AUTHOR=Oreschak Kris , Saba Laura M. , Rafaels Nicholas , Ambardekar Amrut V. , Deininger Kimberly M. , Page Robert L. , Lindenfeld JoAnn , Aquilante Christina L. 

TITLE=Association Between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.658983

DOI=10.3389/fgene.2021.658983

ISSN=1664-8021

ABSTRACT=<p><bold>Background</bold>: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients.</p><p><bold>Methods</bold>: This retrospective analysis included <italic>N</italic> = 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) &lt;45 ml/min/1.73m<sup>2</sup>.</p><p><bold>Results:</bold> Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 (<italic>TGFB1</italic>) rs4803455 C &gt; A and phospholipase C beta 1 (<italic>PLCB1</italic>) rs170549 G &gt; A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers of <italic>TGFB1</italic> rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12–0.62; <italic>p</italic> = 0.002], whereas <italic>PLCB1</italic> rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21–5.84, <italic>p</italic> = 0.015).</p><p><bold>Conclusion</bold>: Our data suggest that genetic variation in <italic>TGFB1</italic> and <italic>PLCB1</italic> may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such as <italic>TGFB1</italic> rs4803455 and <italic>PLCB1</italic> rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.</p>