Prognostic Value of a Genetic Polymorphism in Promotor Region of AQP5 in Sepsis Depends on the Source of Infection

Aquaporins represent proteins contributed to water transport through cell membrane. They are involved in formation and resolution of edema, cell migration and inflammatory reaction. There are only few studies linking the genetic polymorphism of aquaporin 5 (rs3759129 AQP5) and sepsis. At the same time, the apparent heterogeneity of patients along the foci of infection may limit finding the most significant association of AQP5 genotypes with the course of infectious complications of critical conditions and restrict further development of rs3759129 AQP5 as a potentially strong marker of sepsis outcome.

The purpose of the study was to determine whether the preferential localization of the infection affects the prognostic value of the genetic marker AQP5 (1364A/C, rs3759129) in outcome prediction in sepsis (SEPSIS-3, 2016) patients.

Materials and methods. Study groups (n=339) included ICU patients with abdominal sepsis (AS, including pancreatitits, peritonitis, cholecystitis, appendicitis; n=94) sepsis patients with other sources of infections  (n=65) and ICU patients without sepsis (n=180). AQP5 polymorphism was studied by analyzing PCR products in a 2% agarose gel using a AQP5 1364A/C specific tetra primer set.

Result. Distribution of alleles (A and C) and genotypes (AA, AC and CC) AQP5 1364A/C in patients with  sepsis or sepsis subgroups (sepsis with no septic shock and sepsis shock patients) versus control group (healthy  volunteers) did not differ. Although there was a trend to preferential survival of sepsis patients with genotype C AQP5 despite the source of infection, only patients with AQP5 CC or AC genotype and abdominal sepsis (Sepsis-3), or a subgroup of the same AQP5 genotype experiencing septic shock, demonstrated increased 30day survival versus AA homozygotic patients (P=0.002).

Conclusion. The informative value of detecting the AQP5 CC or AC genotype for prognosis of 30-day survival versus AA homozygotic patients is most significant only in abdominal sepsis patients.

1. Angus D.C., van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013; 369 (9): 840-851. DOI: 10.1056/NEJMra1208623

2. Machado FR., Nsutebu E., AbDulaziz S. Sepsis 3 from the perspective of clinicians and quality improvement initiatives. J. Crit Care. 2017; 40: 315-317. Epub 2017 Apr 26, DOI: 10.1016/j.jcrc.2017.04.037

3. Beloborodova N.B., Ostrova I.V Sepsis-Associated Encephalopathy (Review). General Reanimatology=Obshchaya Reanimatologiya. 2017; 13 (5): 121-139. [In Russ.]. DOI: 10.15360/1813-9779-2017-5-121-139

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

5. Ushakova N.D., Kit O.I., MaslovAA., MensheninaA.P Extracorporeal Detoxification in Abdominal Sepsis in Cancer Patients. General Rea-nimatology=Obshchaya Reanimatologiya. 2018; 14 (2): 25-34 [In Russ.]. DOI: 10.15360/1813-9779-2018-2-25-34

6. Verkman A.S. Aquaporins in clinical medicine. Annu Rev Med. 2012; 63: 303-316. DOI: 10.1146/annurev-med-043010-193843

7. Rump K., Unterberg M., Bergmann L., Bankfalvi A., Menon A., Schafer S., Scherag A., Bazzi Z., Siffert W., Peters J., Adamzik M. AQP5-1364A/C polymorphism and the AQP5 expression influence sepsis survival and immune cell migration: a prospective laboratory and patient study. J Transl Med. 2016 Nov 21; 14 (1): 321. PMID: 27871297 DOI: 10.1186/s12967-016-1079-2

8. Rump K., AdamzikM. Function of aquaporins in sepsis: a systematic review. Cell Biosci. 2018; 8: 10. DOI: 10.1186/s13578-018-0211-9

9. Tyurin I.N., Rautbart S.A., Kozlov I.A. Early Characteristics of Circulation in Patients with Poor Outcome of Abdominal Sepsis (Preliminary Report). General Reanimatology=Obshchaya Reani-matologiya. 2017; 13 (3): 13-24 [In Russ.]. DOI: 10.15360/1813-9779-2017-3-13-24

10. Russell J.A. Genomics and pharmacogenomics of sepsis: so close and yet so far. Crit Care. 2016; 20 (1): 185. DOI: 10.1186/s13054-016-1374-6

