title: A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation.
abstract: Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor β (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Budding
authors.affiliation: Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: van de Graaf
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kardol-Hoefnagel
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|Departments of Rheumatology and Dermatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J C A
authors.initials: JC
authors.lastname: Broen
authors.affiliation: Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Kwakkel-van Erp
authors.affiliation: Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: E-J D
authors.initials: EJ
authors.lastname: Oudijk
authors.affiliation: Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: D A
authors.initials: DA
authors.lastname: van Kessel
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|Departments of Rheumatology and Dermatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H G
authors.initials: HG
authors.lastname: Otten
mesh_terms: D000293:Adolescent; D000328:Adult; D018957:CD59 Antigens / Q000235:genetics*; D003167:Complement Activation; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology; D006085:Graft Survival; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011183:Postoperative Complications; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D014019:Tissue Donors; D055815:Young Adult
chemical_list: D018957:CD59 Antigens; C051590:CD59 protein, human
keywords: basic (laboratory) research/science; bronchiolitis obliterans (BOS); complement biology; immunobiology; lung transplantation/pulmonology; translational research/science