6 results on '"Dorr CR"'
Search Results
2. Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups.
- Author
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Mohamed ME, Schladt DP, Guan W, Wu B, van Setten J, Keating BJ, Iklé D, Remmel RP, Dorr CR, Mannon RB, Matas AJ, Israni AK, Oetting WS, and Jacobson PA
- Subjects
- Female, Follow-Up Studies, Gene Frequency, Genotype, Humans, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents metabolism, Kidney Failure, Chronic ethnology, Kidney Failure, Chronic genetics, Kidney Failure, Chronic therapy, Male, Middle Aged, Prognosis, Prospective Studies, Tacrolimus administration & dosage, Cytochrome P-450 CYP3A genetics, Ethnicity statistics & numerical data, Kidney Failure, Chronic metabolism, Kidney Transplantation methods, Polymorphism, Single Nucleotide, Tacrolimus metabolism
- Abstract
Tacrolimus trough and dose requirements vary dramatically between individuals of European 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 one suggestive variant in Asian Americans (P = 5.6 × 10-6 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)- Published
- 2019
- Full Text
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3. Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing.
- Author
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Dorr CR, Wu B, Remmel RP, Muthusamy A, Schladt DP, Abrahante JE, Guan W, Mannon RB, Matas AJ, Oetting WS, Jacobson PA, and Israni AK
- Subjects
- Adolescent, Adult, Black or African American genetics, Aged, Aged, 80 and over, Cytochromes b5 genetics, Female, Gene Frequency genetics, Genotype, Graft Rejection prevention & control, High-Throughput Nucleotide Sequencing methods, Humans, Immunosuppressive Agents therapeutic use, Kidney Transplantation methods, Male, Middle Aged, Phenotype, Prospective Studies, Tacrolimus therapeutic use, Transplant Recipients, White People genetics, Young Adult, Genetic Variation genetics, Graft Rejection genetics, Immunosuppressive Agents metabolism, Tacrolimus metabolism
- Abstract
An extreme phenotype sampling (EPS) model with targeted next-generation sequencing (NGS) identified genetic variants associated with tacrolimus (Tac) metabolism in subjects from the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort which included 1,442 European Americans (EA) and 345 African Americans (AA). This study included 48 subjects separated into 4 groups of 12 (AA high, AA low, EA high, EA low). Groups were selected by the extreme phenotype of dose-normalized Tac trough concentrations after adjusting for common genetic variants and clinical factors. NGS spanned > 3 Mb of 28 genes and identified 18,661 genetic variants (3961 previously unknown). A group of 125 deleterious variants, by SIFT analysis, were associated with Tac troughs in EAs (burden test, p = 0.008), CYB5R2 was associated with Tac troughs in AAs (SKAT, p = 0.00079). In CYB5R2, rs61733057 (increased allele frequency in AAs) was predicted to disrupt protein function by SIFT and PolyPhen2 analysis. The variants merit further validation.
- Published
- 2019
- Full Text
- View/download PDF
4. Genetics of acute rejection after kidney transplantation.
- Author
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Dorr CR, Oetting WS, Jacobson PA, and Israni AK
- Subjects
- Gene Expression Profiling, Humans, Pharmacogenomic Testing, Polymorphism, Single Nucleotide, Graft Rejection genetics, Kidney Transplantation adverse effects
- Abstract
Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review article covers literature in regard to recipient and donor genetics of AR kidney and secondarily of liver allografts. Many candidate gene and some genome-wide association studies (GWASs) have been conducted for AR in kidney transplantation. Genetic associations with AR in kidney and liver are mostly weak, and in most cases, the associations have not been reproducible. A limitation in the study of AR is the lack of sufficiently large populations that account for population stratification to study the AR phenotype which in this era occurs in <10% of transplants. Furthermore, the AR phenotype has been difficult to define and the definitions of classifications have evolved over time. Literature related to the pharmacogenomics of tacrolimus is robust and has been validated in many studies. Associations between gene expression and AR are emerging as markers of outcomes and AR classification. In the future, combinations of pretransplant genotype for AR risk prediction, genotype-based immune suppressant dosing, and pharmacogenomic markers to select AR maintenance or treatment and expression markers from biopsies may provide valuable clinical tools for guiding treatment., (© 2017 Steunstichting ESOT.)
