Validation of Genetic Variants Identified in GWAS for Tacrolimus Troughs
1Experimental and Clinical Pharmacology, Univ of MN, Minneapolis, MN
2Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN
3Division of Biostatistics, Univ of MN, Minneapolis, MN
4Medicinal Chemistry, Univ of MN, Minneapolis, MN
5Medicine, Hennepin County Medical Center, Minneapolis, MN
6Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
7Surgery, Univ of Pennsylvania, Philadelphia, PA
8Surgery, Univ of MN, Minneapolis, MN
9Rho Inc, Chapel Hill, NC
10Department of Medicine and Surgery, Univ of Alabama, Birmingham, AL.
Meeting: 2018 American Transplant Congress
Abstract number: C75
Keywords: African-American, FK506, Gene polymorphism, Kidney transplantation
Session Information
Session Name: Poster Session C: Kidney Immunosuppression: Novel Regimens and Drug Minimization
Session Type: Poster Session
Date: Monday, June 4, 2018
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall 4EF
Purpose: Tacrolimus (TAC) is a substrate for CYP3A4/5 enzymes. It is well-known that variants in these genes are associated with variability in TAC trough concentrations. The purpose of this study is to validate the variants for TAC troughs identified in our GWAS in our newly enrolled cohort.
Methods: Caucasian (n=1446) and African American (AA) (n=345) adult kidney or kidney pancreas transplant recipients enrolled in the DeKAF Genomics were genotyped using an GWAS exome-plus Affymetrix TXArray chip with ~800,000 high quality markers after QC and >34M markers after imputation based on 1000 Genomes project. A GWAS of >30,000 dose-normalized troughs in the first 6 mo posttx was performed using repeated measures regression adjusting for age, gender and top principal components. 19 variants in Caucasians and 11 variants in AA were identified. We validated these variants in the GEN03 cohort (Caucasians [n=609], AA [n=171]) with >13,000 troughs. A p-value of 0.0026 in Caucasians and 0.0045 in AA or lower was required for replication (Bonferroni).
Results: In Caucasians the CYP3A5*3 (p=2.2×10-34) and CYP3A4*22 (p=2.4×10-7) variants were replicated and rs4646450 in CYP3A5 (p=9.5×10-3) was suggestive. In the AA cohort the CYP3A5*3 (p=2.8×10-8), CYP3A5*6 (p=3.3×10-5) and CYP3A5*7 (p=1.2×10-5) were replicated.
Conclusion: We validated the common and known variants, CYP3A5*3, *6, *7 and CYP3A4*22. The variant, rs4646450 was associated but did not reach the validation threshold. This variant is in weak LD with CYP3A5*3 but is independently associated. Future work should evaluate the function of this variant. It is unlikely that other common variants are associated with TAC metabolism in these populations.
CITATION INFORMATION: Jacobson P., Schladt D., Guan W., van Setten J., Remmel R., Wu B., Dorr C., Keating B., Ikle D., Mannon R., Matas A., Israni A., Oetting W. Validation of Genetic Variants Identified in GWAS for Tacrolimus Troughs Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Jacobson P, Schladt D, Guan W, Setten Jvan, Remmel R, Wu B, Dorr C, Keating B, Ikle D, Mannon R, Matas A, Israni A, Oetting W. Validation of Genetic Variants Identified in GWAS for Tacrolimus Troughs [abstract]. https://atcmeetingabstracts.com/abstract/validation-of-genetic-variants-identified-in-gwas-for-tacrolimus-troughs/. Accessed May 16, 2025.« Back to 2018 American Transplant Congress