title: Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients.
abstract: There have been many reports showing significant associations between recipient genetic variants and allograft outcomes, including acute rejection and graft failure, but less is known about the contribution of the donor genotype. We analyzed 37 single-nucleotide polymorphisms (SNPs) within the toll-like receptor 4 (TLR4) gene from deceased donor liver allografts transplanted into 738 recipients to determine their effects on liver graft failure (LGF). Two SNPs exhibited a significant association with LGF after adjustments for donor race and recipient race and corrections for multiple test comparisons: rs11536865 [hazard ratio (HR) = 2.5, P = 0.0003] and rs5030717 (HR = 1.67, P = 0.0008). An additional SNP, rs913930, exhibited a significant association in Caucasian donors (HR = 1.62, P = 0.0006), and 2 SNPs exhibited a suggestive association in African American donors: rs11536865 (HR = 2.45, P = 0.002) and rs5030717 (HR = 2.32, P = 0.002). Additionally, the liver donor risk index (HR = 2.56, 95% confidence interval = 1.54-4.26, P = 0.0003) and the recipient hepatitis C virus (HCV) status (HR = 1.53, 95% confidence interval = 1.04-2.24, P = 0.032) increased the risk of all-cause LGF in a Cox proportional hazards model adjusted for recipient race. Donor polymorphisms in TLR4 could be important factors in modulating TLR4 activity and, therefore, affect the risk of graft loss. Additionally, there is a suggestion of an interaction between polymorphisms within TLR4 and the HCV status.
authors.affiliation: College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA. oetti001@umn.edu
authors.forename: William S
authors.initials: WS
authors.lastname: Oetting
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.forename: David P
authors.initials: DP
authors.lastname: Schladt
authors.forename: Robert E
authors.initials: RE
authors.lastname: Leduc
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
authors.forename: Srinath
authors.initials: S
authors.lastname: Chinnakotla
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröppel
authors.forename: Barbara T
authors.initials: BT
authors.lastname: Murphy
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Israni
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D005260:Female; D006085:Graft Survival / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D016014:Linear Models; D016031:Liver Transplantation / Q000009:adverse effects* / Q000208:ethnology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D014019:Tissue Donors; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4