Association of four DNA polymorphisms with acute rejection after kidney transplantation.
Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50-6.67]; P=0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42-8.09]; P=0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52-14.55]; P=0.007) and twice as likely in patients with at least one A allele of TNF-alpha G-308A (OR: 2.18, 95% CI [1.08-4.41]; P=0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.
Grinyó
Josep
J
Department of Nephrology, Hospital de Bellvitge, University of Barcelona, Barcelona, Spain. jgrinyo@csub.scs.es
Vanrenterghem
Yves
Y
Nashan
Björn
B
Vincenti
Flavio
F
Ekberg
Henrik
H
Lindpaintner
Klaus
K
Rashford
Michelle
M
Nasmyth-Miller
Clare
C
Voulgari
Athina
A
Spleiss
Olivia
O
Truman
Matthew
M
Essioux
Laurent
L
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human