Genome-Wide Association Study of Tacrolimus Dose in Pediatric Solid Organ Transplant Recipients in the CNTRP POSITIVE Study
1The Hospital for Sick Children, Toronto, Canada
2Winnipeg Children's Hospital, Winnipeg, Canada
3BC Children's Hospital, Vancouver, Canada
4Alberta Children's Hospital, Calgary, Canada
5CHU Ste-Justine, Montreal, Canada
6University Health Network, Toronto, Canada
7Stollery Children's Hospital, Edmonton, Canada
8Montreal Children's Hospital, Montreal, Canada.
Meeting: 2018 American Transplant Congress
Abstract number: A445
Keywords: Calcineurin, Dosage, Genomics, Immunosuppression
Session Information
Session Name: Poster Session A: Tolerance: Clinical Studies
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
PURPOSE: There are significant challenges in achieving therapeutic tacrolimus (Tac) concentrations after transplant. We explored variants associated with tacrolimus dose requirements in pediatric solid organ transplantation (SOT).
METHODS: In a multicentre prospective cohort study, pediatric SOT recipients were genotyped using the Axiom SNP array.490,311 variants with minor allele frequency > 0.01 and meeting Hardy Weinberg equilibrium were included in the analysis. SNP based linear regression model was used to detect association between recipient and donor genotype and Tac dose requirements for one year post transplant.
RESULTS: 455 SOT recipients (151 heart, 161 liver, 133 kidney, 10 lung) and 146 matched donors were analyzed. Organ type, age at transplant, hemoglobin, alanine transaminase, albumin and concomitant medications were significantly associated with Tac dose. 6 SNPs were associated with Tac dose at a genome-wide significance level (adjusted p<0.05) of which 5 were mapped to the CYP3A5 gene. In addition, 17 SNPs were associated with Tac dose at a p value cut-off of 10-5 and mapped to CYP3A4, CYP3A5, CYP3A7, CYP3A7-CYP3AP1 and ZKSCAN5 genes. Tac dose requirement increased by 0.004 mg/kg for every additional SNP (p=0.014) at 7 days post-transplant and this effect persisted throughout the follow up period. There was no association of donor genotype with Tac dose.
CONCLUSION: SNPs in CYP3A5 and other CYP genes were significantly associated with Tac dose requirements. Current clinical guidelines for Tac genotype-guided dosing only include adjustment of starting dose by CYP3A5 rs776746 SNP. Our findings highlight the need to include additional SNPs as well as organ type, age, and biochemical factors into a individualized dose prediction algorithm.
CITATION INFORMATION: Min S., Papaz T., Blydt-Hansen T., Lee O., Allen U., Birk P., Grasemann H., Hamiwka L., Litalien C., Ng V., Parekh R., Tinckam K., Urschel S., Foster B., Mital S. Genome-Wide Association Study of Tacrolimus Dose in Pediatric Solid Organ Transplant Recipients in the CNTRP POSITIVE Study Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Min S, Papaz T, Blydt-Hansen T, Lee O, Allen U, Birk P, Grasemann H, Hamiwka L, Litalien C, Ng V, Parekh R, Tinckam K, Urschel S, Foster B, Mital S. Genome-Wide Association Study of Tacrolimus Dose in Pediatric Solid Organ Transplant Recipients in the CNTRP POSITIVE Study [abstract]. https://atcmeetingabstracts.com/abstract/genome-wide-association-study-of-tacrolimus-dose-in-pediatric-solid-organ-transplant-recipients-in-the-cntrp-positive-study/. Accessed May 13, 2025.« Back to 2018 American Transplant Congress