2018
DOI: 10.2217/pgs-2017-0187
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Attempted Validation of 44 Reported SNPs Associated with Tacrolimus Troughs in a Cohort of Kidney Allograft Recipients

Abstract: There is no evidence that common variants outside the CYP3A4 and CYP3A5 loci are associated with variation in TAC trough concentrations. In the future rare variants may be important and identified using DNA sequencing.

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Cited by 25 publications
(38 citation statements)
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“…Although the effect of ABCB1 genetic variability on TAC PK has been extensively studied [], to our knowledge, this is the first TAC pharmacogenetic study in solid organ transplantation patients to identify a significant impact of ABCB1 61A>G on TAC C 0 /D in the first 3 months post‐transplant. A LME model was used to analyse genetic determinants of log‐transformed TAC C 0 /D, which allowed for assessment of repeated measurements, accounted for confounding non‐genetic effects and adjusted for the expected major effect of CYP3A5*3 genotype in identifying additional genetic factors, such as ABCB1 61A>G. However, since this study was conducted predominantly in Caucasians, the significance of 61A>G is unknown in other ethnicities.…”
Section: Discussionmentioning
confidence: 99%
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“…Although the effect of ABCB1 genetic variability on TAC PK has been extensively studied [], to our knowledge, this is the first TAC pharmacogenetic study in solid organ transplantation patients to identify a significant impact of ABCB1 61A>G on TAC C 0 /D in the first 3 months post‐transplant. A LME model was used to analyse genetic determinants of log‐transformed TAC C 0 /D, which allowed for assessment of repeated measurements, accounted for confounding non‐genetic effects and adjusted for the expected major effect of CYP3A5*3 genotype in identifying additional genetic factors, such as ABCB1 61A>G. However, since this study was conducted predominantly in Caucasians, the significance of 61A>G is unknown in other ethnicities.…”
Section: Discussionmentioning
confidence: 99%
“…Cytochrome P450 reductase (encoded by POR ) is essential for CYP3A activity and the pregnane X receptor (encoded by NR1I2 ) regulates CYP3A4/5 and P‐gp expression ; with the potential for these genes to affect TAC PK. However, only CYP3A5*3 [the most common CYP3A5 single nucleotide polymorphism (SNP)] significantly affects TAC PK across different studies . The CYP3A5*3 allele (6986A>G, rs776746) leads to non‐functional CYP3A5 , and consequently, transplant recipients with CYP3A5*3/*3 genotype (termed ‘non‐expressors’) exhibit two times higher TAC C 0 /D than CYP3A5 *1/*1 and *1/*3 genotypes (collectively termed ‘expressors’) .…”
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confidence: 99%
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“…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%