Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing

Dorr, Casey; Wu, Baolin; Muthusamy, Amutha; Schladt, David; Abrahante, Juan E.; Guan, Weihua; Mannon, Roslyn B.; Matas, Arthur J.; Oetting, William S.; Jacobson, Pamala A.; Israni, Ajay K.

doi:10.1038/s41397-018-0063-z

Cited by 15 publications

(18 citation statements)

References 82 publications

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“…However, importantly, approximately 40% of patients were diagnosed with aGVHD, which is consistent with previously reported estimates (35-50% aGVHD incidence among allogeneic HSCT patients) [45,46]. Therefore, a future direction of this work will be to evaluate SNPs in additional candidate genes of interest (e.g., POR*28 and CYB5R2) that could impact tacrolimus PK/PD [34,47,48].…”

Section: Discussionsupporting

confidence: 88%

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

Zhu

Patel

Miller

et al. 2020

IJMS

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Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

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Section: Discussionsupporting

confidence: 88%

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

Zhu

Patel

Miller

et al. 2020

IJMS

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“…We ob-served CYP3A4*22 in our European American, African American, and Native American ancestry recipients (MAF ≤ 0.05), whereas it was not found in our Asian American group, which is consistent with other published data. Numerous variants in the CYB5R2 gene were associated with extreme tacrolimus troughs in African Americans, including the potential lossof-function variant rs61733057 72. The lack of effect in our other populations may be due to its low AF and it will require a larger sample size to identify the effect.…”

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confidence: 89%

“…Numerous variants in the CYB5R2 gene were associated with extreme tacrolimus troughs in African Americans, including the potential lossof-function variant rs61733057. 72 We hypothesized that genetic variants beyond CYP3A5*3 may also explain additional tacrolimus trough variability in Asian American and Native American transplant recipients. Therefore, we conducted an exploratory gene-wide association analysis in the CYP3A4 and CYP3A5 genes and found no variants that were significantly associated at a gene-wide significance level; however, several variants were suggestive and worthy of further investigation.…”

Section: Native Americans Asian Americansmentioning

confidence: 99%

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

Mohamed

Schladt

Guan

et al. 2019

American Journal of Transplantation

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Tacrolimus trough and dose requirements vary dramatically between individuals ofEuropean and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10 −5 -8.8 × 10 −6 ) and

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“…CYP3A5 is highly polymorphic with signi cant inter-individual variation in the enzyme activity contributing to the absorption, metabolism and tissue distribution of drugs ( 22) (23). Homozygous carriers (*3/*3 or CC) of this variant lack functional CYP3A5 protein because of the frame shift mutation and truncation of the translated protein.…”

Section: Discussionmentioning

confidence: 99%

The Design and Implementation of a Novel Pharmacogenomic Assay to Genotype the CYP3A53 (rs776746) and CYP3A51E (rs4646453) Genetic Variants

Sameem

Noordeen

Somasundaram

et al. 2023

Preprint

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Background The cytochrome P450 3A5 CYP3A5 enzymes are important for metabolizing the drug tacrilomus, an immunosuppressive agent used in solid organ transplantation. Genetic variants in the CYP3A5 gene are significant determinants of tacrolimus efficacy. The present study was undertaken to design a novel pharmacogenetic assay (Single step-Tetra Arms Polymerase Chain Reaction) to study the distribution of the CYP3A5*3 (rs776746) and CYP3A5*1E (rs4646453) variants by genotyping a cohort of healthy individuals.Results The CYP3A5*3 variant was the most frequent allele detected at 82% and the CYP3A5*1E C allele was found in 66.5% of the samples. The allele frequencies of CYP3A5*3 (rs776746) and CYP3A5*1E (rs4646453) were statistically significant (p < 0.05) when compared with the Asian ethnic group. The observed CYP3A5 genotype frequency distributions for the CYP3A5*3 (rs776746) and CYP3A5*1E (rs4646453) variants in the study population were consistent with the Hardy–Weinberg equilibrium (P > 0.05). For the CYP3A5*3 variant the frequency of the T/T [extensive metabolizer], C/T [intermediate metabolizer] and C/C [poor metabolizer] variants were 4%, 28% and 68% respectively. Furthermore, a significant linkage disequilibrium among rs4646453 and rs776746 was identified (p < 0.05).Conclusions A novel tetra-primer ARMS PCR assay was successfully designed and implemented for genotyping of the CYP3A5 variants CYP3A5*3 (rs776746) and CYP3A5*1E (rs4646453). These pharmacogenomic assays could be offered to patients to predict their response to tacrolimus.

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Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing

Cited by 15 publications

References 82 publications

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

The Design and Implementation of a Novel Pharmacogenomic Assay to Genotype the CYP3A53 (rs776746) and CYP3A51E (rs4646453) Genetic Variants

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