berikashvili L.B., Likhvantsev V.V. Modern Vasopressor Therapy of Septic Shock (Review). Obshchaya Reanimatologiya=General Reanimatology. 2020; 16 (2): 77-93 [In Russ.]. DOI: 10.15360/1813-9779-2020-2-77-93

38. Aouizerat B.E., Vittinghoff E., Musone S.L., Pawlikowska L., Kwok P.-Y., Jeffrey E Olginand Tseng Z.H. GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease. BMC Cardiovasc Disord. 2011; 11: 29. DOI: 10.1186/1471-2261-11-29

39. Zhang K., Zhou B., ZhangL. Association study of angiotensin II type 1 receptor: A1166C (rs5186) polymorphism with coronary heart disease using systematic meta-analysis. J Renin Angiotensin Aldosterone Syst. 2013; 14 (2): 181-188. DOI: 10.1177/1470320312447652

40. Martin M.M., Buckenberger J.A., Jiang J., Geraldine E. Malana G.E. Nuovo G.J., Chotani M., Feldman D.S., Schmittgen T.D., Elton T.S. The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA-155 binding. Journal of Biological Chemistry. 2007; 282 (33): 24262-24269. DOI: 10.1074/jbc.M701050200

41. Shah V. N., Cheema B. S,, Rajni Sharma, Khullar M., Kohli H.S., Ahluwalia T.S., Mohan V., Bhansali A. ACACb gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes. Mol Cell Biochem. 2013; 372 (1-2): 191-198. DOI: 10.1007/s11010-012-1460-2

42. Hou L., Quan X., Li X., Su X. Correlation between gene polymorphism in angiotensin II type 1 receptor and type 2 diabetes mellitus complicated by hypertension in a population of Inner Mongolia. BMC Med Genet. 2020; 21 (1): 83. DOI: 10.1186/s12881-020-01021-1

43. Benigni A., Orisio S., Noris M., Iatropoulos P., Castaldi D., Kamide K., Rakugi H., Arai Y., Todeschini M., Giulia Ogliari, Imai E., Gondo Y., Hi-rose N., Mari D., Remuzzi G. Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity. Age (Dordr). 2013; 35 (3): 993-1005. DOI: 10.1007/s11357-012-9408-8. Epub 2012 May 9

44. Li Y., Peng Y., Yao S., Chen L., Li S., Wang M., Chen S, Chen X., Deng F., Hu W., Zhu P., Zhao B., Zhong W., Ma G. Association of miR-155 and Angiotensin Receptor Type 1 Polymorphisms with the Risk of Ischemic Stroke in a Chinese Population. DNA Cell Biol. 2020; 39 (1): 92-104. DOI: 10.1089/dna.2019.4948. Epub 2019 Nov 13

45. Rodriguez-Reynan T.S., Nunez-Alvarez C., Cruz-Lagunas A., Posadas-Sanchez R., Perez-Hernandez N., Jimenez-Alvarez L., Ramrrez-Martinez G., Granados J., Vargas-Alarcon G., Zuniga J. Angiotensin II Type 1 receptor (AGTR1) gene polymorphisms are associated with vascular manifestations in patients with systemic sclerosis (SSc). J Renin Angiotensin Aldosterone Syst. 2016; 17 (3): 1470320316659954. DOI: 10.1177/1470320316659954

46. Luft F.C., Dechend R., MUller D.N. Immune mechanisms in angiotensin II-induced target-organ damage. Ann Med. 2012 Jun; 44 Suppl 1: S49-54. DOI: 10.3109/07853890.2011.653396.

47. Chang Y., Wei W. Angiotensin II in inflammation, immunity and rheumatoid arthritis. Clin Exp Immunol. 2015; 179 (2): 137-145. DOI: 10.1111/cei.12467

48. Biancardi V.C., Bomfim G.F., Reis W.L., Al-Gassimi S., Nunes K.P. The interplay between Angiotensin II, TLR4 and hypertension. Pharmacol Res. 2017; 120: 88-96. DOI: 10.1016/j.phrs.2017.03.017

49. Shah K.H., Shi P., Giani J.F., Janjulia T., Bernstein E.A., Li Y., Zhao T, Harrison D.G., Bernstein K.E., Shen X.Z. Myeloid Suppressor Cells Accumulate and Regulate Blood Pressure in Hypertension. Circ Res. 2015; 117 (10): 858-869. DOI: 10.1161/CIRCRESAHA.115.306539

50. Cuenca A.G., Delano M.J, Kelly-Scumpia K.M, Moreno C., Scumpia P.O., Laface D.M., Heyworth P.G., Efron P.A, Moldawer L.L. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011; 17 (3-4): 281-292. DOI: 10.2119/molmed.2010.00178

51. Schrijver I.T., Theroude C., Roger T. Myeloid-Derived Suppressor Cells in Sepsis. Front Immunol. 2019; 10: 327. DOI: 10.3389/fimmu.2019. 00327

52. Gaponov M.A., Khaydukov S.V., Pisarev V.M., Grebenshchikov O.A., Gaponov A.M., Tutelyan A.V. Population heterogeneity of myeloid immunosuppressive cells in patients with septic conditions. Rossijskij immunologicheskiy zhurnal. 2015; 9 (18): 11-14 [In Russ.]

53. Gaponov M.A., Pisarev V.M., Tutelyan A.V., Likhvantsev V.V., Grebenchikov O.A. Prognostic value of the content of monocytic myeloid immunosuppressive cells in sepsis. Infektsionniye bolezni. 2015; 13 (4): 72-74 [In Russ.].