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

12. MyazinA.E., Chumachenko A.G., KuzovlevA.N., GolubevA.M., Moroz V.V., GaponovA.M., TutelianA.V., GolubevMA., Pisarev V.M. Genetic Variants of Intron Region of Aquaporin AQP5 Gene and Development of Pulmonary Edema in Lung Infection Complicated by Septic Shock. General Reanimatology=Obshchaya Reanimatologiya. 2016; 12 (3): 8-23 [In Russ.]. DOI: 10.15360/1813-9779-2016-3-8-23

13. Adamzik M., Frey U.H., Mohlenkamp S., Scherag A., Waydhas C., MarggrafG., Dammann M., Steinmann J., Siffert W., Peters J. Aquapo-rin 5 gene promoter—1364A/C polymorphism associated with 30-day survival in severe sepsis. Anesthesiology. 2011; 114 (4): 912-917. DOI: 10.1097/ALN.0b013e31820ca911. PMID: 21427539

14. Rahmel T., Rump K., Peters J., Adamzik M. Aquaporin 5 -1364A/C Promoter Polymorphism Is Associated with Pulmonary Inflammation and Survival in Acute Respiratory Distress Syndrome. Anesthesiology. 2019; 130 (3): 404-413. DOI: 10.1097/ALN.0000000000002560,

15. Lambertz N., Hindy N.E., Adler C., AdamzikM., Keyvani K., Bankfalvi A., Siffert I W., Sandalcioglu E., Bachmann S.H. Expression of aqua-porin 5 and the AQP5 polymorphism A (-1364)C in association with peritumoral brain edema in meningioma patients. J Neurooncol. 2013; 112 (2): 297-305. DOI: 10.1007/s11060-013-1064-z. Epub 2013 Feb 8. PMID: 23392848

16. Adamzik M., Frey U.H., Bitzer K., Jakob H., Baba H.A., Schmieder R. E., Schneider M.P., Heusch G., Peters J., Siffert W. A novel-1364A/C aquaporin 5 gene promoter polymorphism influences the responses to salt loading of the renin-angiotensin-aldosterone system and of blood pressure in young healthy men. Basic Res Cardiol. 2008; 103: 598-610. DOI: 10.1007/s00395-008-0750-z PMID: 18846354

17. ZhangZ.Q., Song Y.L., Chen Z.H., Shen Y., Bai C-X Deletion of aqua-porin 5 aggravates acute lung injury induced by Pseudomonas aeruginosa. J Trauma 2011; 71: 1305-1311 DOI: 10.1097/TA.0b013e 3182128528

18. Singer M., Deutschman C.S., Seymour C.W., Manu Shankar-Hari M., Annane D., Bauer M., Bellomo R., Bernard G. R., Chiche J-L., Coopers-mith C.M., HotchkissR.S., LevyM.M., MarshallJ.C., Martin G.S., Opal S. M., Rubenfeld G.D., van der Poll T., Angus D.C. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315 (8): 801-810. DOI: 10.1001/jama.2016.0287

19. SalnikovaL.E., Chumachenko A.G., VesninaI.N., LaptevaN.Sh., Kuznetsova G.I., Abilev S.K., Rubanovich A.V Polymorphism of repair genes and cytogenetic effects of radiation. Radiacionnaya biologiya. Radioekologiya. 2010; 50 (6): 656-662 [In Russ.]. ISSN: 0869-8031, УДК [57+61]: 539.1.047: 575.224: 23

20. Khan A., Fornes O., Stigliani A., Gheorghe M., Castro-Mondragon J.A., van der Lee R., Bessy A., Cheneby J., Kulkarni S., Tan G., Baranasic D., Arenillas D., Sandelin A., Vandepoele K., Lenhard B., Ballester B., Was-serman W.W., Parcy F, Mathelier A. JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res. 2018; 46: D260-D266, DOI: 10.1093/nar/gkx1126

21. Kumar S., Ambrosini G., Bucher P. SNP2TFBS - a database of regulatory SNPs affecting predicted transcription factor binding site affinity, Nucleic Acids Res. 2017 Jan4. PMC5210548, DOI: 10.1093/nar/gkw1064,

22. Li S.-L., Schlegel W., Valente A.J., Clark R.A. Critical flanking sequences of PU.1 binding sites in myeloid-specific promoters. The Journal of Biological Chemistry, Nov.5, 1999; DOI: 10.1074/jbc274.45.32453

