{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T23:05:57Z","timestamp":1776294357966,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006254","name":"Ruhr-Universit\u00e4t Bochum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006254","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The aquaporin 5 (<jats:italic>AQP5)<\/jats:italic> \u22121364A\/C promoter single nucleotide polymorphism affects key mechanisms of inflammation and immune cell migration. Thus, it could be involved in the pathogenesis of cytomegalovirus infection. Accordingly, we tested the hypothesis that the <jats:italic>AQP5<\/jats:italic> promoter \u22121364A\/C polymorphism is associated with the risk of cytomegalovirus infection in kidney transplantation recipients.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We included 259 adult patients who received a kidney transplant from 2007 and 2014 in this observational study. Patients were genotyped for the <jats:italic>AQP5<\/jats:italic> promoter \u22121364A\/C single nucleotide polymorphism and followed up for 12 months after transplantation. Kaplan\u2013Meier plots and multivariable proportional hazard analyses were used to evaluate the relationship between genotypes and the incidence of cytomegalovirus infection.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The incidences of cytomegalovirus infection within 12 months after kidney transplantation were 22.9% for the AA genotypes (43\/188) and 42.3% for the AC\/CC genotypes (30\/71; <jats:italic>p<\/jats:italic> = 0.002). Furthermore, multivariable COX regression revealed the C-allele of the <jats:italic>AQP5<\/jats:italic> \u22121364A\/C polymorphism to be a strong and independent risk factor for cytomegalovirus infection. In this analysis, AC\/CC subjects demonstrated a more than 2-fold increased risk for cytomegalovirus infection within the first year after kidney transplantation (hazard ratio: 2.28; 95% CI: 1.40\u20133.73; <jats:italic>p<\/jats:italic> = 0.001) compared to that in individuals with homozygous AA genotypes.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> With respect to opportunistic cytomegalovirus infections (attributable to immunosuppression after kidney transplantation), the C-allele of the <jats:italic>AQP5<\/jats:italic> \u22121364A\/C promoter polymorphism is independently associated with an increased 12-months infection risk. These findings emphasize the importance of genetic variations as additional risk factors of cytomegalovirus infection after solid organ transplantations and might also facilitate the discovery of novel therapeutic targets.<\/jats:p>","DOI":"10.3389\/fimmu.2019.02871","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T04:43:56Z","timestamp":1575521036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["The Aquaporin 5 \u22121364A\/C Promoter Polymorphism Is Associated With Cytomegalovirus Infection Risk in Kidney Transplant Recipients"],"prefix":"10.3389","volume":"10","author":[{"given":"Tim","family":"Rahmel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hartmuth","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Frisenda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Rump","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bj\u00f6rn","family":"Koos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Schenker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Viebahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Adamzik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Bergmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2019,12,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1056\/NEJM199806113382407","article-title":"Infection in organ-transplant recipients","volume":"338","author":"Fishman","year":"1998","journal-title":"N Engl J Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1097\/TP.0000000000002191","article-title":"The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation","volume":"102","author":"Kotton","year":"2018","journal-title":"Transplantation."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1111\/tri.12629","article-title":"Cytomegalovirus post kidney transplantation: prophylaxis versus pre-emptive therapy?","volume":"28","author":"Fehr","year":"2015","journal-title":"Transpl Int."},{"key":"B4","first-page":"337","article-title":"Look-up survival tables for living-donor renal transplants: OPTN\/UNOS data 1995\u20132002","volume":"5","author":"Gjertson","year":"2003","journal-title":"Clin Transpl."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1111\/ajt.13107","article-title":"Association between individual and combined SNPs in genes related to innate immunity and incidence of CMV infection in seropositive kidney transplant recipients","volume":"15","author":"Fernandez-Ruiz","year":"2015","journal-title":"Am J Transplant."},{"key":"B6","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1007\/s00395-008-0750-z","article-title":"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","volume":"103","author":"Adamzik","year":"2008","journal-title":"Basic Res Cardiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1007\/s00424-007-0357-5","article-title":"Aquaporins and cell migration","volume":"456","author":"Papadopoulos","year":"2008","journal-title":"Pflugers Arch."},{"key":"B8","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1186\/s12967-016-1079-2","article-title":"AQP5-1364A\/C polymorphism and the AQP5 expression influence sepsis survival and immune cell migration: a prospective laboratory and patient study","volume":"14","author":"Rump","year":"2016","journal-title":"J Transl Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"18657","DOI":"10.1074\/jbc.M100322200","article-title":"Tumor necrosis factor-alpha inhibits aquaporin 5 expression in mouse lung epithelial cells","volume":"276","author":"Towne","year":"2001","journal-title":"J Biol Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1097\/ALN.0000000000002560","article-title":"Aquaporin 5-1364A\/C promoter polymorphism is associated with pulmonary inflammation and survival in acute respiratory distress syndrome","volume":"130","author":"Rahmel","year":"2019","journal-title":"Anesthesiology."},{"key":"B11","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1097\/ALN.0b013e31820ca911","article-title":"Aquaporin 5 gene promoter-1364A\/C polymorphism associated with 30-day survival in severe sepsis","volume":"114","author":"Adamzik","year":"2011","journal-title":"Anesthesiology."