Genetic Differences in Native Americans and Tacrolimus Dosing After Kidney Transplantation

Chakkera, Harini A.; Chang, Youngil; Bodner, J.; Behmen, Senaida; Heilman, Raymond L.; Reddy, K. S.; Mulligan, David C.; Moss, Adyr; Khamash, Hasan; Katariya, Nitin; Hewitt, Winston R.; Pitta, T.L.; Frassetto, Lynda

doi:10.1016/j.transproceed.2012.10.023

Cited by 18 publications

(18 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The clinical implications of this low LD in the CYP3A locus in the CSKT is unclear, but because a significant portion of CSKT individuals may carry a haplotype consisting of a putative reduced function CYP3A4*1G and nonfunctional CYP3A5*3 , the preponderance of clinical data suggests that this combination is associated with lower CYP3A metabolic activity. While very limited data exist regarding genetic variation and ensuing differences in drug response in AI/AN populations, our findings may help explain the lower than average required dose to maintain stable tacrolimus levels in American Indians compared to European populations, although CYP3A4*1G allele frequencies were not reported [81, 82]. …”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics in American Indian populations

Fohner

Muzquiz

Austin

et al. 2013

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Objectives Cytochrome P450 enzymes play a dominant role in drug elimination and variation in these genes is a major source of interindividual differences in drug response. Little is known, however, about pharmacogenetic variation in American Indian and Alaska Native (AI/AN) populations. We have developed a partnership with the Confederated Salish and Kootenai Tribes (CSKT) in northwestern Montana to address this knowledge gap. Methods We resequenced CYP2D6 in 187 CSKT subjects and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT subjects. Results We identified 67 variants in CYP2D6, 15 in CYP3A4, 10 in CYP3A5, and 41 in CYP2C9. The most common CYP2D6 alleles were CYP2D6*4 and *41 (20.86 and 11.23%, respectively). CYP2D6*3, *5, *6, *9, *10, *17, *28, *33, *35, *49, *1xN, *2xN, and *4xN frequencies were less than 2%. CYP3A5*3, CYP3A4*1G, and *1B were detected with frequencies of 92.47, 26.81, and 2.20%, respectively. Allelic variation in CYP2C9 was low: CYP2C9*2 (5.17%) and *3 (2.69%). In general, allele frequencies in CYP2D6, CYP2C9 and CYP3A5 were similar to those observed in European Americans. There was, however, a marked divergence in CYP3A4 for the CYP3A4*1G allele. We also observed low levels of linkage between CYP3A4*1G and CYP3A5*1 in the CSKT. The combination of nonfunctional CYP3A5*3 and putative reduced function CYP3A4*1G alleles may predict diminished clearance of CYP3A substrates. Conclusions These results highlight the importance of conducting pharmacogenomic research in AI/AN populations and demonstrate that extrapolation from other populations is not appropriate. This information could help to optimize drug therapy for the CSKT population.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics in American Indian populations

Fohner

Muzquiz

Austin

et al. 2013

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…2 Tacrolimus has high inter-individual pharmacokinetic variability. [4][5][6] Little is known about tacrolimus trough and dose requirements in other populations, although some data suggest that Native American transplant recipients require lower tacrolimus doses possibly due to decreased oral clearance, 7,8 others found that there were no difference between tacrolimus doses between European Americans and Native Americans. [4][5][6] Little is known about tacrolimus trough and dose requirements in other populations, although some data suggest that Native American transplant recipients require lower tacrolimus doses possibly due to decreased oral clearance, 7,8 others found that there were no difference between tacrolimus doses between European Americans and Native Americans.…”

