OBJECTIVES: Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S-methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. METHODS: We genotyped TPMT in 264 pediatric HT recipients for the presence of the TPMT*2, TPMT*3A, and TPMT*3C variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups. RESULTS: TPMT variants were identified in 26 pediatric HT recipients (10%): *3A (n = 17), *3C (n = 8), and *2 (n = 1). Among those with a variant allele, *3C was most prevalent in black patients (4 of 5) and *3A most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 ± 1.3; range, 0-6 versus 0.5 ± 0.9; range, 0-3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group. CONCLUSIONS: In this multicenter cohort of pediatric HT recipients, the prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.
OBJECTIVES: Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S-methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. METHODS: We genotyped TPMT in 264 pediatric HT recipients for the presence of the TPMT*2, TPMT*3A, and TPMT*3C variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups. RESULTS:TPMT variants were identified in 26 pediatric HT recipients (10%): *3A (n = 17), *3C (n = 8), and *2 (n = 1). Among those with a variant allele, *3C was most prevalent in black patients (4 of 5) and *3A most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 ± 1.3; range, 0-6 versus 0.5 ± 0.9; range, 0-3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group. CONCLUSIONS: In this multicenter cohort of pediatric HT recipients, the prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.
Authors: Zuzana Zelinkova; Luc J J Derijks; Pieter C F Stokkers; Esther W M Vogels; Antoine H C van Kampen; Wouter L Curvers; Danny Cohn; Sander J H van Deventer; Daniël W Hommes Journal: Clin Gastroenterol Hepatol Date: 2006-01 Impact factor: 11.382
Authors: Daphne T Hsu; David C Naftel; Steven A Webber; William R Morrow; Charles E Canter; Richard E Chinnock; Mary Lynne Clark; James K Kirklin Journal: Congenit Heart Dis Date: 2006-05 Impact factor: 2.007
Authors: Anne I Dipchand; Leah B Edwards; Anna Y Kucheryavaya; Christian Benden; Fabienne Dobbels; Bronwyn J Levvey; Lars H Lund; Bruno Meiser; Roger D Yusen; Josef Stehlik Journal: J Heart Lung Transplant Date: 2014-08-14 Impact factor: 10.247
Authors: C R Yates; E Y Krynetski; T Loennechen; M Y Fessing; H L Tai; C H Pui; M V Relling; W E Evans Journal: Ann Intern Med Date: 1997-04-15 Impact factor: 25.391
Authors: L Sebbag; P Boucher; P Davelu; P Boissonnat; G Champsaur; J Ninet; G Dureau; J F Obadia; J J Vallon; J Delaye Journal: Transplantation Date: 2000-04-15 Impact factor: 4.939
Authors: H L Tai; E Y Krynetski; C R Yates; T Loennechen; M Y Fessing; N F Krynetskaia; W E Evans Journal: Am J Hum Genet Date: 1996-04 Impact factor: 11.025
Authors: Margarete A Fabre; Des C Jones; Mike Bunce; Peter J Morris; Peter J Friend; Ken I Welsh; Sara E Marshall Journal: Transpl Int Date: 2004-09-02 Impact factor: 3.782