A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Dahlin, Amber; Wittwer, Matthias; de la Cruz, Melanie; Woo, Jonathan M.; Bam, Rujuta; Scharen-Guivel, Valeska; Flaherty, John; Ray, Adrian S.; Cihlar, Tomas; Gupta, Samir K.; Giacomini, Kathleen M.
• Is Part Of: Pharmaocogenetics and genomics. Volume 25:Issue 2(2015:Feb.)
• Publication Date: 2015-02
• Subjects: Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000110
• Languages: English
• ISSNs: 1744-6872

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background</title> <p>Tenofovir disoproxil fumarate (TDF) is a widely used antiretroviral agent with favorable efficacy, safety, and tolerability profiles. However, renal adverse events, including the rare Fanconi syndrome (FS), may occur in a small subset of patients treated for HIV infections.</p> </sec> <sec> <title>Objectives</title> <p>The aim of this study was to identify genetic variants that may be associated with TDF-associated FS (TDF-FS).</p> </sec> <sec> <title>Methods</title> <p>DNA samples collected from 19 cases with TDF-FS and 36 matched controls were sequenced, and genetic association studies were conducted on eight candidate genes: ATP-binding cassette (ABC) transporters <italic>ABCC2</italic> (MRP2) and <italic>ABCC4</italic> (MRP4), solute carrier family members <italic>SLC22A6</italic> (OAT1) and <italic>SLC22A8</italic> (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 <italic>CLCN5</italic>, and Lowe syndrome protein <italic>OCRL</italic>. The functional effects of a single nucleotide polymorphism (SNP) predicted to alter the transport of tenofovir were then investigated in cells expressing an identified variant of <italic>ABCC4</italic>.</p> </sec> <sec> <title>Results</title> <p>The case group showed a trend toward a higher proportion of rare alleles. Six SNPs in <italic>ABCC2</italic> (three SNPs), <italic>ABCC4</italic> (one SNP), and <italic>OCRL</italic> (two SNPs) were associated with TDF-FS case status; however, this association did not remain significant after correction for multiple testing. Six SNPs, present in <italic>OCRL</italic> (four SNPs) and <italic>ABCC2</italic> (two SNPs), were significantly associated with increased serum creatinine levels in the cases, and this association remained significant after multiple test correction (<italic>P</italic><2×10<sup>–4</sup>). One synonymous SNP in <italic>ABCC2</italic> (rs8187707, <italic>P</italic>=2.10×10<sup>–4</sup>, <italic>β</italic>=−73.3 ml/min/1.73 m<sup>2</sup>) was also significantly associated with the decreased estimated glomerular filtration rate of creatinine among cases. However, these results were driven by rare SNPs present in a small number of severely affected cases. Finally, a previously uncharacterized, nonsynonymous SNP, rs11568694, that was predicted to alter MRP4 function had no significant effect on tenofovir cellular accumulation <italic>in vitro</italic>.</p> </sec> <sec> <title>Conclusion</title> <p>Although no single predictive genetic marker for the development of TDF-FS was identified, the findings from our study suggest that rare variants in multiple genes involved in the renal handling of tenofovir, and/or renal cell homeostasis, may be associated with increased susceptibility to TDF-FS.</p> </sec> </abstract>