title: Cytokine gene polymorphisms and acute human liver graft rejection.
abstract: Interindividual differences exist in the capacity to produce cytokines. It has been reported that levels of in vitro cytokine production measured after stimulated cell culture are associated with polymorphisms in cytokine genes. Moreover, a correlation between heart, kidney, liver, and lung graft rejection or survival with cytokine gene polymorphisms has been described. In the present study, we analyzed the association of gene polymorphisms in T helper subtype 1 (T(H)1-), T(H)2-, and regulatory-type cytokines with human liver allograft rejection. Patients who received a primary liver graft from 1992 onward and were seen at the transplant outpatient clinic since then were included on this study (n = 89). Patients were HLA typed routinely. Biopsy-proven acute rejection occurred in 41 of 89 patients. After informed consent, blood was collected and DNA was obtained. Using amplification-refractory mutation system polymerase chain reaction, the following cytokine gene polymorphisms were determined: IL-2+166, IL-2-330, IL-15+13689, IL-15-80, TNF-A-308, TNFd3, IFN-G+874 (T(H)1-type cytokines), IL-4+33, IL-4-590, IL-6-174, IL-10-592, IL-10-819, IL-10-1082, IL-13+2043, IL-13-1055 (T(H)2 type cytokines), TGF-B1+869, and TGF-B1+915 (regulatory-type cytokines). Univariate analysis showed that polymorphisms of IL-10-1082, TGF-B1+869, and HLA-DR6 were significantly related to liver graft rejection. Multiple logistic regression analysis was used to assess which variables remained significantly predictive of acute rejection. Multivariate analysis showed that TGF-B1+869 and HLA-DR6 were independently associated with the occurrence of acute rejection. These findings suggest a role for the regulatory-type cytokine transforming growth factor-beta1 in human liver graft rejection.
authors.affiliation: Department of Surgery, Liver Transplant Research Unit Rotterdam, Erasmus Medical Centre Rotterdam, The Netherlands.
authors.forename: Michiel C
authors.initials: MC
authors.lastname: Warlé
authors.forename: Ayar
authors.initials: A
authors.lastname: Farhan
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Wim C j
authors.initials: WC
authors.lastname: Hop
authors.forename: Chris
authors.initials: C
authors.lastname: Perrey
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: Marcel
authors.initials: M
authors.lastname: Kap
authors.forename: Sjoerd
authors.initials: S
authors.lastname: de Rave
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: Vera
authors.initials: V
authors.lastname: Pravica
authors.forename: Ian V
authors.initials: IV
authors.lastname: Hutchinson
authors.forename: Gerda J
authors.initials: GJ
authors.lastname: Bouma
mesh_terms: D000328:Adult; D016207:Cytokines / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006084:Graft Rejection / Q000235:genetics*; D015808:HLA-DR6 Antigen / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D016031:Liver Transplantation / Q000276:immunology*; D016015:Logistic Models; D008233:Lymphotoxin-alpha / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000276:immunology / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D015808:HLA-DR6 Antigen; D018793:Interleukin-13; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma