Variants Associated With Tacrolimus Troughs in European American Kidney Transplant Recipients: A Genome Wide Association Study
1College of Pharmacy, University of MN, Minneapolis, MN
2Department of Psychology, University of MN, Minneapolis, MN
3Department of Nephrology and Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN
4Department of Biostatistics, University of MN, Minneapolis, MN
5Department of Surgery, University of MN, Minneapolis, MN.
Meeting: 2015 American Transplant Congress
Abstract number: B257
Keywords: Calcineurin, Gene polymorphism, Immunosuppression, Monitoring
Session Information
Date: Sunday, May 3, 2015
Session Name: Poster Session B: Translational Genetics and Proteomics in Transplantation
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Tacrolimus (tac) is dependent on CYP3A4/5 for metabolism. Variability in the metabolism is influenced by CYP3A5*3 alleles. This variant and clinical factors explain around 50% of variability in tac troughs. Other variants may be present that explain additional variability. The purpose of this study is to identify new variants which are determinants of tac troughs in a large, European ancestry cohort of (n=1457) adult kidney or kidney pancreas transplant recipients in a 7-center consortium. European kidney transplant recipients enrolled in the DeKAF Genomics study and received tac were genotyped using an exome-plus Affymetrix TXArray chip containing 450,130 markers after QC. The associations between variants across the genome and dose normalized whole blood tac troughs (n=25481) in the first 6 mo posttx were evaluated using repeated measures regression analysis.
The median (range) recipient age was 52.6 yrs (18-83), 63% were males and 66% received a living donor transplant. Median (range) tac troughs and dose were 8.4 ng/mL (0.3-75.9) and 5.5 mg/day (0.1-36), respectively. Seven variants (rs35599367, rs74516408, rs7792939, rs62471929, rs4986910, rs62471957, rs62474460) were associated with tac troughs after adjusting for CYP3A5*3 and four ancestry principal components (all genome wide significant, p<10-8). The analysis was then adjusted for the top SNP, rs35599367 (CYP3A4*22) and no variants remained significant at the genome wide level (p>10-7), although, rs4986910 (CYP3A4*3) continued to be important with p=0.001. Each CYP3A5*3 allele increased the dose-normalized tac trough by 84% and each CYP3A4*22 by 37% and CYP3A4*3 by 41%. Allele frequencies for CYP3A5*3, CYP3A4*22 and CYP3A4*3 were 0.93, 0.057 and was 0.011, respectively. CYP3A5*3, CYP3A4*22 and CYP3A4*3 were associated with tac troughs in our cohort of European Americans. Future studies identifying less frequent variants which may have important effects on troughs are warranted. This project was supported by NIAID.
To cite this abstract in AMA style:
Jacobson P, Miller M, Schladt D, Israni A, Sanghavi K, Dorr C, Remmel R, Guan W, Matas A, Oetting W. Variants Associated With Tacrolimus Troughs in European American Kidney Transplant Recipients: A Genome Wide Association Study [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/variants-associated-with-tacrolimus-troughs-in-european-american-kidney-transplant-recipients-a-genome-wide-association-study/. Accessed September 27, 2020.« Back to 2015 American Transplant Congress