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e0208582","DOI":"10.1371\/journal.pone.0208582","article-title":"The aquaporin 5-1364A\/C promoter polymorphism impacts on resolution of acute kidney injury in pneumonia evoked ARDS","volume":"13","author":"Rahmel","year":"2018","journal-title":"PLoS ONE."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1097\/TA.0b013e3182128528","article-title":"Deletion of aquaporin 5 aggravates acute lung injury induced by Pseudomonas aeruginosa","volume":"71","author":"Zhang","year":"2011","journal-title":"J Trauma."},{"key":"B14","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1093\/cid\/ciw668","article-title":"Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials","volume":"64","author":"Ljungman","year":"2017","journal-title":"Clin Infect Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1111\/j.1600-6143.2004.00382.x","article-title":"Efficacy and safety of valganciclovir vs","volume":"4","author":"Paya","year":"2004","journal-title":"Am J Transplant."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1111\/j.1600-6143.2010.03074.x","article-title":"The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients","volume":"10","author":"Humar","year":"2010","journal-title":"Am J Transplant."},{"key":"B17","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1002\/jmv.23539","article-title":"High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy","volume":"85","author":"Harvala","year":"2013","journal-title":"J Med Virol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1086\/528718","article-title":"Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation","volume":"46","author":"Arthurs","year":"2008","journal-title":"Clin Infect Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1097\/TP.0b013e31822fa4b7","article-title":"Clinical utility of molecular surveillance for cytomegalovirus after antiviral prophylaxis in high-risk solid organ transplant recipients","volume":"92","author":"Lisboa","year":"2011","journal-title":"Transplantation."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2468","DOI":"10.1111\/ajt.14347","article-title":"An interventional study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation","volume":"17","author":"Kumar","year":"2017","journal-title":"Am J Transplant."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e472","DOI":"10.1097\/TP.0000000000002421","article-title":"CMV-specific cell-mediated immunity at 3-month prophylaxis withdrawal discriminates D+\/R+ kidney transplants at risk of late-onset CMV infection regardless the type of induction therapy","volume":"102","author":"Jarque","year":"2018","journal-title":"Transplantation."},{"key":"B22","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s13578-018-0211-9","article-title":"Function of aquaporins in sepsis: a systematic review","volume":"8","author":"Rump","year":"2018","journal-title":"Cell Biosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3389\/fphys.2018.00101","article-title":"New perspectives on the potential role of aquaporins (AQPs) in the physiology of inflammation","volume":"9","author":"Meli","year":"2018","journal-title":"Front Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"S11","DOI":"10.1097\/TP.0000000000001095","article-title":"The immunology of posttransplant CMV infection: potential effect of CMV immunoglobulins on distinct components of the immune response to CMV","volume":"100","author":"Carbone","year":"2016","journal-title":"Transplantation."},{"key":"B25","doi-asserted-by":"publisher","first-page":"7094","DOI":"10.4049\/jimmunol.177.10.7094","article-title":"Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells","volume":"177","author":"Boehme","year":"2006","journal-title":"J Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.chom.2014.03.003","article-title":"Neutrophils recruited by IL-22 in peripheral tissues function as TRAIL-dependent antiviral effectors against MCMV","volume":"15","author":"Stacey","year":"2014","journal-title":"Cell Host Microbe."},{"key":"B27","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1084\/jem.20050882","article-title":"Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects","volume":"202","author":"Sylwester","year":"2005","journal-title":"J Exp Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.4049\/jimmunol.173.3.1834","article-title":"Emergence of a CD4+CD28\u2212 granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection","volume":"173","author":"van Leeuwen","year":"2004","journal-title":"J Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1097\/00007890-200105150-00018","article-title":"Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation","volume":"71","author":"Sester","year":"2001","journal-title":"Transplantation."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1161\/CIRCULATIONAHA.105.607549","article-title":"T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease","volume":"114","author":"Tu","year":"2006","journal-title":"Circulation."},{"key":"B31","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/1479-5876-6-29","article-title":"Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients","volume":"6","author":"Egli","year":"2008","journal-title":"J Transl Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1165\/rcmb.2005-0456OC","article-title":"Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice","volume":"36","author":"Karras","year":"2007","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1111\/j.1582-4934.2010.01103.x","article-title":"Role of aquaporin 5 in antigen-induced airway inflammation and mucous hyperproduction in mice","volume":"15","author":"Shen","year":"2011","journal-title":"J Cell Mol Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.resp.2007.12.007","article-title":"Upregulation of AQP3 and AQP5 induced by dexamethasone and ambroxol in A549 cells","volume":"161","author":"Ben","year":"2008","journal-title":"Respir Physiol Neurobiol."}],"updated-by":[{"DOI":"10.3389\/fimmu.2021.739229","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2019.02871\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T10:15:04Z","timestamp":1628763304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2019.02871\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,5]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2019.02871"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2019.02871","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fimmu.2021.739229","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,5]]},"article-number":"2871"}}