Identification of Genetic Variants Associated With Variation of Tacrolimus Levels in African Americans Using GWAS

W. Oetting,¹ D. Schladt,² W. Guan,¹ A. Israni,² R. Remmel,¹ C. Dorr,² K. Sanghavi,¹ R. Mannon,³ B. Herrera,⁴ A. Matas,¹ D. Salomon,⁵ P. Kwok,⁴ P. Jacobson,¹ for DeKAF Genomics.¹

¹Univ. of Minnesota, Minneapolis
²Minneapolis Medical Research Foundation, Minneapolis
³Univ. of Alabama, Birmingham
⁴Univ. of California, San Francisco
⁵Scripps Research Center, La Jolla.

Meeting: 2015 American Transplant Congress

Abstract number: B277

Keywords: African-American, Genomics, Immunosuppression, Polymorphism

Session Information

Session Name: Poster Session B: Vascularized Composite Tissue Allografts and Xenotransplantation

Session Type: Poster Session

Date: Sunday, May 3, 2015

Session Time: 5:30pm-6:30pm

Presentation Time: 5:30pm-6:30pm

Location: Exhibit Hall E

African American kidney transplant recipients (AA) have a higher incidence of allograft failure when compared to Caucasians. We have previously reported that tacrolimus troughs (TT) for AA are much lower than observed in Caucasians and subtherapeutic TT may be associated with allograft failure, which in part may be due to the CYP3A5*1 genotype that is more frequent in AA. However, even after accounting for this genotype there is significant variability in AA associated TT. Thus, we wished to identify additional genetic variants associated with this variability. We analyzed 197 AA with TT using a GWAS chip with >800,000 SNPs. TT were measured from whole blood using liquid chromatography-MS. In general, two TT measurements were obtained in weeks 1 and 8, and in months 3, 4, 5 and 6 for a maximum of 24 TT concentrations per patient (avg. = 17.1). In the analysis of dose-normalized TT, two variants (rs17161880, p=1.00E^-14 and rs34880695, p=7.80E^-14) within the pseudogene CYP3AP2 were the most significant variants in the initial analysis. Both variants are in linkage disequilibrium (LD) with rs776746, a well-known loss-of-function (LoF) allele in CYP3A5 (CYP3A5*3). After adjusting for rs776746, rs6956305 was the most significant variant (p=2.9E^-15), which is in high LD with another CYP3A5 LoF variant rs41303343 (CYP3A5*7, p=3.00E^-16). We then adjusted for CYP3A5*3, *7, and *6 (rs10264272, a LoF AA variant reported in the literature, p=3.10E^-5) after which no other SNPs in the GWAS were significant. Recipient age, GFR, antiviral use, SPK and antibody induction were the most significant clinical variables. Using multivariable analysis, within the AA population, the clinical variables alone captured 14.8% of the variance in TT and the 3 LoF alleles captured an additional 36.4% for a total of 51.2% explained variance. We conclude that the AA specific variants CYP3A5*3 (MAF=.31), CYP3A5*6 (MAF=.11) and CYP3A5*7 (MAF=.10) explain a great proportion of the observed TT variability in AA. A better understanding of population specific impact on genomic variants is a critical step to personalized medicine approach to transplant immunosuppression. (Funded by NIAID)

To cite this abstract in AMA style:

Oetting W, Schladt D, Guan W, Israni A, Remmel R, Dorr C, Sanghavi K, Mannon R, Herrera B, Matas A, Salomon D, Kwok P, Jacobson P, Genomics forDeKAF. Identification of Genetic Variants Associated With Variation of Tacrolimus Levels in African Americans Using GWAS [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/identification-of-genetic-variants-associated-with-variation-of-tacrolimus-levels-in-african-americans-using-gwas/. Accessed November 21, 2024.

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