23. Song Y., Fukuda N., Bai C., Ma T., Matthay M.A., Verkman A.S. Role of aquaporins in alveolar fluid clearance in neonatal and adult lung, and in oedema formation following acute lung injury: studies in transgenic aquaporin null mice. J Physiol. 2000; 525 Pt 3: 771-779. PMID: 10856128

24. Zhang Z., Chen Z., Song Y., Zhang P, Hu J., Bai C. Expression of aqua-porin 5 increases proliferation and metastasis potential of lung cancer. J Pathol. 2010; 221: 210-20. DOI: 10.1002/path.2702 PMID: 20455256

25. Papadopoulos M.C., Saadoun S., Verkman A.S. Aquaporins and cell migration. Pflugers Arch. 2008; 456: 693-700. DOI: 10.1007/s00424-007-0357-5 PMID: 17968585,

26. Lerman Y.V., Kim M. Neutrophil migration under normal and sepsis conditions. Cardiovasc Hematol Disord Drug Targets. 2015; 15: 19-28. DOI: 10.2174/1871529X15666150108113236. PMID: 25567338,

27. Castanheira S.F, Silva F.V.E., Ferreira R.G.,Kanashiro A., Gongalves Leite C.A.V., Nascimento D.C., Colon D.F., Borges V., Alves-Filho J-C., Queiroz Cunha F. Paradoxical roles of the neutrophil in sepsis: protective and deleterious. Front Immunol. 2016; 7: 155. PMID: 27199981, DOI: 10.3389/fimmu.2016.00155

28. Craciun F.L., Schuller E.R., Remick D.G. Early enhanced local neutrophil recruitment in peritonitis-induced sepsis improves bacterial clearance and survival. J Immunol. 2010; 185: 6930-6938. DOI: 10.4049/jimmunol.1002300. PMID: 21041722

29. Rahmel T., Nowak H., Rump K., Siffert W., Peters J., Adamzik M. The aquaporin 5 -1364A/C promoter polymorphism impacts on resolution of acute kidney injury in pneumonia evoked ARDS. PLoS One. 2018 Dec 5; 13 (12): e0208582. DOI: 10.1371/journal.pone.0208582

30. Leligdo wicz A., Dodek PM., No rena M., Wong H., Kumar A., Kumar A., Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Association between source of infection and hospital mortality in patients who have septic shock. Am J Respir Crit Care Med. 2014; 189 (10): 1204-1213 PMID: 24635548 DOI: 10.1164/rccm.201310-1875OC

31. Cahill R.A, Wang J.H, Redmond H.P. Enteric bacteria and their antigens may stimulate postoperative peritoneal adhesion formation. Surgery. 2007; 141: 403- 410. DOI: 10.1016/j.surg.2006.09.010

32. Karantonis F.F., Nikiteas N., Perrea D., Vlachou A., Giamarellos-Bo-urboulis E.J., Tsigris C., Kostakis A. Evaluation of the effects of laparotomy and laparoscopy on the immune system in intra-abdominal sepsis — a review. J Invest Surg. 2008; 21: 330-339. DOI: 10.1080/08941930802438914

33. Dupont H., Paugam-Burtz C., Muller-Serieys C., Fierobe.L, Chosidow D., Marmuse J.P, Mantz J., Desmonts J.M. Predictive factors of mortality due to polymicrobial peritonitis with Candida isolation in peritoneal fluid in critically ill patients. Arch Surg. 2002; 137: 1341-1346. DOI: 10.1001/archsurg.137.12.1341

34. Jawad I., Luksic I., Rafnsson S.B. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health. 2012; 2 (1): 010404 PMID: 23198133 PMCID: PMC3484761 DOI: 10.7189/jogh.02.010404

35. Sartelli M., Abu-Zidan F.M., Ansaloni L, Bala M., Beltran M.A., Biffl W.L., Catena F, Chiara O., Coccolini F., Coimbra R., Demetrashvili Z., Demetriades D., Diaz J.J., Di Saverio S., Fraga G.P., Ghnnam W., Griffiths E.A., Gupta S., Hecker A., Karamarkovic A., Kong V.Y., Kafka-Ritsch R., Kluger Y., Latifi R., Leppaniemi A., Lee J.G., McFar-lane M., Marwah S., Moore F.A., Ordonez C.A., Pereira G.A., Plaudis H., Shelat V.G., Ulrych J., Zachariah S.K., Zielinski M.D., Garcia M.P., Moore E.E. The role of the open abdomen procedure in managing severe abdominal sepsis: WSES position paper. World J Emerg Surg. 2015; 10: 35. PMID: 26269709 PMCID: PMC4534034 DOI: 10.1186/s13017-015-0032-7