Section: Introductionmentioning

confidence: 99%

“…3 It is well known that tacrolimus troughs and dose requirements vary between recipients of European and African ancestry, African Americans have significantly lower tacrolimus trough concentrations in comparison with European Americans and require higher tacrolimus doses to achieve similar trough concentrations. [4][5][6] Little is known about tacrolimus trough and dose requirements in other populations, although some data suggest that Native American transplant recipients require lower tacrolimus doses possibly due to decreased oral clearance, 7,8 others found that there were no difference between tacrolimus doses between European Americans and Native Americans. 9 Cytochromes P450 (CYP) 3A4 and 5 are the main drug metabolizing enzymes for tacrolimus and the genes encoding for these proteins contain important genetic variants.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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

show abstract

“…This may be due to, in part, highly variable conditioning regimens, transplantation-related renal and hepatic toxicity, and disruption of the gastrointestinal tract because of mucositis. The impact of the patient’s race or ethnicity on achieving therapeutic tacrolimus levels has been studied in patients receiving solid organ transplants [2,4,18,19], and is thought to be related, in part, to the expression of cytochrome p450 3A5 and p-glycoprotein in different patient cohorts [2]. To our knowledge, this is the first study that demonstrated the impact of ethnicity on achieving therapeutic levels of PO tacrolimus in pediatric alloHCT recipients.…”

Section: Discussionmentioning

confidence: 99%

“…tacrolimus also took the above median number of days to achieve tacrolimus trough concentration on oral tacrolimus. This observation is suggestive of faster clearance of tacrolimus in these patients, which may be related to genetic polymorphisms in drug metabolism [2,18–20]. …”

Section: Discussionmentioning

confidence: 99%

Risk Factors for Subtherapeutic Tacrolimus Levels after Conversion from Continuous Intravenous Infusion to Oral in Children after Allogeneic Hematopoietic Cell Transplantation

Kolb

Offer

Jin

et al. 2016

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

Tacrolimus (FK506) is a calcineurin inhibitor and is an essential component of many immunosuppressive regimens. The oral bioavailability of tacrolimus may be affected by many factors, including patient age and gender, as well as by drug-drug interactions or genetic polymorphisms in drug metabolism. The dosing recommendations for pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients have been derived from tacrolimus use in adult solid-organ transplantation patients. Data describing the impact of conversion of i.v. tacrolimus to oral on the incidence of acute graft-versus-host disease (aGVHD) are limited in children after alloHCT. In this study, we describe the incidence of grades II to IV aGVHD after conversion from i.v. tacrolimus to oral tacrolimus and study the clinical factors associated with delayed achievement of therapeutic blood levels. In this retrospective analysis, 68 pediatric patients (median age, 6.7 years; range, .25 to 22 years), underwent alloHCT for malignant and nonmalignant diseases and received tacrolimus and mycophenolate mofetil for aGVHD prophylaxis. Among all patients, the median number of days to achieve therapeutic tacrolimus trough concentration (10 ng/mL to 20 ng/mL) was 7 days (range, 0 to 37 days). Twenty-two patients developed grades II to IV aGVHD and the cumulative incidence of grades II to IV aGVHD in all patients was 32.4% (standard error, .06). On multivariate analysis ethnicity (white versus others: odds ratio [OR], −4.5; 95% confidence interval [95% CI], 1.091 to 18.91; P = .038) and ≥ 10 days of subtherapeutic tacrolimus levels in first 30 days on i.v. (OR, −3.8; 95% CI, 1.276 to 11.43; P =.017) were significantly associated with delay in achieving therapeutic tacrolimus trough concentration. The impact of race/ethnicity on therapeutic tacrolimus trough concentration in pediatric alloHCT recipients should be further studied prospectively so that individualized dosing plans can be developed.

show abstract

Genetic Differences in Native Americans and Tacrolimus Dosing After Kidney Transplantation

Cited by 18 publications

References 14 publications

Pharmacogenetics in American Indian populations

Pharmacogenetics in American Indian populations

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

Risk Factors for Subtherapeutic Tacrolimus Levels after Conversion from Continuous Intravenous Infusion to Oral in Children after Allogeneic Hematopoietic Cell Transplantation

Contact Info

Product

Resources

About