- Published
- 2018
- Full Text
- View/download PDF
5. CRISPR/Cas9 Genetic Modification of CYP3A5 *3 in HuH-7 Human Hepatocyte Cell Line Leads to Cell Lines with Increased Midazolam and Tacrolimus Metabolism.
- Author
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Dorr CR, Remmel RP, Muthusamy A, Fisher J, Moriarity BS, Yasuda K, Wu B, Guan W, Schuetz EG, Oetting WS, Jacobson PA, and Israni AK
- Subjects
- Cell Line, Humans, Liver metabolism, Male, Middle Aged, Point Mutation genetics, RNA, Messenger genetics, Sequence Deletion genetics, CRISPR-Cas Systems genetics, Clustered Regularly Interspaced Short Palindromic Repeats genetics, Cytochrome P-450 CYP3A genetics, Hepatocytes metabolism, Midazolam metabolism, Tacrolimus metabolism
- Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 engineering of the CYP3A5 *3 locus (rs776746) in human liver cell line HuH-7 ( CYP3A5 *3/*3 ) has led to three CYP3A5 *1 cell lines by deletion of the exon 3B splice junction or point mutation. Cell lines CYP3A5 *1/*3 sd (single deletion), CYP3A5 *1/*1 dd (double deletion), or CYP3A5 *1/*3 pm (point mutation) expressed the CYP3A5 *1 mRNA and had elevated CYP3A5 mRNA ( P < 0.0005 for all engineered cell lines) and protein expression compared with HuH-7. In metabolism assays, HuH-7 had less tacrolimus (all P < 0.05) or midazolam (MDZ) (all P < 0.005) disappearance than all engineered cell lines. HuH-7 had less 1-OH MDZ (all P < 0.0005) or 4-OH (all P < 0.005) production in metabolism assays than all bioengineered cell lines. We confirmed CYP3A5 metabolic activity with the CYP3A4 selective inhibitor CYP3CIDE. This is the first report of genomic CYP3A5 bioengineering in human cell lines with drug metabolism analysis., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2017
- Full Text
- View/download PDF
6. Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes.
- Author
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Dorr CR, Freedman BI, Hicks PJ, Brown WM, Russell GB, Julian BA, Pastan SO, Gautreaux MD, Muthusamy A, Chinnakotla S, Hauptfeld V, Bray RA, Kirk AD, Divers J, and Israni AK
- Subjects
- Adult, Black or African American genetics, Allografts, Apolipoprotein L1, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Survival Rate, Treatment Outcome, Apolipoproteins genetics, Lipoproteins, HDL genetics, Liver Transplantation, Tissue Donors
- Abstract
Background: Apolipoprotein L1 gene (APOL1) G1 and G2 renal-risk variants, common in populations with recent African ancestry, are strongly associated with non-diabetic nephropathy, end-stage kidney disease, and shorter allograft survival in deceased-donor kidneys (autosomal recessive inheritance). Circulating APOL1 protein is synthesized primarily in the liver and hydrodynamic gene delivery of APOL1 G1 and G2 risk variants has caused hepatic necrosis in a murine model., Methods: To evaluate the impact of these variants in liver transplantation, this multicenter study investigated the association of APOL1 G1 and G2 alleles in deceased African American liver donors with allograft survival. Transplant recipients were followed for liver allograft survival using data from the Scientific Registry of Transplant Recipients., Results: Of the 639 liver donors evaluated, 247 had no APOL1 risk allele, 300 had 1 risk allele, and 92 had 2 risk alleles. Graft failure assessed at 15 days, 6 months, 1 year and total was not significantly associated with donor APOL1 genotype (p-values = 0.25, 0.19, 0.67 and 0.89, respectively)., Conclusions: In contrast to kidney transplantation, deceased-donor APOL1 G1 and G2 risk variants do not significantly impact outcomes in liver transplantation.
- Published
- 2016
- Full Text
- View/download PDF
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