36. Sartelli M., Viale P., Catena F., Ansaloni L., Moore E., Malangoni M., Moore FA., Velmahos G., Coimbra R., Ivatury R., Peitzman A., Koike K., Leppaniemi A., Biffl W., Burlew C.C., Balogh Z.J., Boffard K., Bendinelli C., Gupta S., Kluger Y., Agresta F., Di Saverio S., Wani I., Escalona A., Ordonez C., Fraga G.P, Alves Pereira Jr. G., Bala M., Cui Y., Marwah S., Sakakushev B., Kong V., Naidoo N., Ahmed A., Abbas A., Guercioni G., Vettoretto N., Diaz-Nieto R., Gerych I., Trana C., Faro M.P., Yuan K-Ch.,K. Yuh Yen Kok, Chichom Mefire A., Lee J.G.,Hong S-K., Ghnnam W., Siribumrungwong B.,Sato N.,Murata K., Irahara T., Coccolini F., Segovia Lohse H.A., Verni A., Shoko T. 2013 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2013; 8 (1): 3 DOI: 10.1186/1749-7922-8-3

37. Montravers P, Gauzit R., Muller C., Marmuse J.P, Fichelle A., Desmonts J.M. Emergence of antibiotic-resistant bacteria in cases of peritonitis after intraabdominal surgery affects the efficacy of empirical antimicrobial therapy. Clin Infect Dis. 1996; 23: 486-494. DOI: 10.1093/clinids/ 23.3.486

38. Calandra T., Bille J., Schneider R., Mosimann F., Francioli P. Clinical significance of Candida isolated from peritoneum in surgical patients. Lancet. 1989; 2: 1437-1440 DOI: 10.1016/S0140-6736 (89)92043-6

39. Hensler T., Hecker H., HeegK., Heidecke C.D., Bartels H., Barthlen W., Wagner H., Siewert J.R., Holzmann B. Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun. 1997; 65 (6): 2283-2291 PMID: 9169765 PMCID: PMC175317

40. Kimura F., Shimizu H., Yoshidome H., Ohtsuka M., Miyazaki M. Immunosuppression following surgical and traumatic injury. Surg Today. 2010; 40 (9): 793-808. DOI: 10.1007/s00595-010-4323-z

41. SchrijverI.T., Theroude C., Roger T. Myeloid-Derived Suppressor Cells in Sepsis. Front. Immunol. 2019; 10: 327 PMID: 30873175 PMCID: PMC6400980 DOI: 10.3389/fimmu.2019.00327

42. GaponovM.A., Pisarev V.M., Tutelyan A.V., Lihvantsev VV, Grebenchi-kov OA. The prognostic value of the content of monocytic myeloid immunosuppressive cells in sepsis.. Infektsionnye bolezni. 2015; 13 (4): 72-74 [In Russ.]

43. GaponovM.A., Hajdukov S.V, Pisarev V.M., Grebenchikov O.A., Gaponov A.M., Tutelyan A.V. Subpopulation heterogeneity of myeloid immunosuppressive cells in patients with septic conditions. Rossijskij immunologicheskij zhurnal. 2015; 9 (18): 11-14 [In Russ.]

44. Patel J.J., Rosenthal M.D., McClave S.A., Martindale R.G. Tempering the Clinical Effects of Early Myeloid-derived Suppressor Cell Expansion in Severe Sepsis and Septic Shock. American Journal of Respiratory and Critical Care Medicine, 2018; 197 (5): 677-678. DOI: 10.1164/rccm.201708-1701le

45. Brudecki L.,Ferguson DA., McCall C.E.,El Gazzar, M. Myeloid-derived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. Infect. Immun. 2012, 80, 2026-2034 PMID: 22451518 PMCID: PMC3370575 DOI: 10.1128/IAI.00239-12

46. Waeckel L., Venet F., Gossez M., Monard C., Rimmele T., Monneret G. Delayed persistence of elevated monocytic MDSC associates with deleterious outcomes in septic shock: a retrospective cohort study. Crit Care. 2020; 24 (1): 132. DOI: 10.1186/s13054-020-02857-y

47. Mathias B., Delmas A.L., Ozrazgat-Baslanti T., Vanzan, E.L., Szpila B.E., Mohr A.M., Moore F.A., Brakenridge S.C., Brumback B.A., Molda-wer L.L., Efron P.A., the Sepsis, Critical Illness Research Center Investigators. Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock. Ann. Surg. 2017; 265: 827-834 PMID: 27163951 PMCID: PMC5102824 DOI: 10.1097/SLA.0000000000001783

48. Albertsmeier M., Prix N.J., Winter H., Bazhin A., Werner J., Angele M.K. Monocyte-Dependent Suppression of T-Cell Function in Postoperative Patients and Abdominal Sepsis. Shock. 2017; 48 (6): 651-656. DOI: 10.1097/SHK.0000000000000924

49. Pisarev V.M., ChumachenkoA.G., GaponovA.M., TyurinI.N., Cherpa-kov R., Tutelyan A.V. Promoter polymorphism in AQP5 gene associates with increased survival and decreased numbers of monocytic MDSC in abdominal sepsis (by SEPSIS-3). Shock, 2018. 49: S.1. p.27. https://journals.lww.com/shockjournal/pages/default.aspx

50. De Waele J., Lipman J., Sakr Y., Marshall J.C., Vanhems P.,Barrera Groba C., Leone M., Vincent J-L. for the EPIC IIInvestigators. Abdominal infections in the intensive care unit: characteristics, treatment and determinants of outcome. BMC Infect Dis. 2014; 14: 420. 2014. DOI: 10.1186/1471-2334-14-420

51. JawaR.S, QuistE., Boyer C.W, Shostrom V.K, MercerD.W. Mesenteric ischemia-reperfusion injury up-regulates certain CC, CXC, and XC chemokines and results in multi-organ injury in a time-dependent manner. Eur Cytokine Netw. 2013; 24 (4): 148-156. DOI: 10.1684/ecn.2014.0345

52. Rump K., Siffert W., Peters J., Adamzik M. The Transcription Factor NMP4 Binds to the AQP5 Promoter and Is a Novel Transcriptional Regulator of the AQP5 Gene. DNA Cell Biol. 2016; 35 (7): 322-327. DOI: 10.1089/dna.2015.3110

53. Nagaraj S., Nelson A., Youn J.I., Cheng P., Quiceno D., Gabrilovich D.I. Antigen-specific CD4 (+)T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res. 2012; 72 (4): 928-938. DOI: 10.1158/0008-5472

54. Hou Y., Feng Q., Xu M., Li G-S., Xue-Na Liu X-N., Sheng Z., Zhou H., Ma J., Wei Y., Sun Y-X., Yu Y-Y., Qiu J-H., Shao L-L., Liu X-G., Hou M., Peng J. High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia. Blood. 2016; 127 (12): 1587-1597. DOI: 10.1182/blood-2015-10-674531

55. Hanisch E., Brause R., Paetz J., Arlt B. Review of a large clinical series: predicting death for patients with abdominal septic shock. J Intensive Care Med. 2011; 26 (1): 27-33 PMID: 21262751 DOI: 10.1177/0885066610384058

56. ester M.A., Reitsma J.B. Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy. BMC Surg. 2011; 11: 38 PMID: 22196238 PMCID: PMC3268736 DOI: 10.1186/1471-2482-11-38

57. Chen Y.X., Li C.S. Risk stratification and prognostic performance of the predisposition, infection, response, and organ dysfunction (PIRO)scoring system in septic patients in the emergency department: a cohort study. Crit Care. 2014; 18 (2): R74 PMID: 24739219 PMCID: PMC4056311 DOI: 10.1186/cc13832

58. PisarevV.M., ChumachenkoA.G., TyurinI.N., CherpakovR., Tutelyan A.V. Prognostic value of a genetic polymorphism of AQP5 in sepsis depends on a source of infection. 39th International Symposium on Intensive Care and Emergency Medicine. Critical Care 2019, 23 (Suppl 2): 82. https: //ccforum.biomedcentral.com/articles/supple-ments/volume-23-supplement-2.