A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome

Amber Dahlin, Matthias Wittwer, Melanie De La Cruz, Jonathan M. Woo, Rujuta Bam, Valeska Scharen-Guivel, John Flaherty, Adrian S. Ray, Tomas Cihlar, Samir Gupta, Kathleen M. Giacomini

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: 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. OBJECTIVES: The aim of this study was to identify genetic variants that may be associated with TDF-associated FS (TDF-FS). METHODS: 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 ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. 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 ABCC4. Results: The case group showed a trend toward a higher proportion of rare alleles. Six SNPs in ABCC2 (three SNPs), ABCC4 (one SNP), and OCRL (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 OCRL (four SNPs) and ABCC2 (two SNPs), were significantly associated with increased serum creatinine levels in the cases, and this association remained significant after multiple test correction (P<2×10). One synonymous SNP in ABCC2 (rs8187707, P=2.10×10, β=-73.3ml/min/1.73m) 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 in vitro. Conclusion: 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.

Original languageEnglish
Pages (from-to)82-92
Number of pages11
JournalPharmacogenetics and Genomics
Volume25
Issue number2
DOIs
StatePublished - Feb 13 2015

Fingerprint

Tenofovir
Fanconi Syndrome
Pharmacogenetics
Single Nucleotide Polymorphism
Genes
Kidney
Creatinine
Oculocerebrorenal Syndrome
Anti-Retroviral Agents

Keywords

  • Anconi syndrome
  • HIV
  • pharmacogenetics
  • tenofovir
  • transporter

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Dahlin, A., Wittwer, M., De La Cruz, M., Woo, J. M., Bam, R., Scharen-Guivel, V., ... Giacomini, K. M. (2015). A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. Pharmacogenetics and Genomics, 25(2), 82-92. https://doi.org/10.1097/FPC.0000000000000110

A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. / 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; Giacomini, Kathleen M.

In: Pharmacogenetics and Genomics, Vol. 25, No. 2, 13.02.2015, p. 82-92.

Research output: Contribution to journalArticle

Dahlin, A, Wittwer, M, De La Cruz, M, Woo, JM, Bam, R, Scharen-Guivel, V, Flaherty, J, Ray, AS, Cihlar, T, Gupta, S & Giacomini, KM 2015, 'A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome', Pharmacogenetics and Genomics, vol. 25, no. 2, pp. 82-92. https://doi.org/10.1097/FPC.0000000000000110
Dahlin A, Wittwer M, De La Cruz M, Woo JM, Bam R, Scharen-Guivel V et al. A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. Pharmacogenetics and Genomics. 2015 Feb 13;25(2):82-92. https://doi.org/10.1097/FPC.0000000000000110
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 ; Giacomini, Kathleen M. / A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. In: Pharmacogenetics and Genomics. 2015 ; Vol. 25, No. 2. pp. 82-92.
@article{171d03380c7748cf98bbad7ba9cde476,
title = "A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome",
abstract = "Background: 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. OBJECTIVES: The aim of this study was to identify genetic variants that may be associated with TDF-associated FS (TDF-FS). METHODS: 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 ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. 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 ABCC4. Results: The case group showed a trend toward a higher proportion of rare alleles. Six SNPs in ABCC2 (three SNPs), ABCC4 (one SNP), and OCRL (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 OCRL (four SNPs) and ABCC2 (two SNPs), were significantly associated with increased serum creatinine levels in the cases, and this association remained significant after multiple test correction (P<2×10). One synonymous SNP in ABCC2 (rs8187707, P=2.10×10, β=-73.3ml/min/1.73m) 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 in vitro. Conclusion: 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.",
keywords = "Anconi syndrome, HIV, pharmacogenetics, tenofovir, transporter",
author = "Amber Dahlin and Matthias Wittwer and {De La Cruz}, Melanie and Woo, {Jonathan M.} and Rujuta Bam and Valeska Scharen-Guivel and John Flaherty and Ray, {Adrian S.} and Tomas Cihlar and Samir Gupta and Giacomini, {Kathleen M.}",
year = "2015",
month = "2",
day = "13",
doi = "10.1097/FPC.0000000000000110",
language = "English",
volume = "25",
pages = "82--92",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome

AU - Dahlin, Amber

AU - Wittwer, Matthias

AU - De La Cruz, Melanie

AU - Woo, Jonathan M.

AU - Bam, Rujuta

AU - Scharen-Guivel, Valeska

AU - Flaherty, John

AU - Ray, Adrian S.

AU - Cihlar, Tomas

AU - Gupta, Samir

AU - Giacomini, Kathleen M.

PY - 2015/2/13

Y1 - 2015/2/13

N2 - Background: 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. OBJECTIVES: The aim of this study was to identify genetic variants that may be associated with TDF-associated FS (TDF-FS). METHODS: 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 ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. 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 ABCC4. Results: The case group showed a trend toward a higher proportion of rare alleles. Six SNPs in ABCC2 (three SNPs), ABCC4 (one SNP), and OCRL (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 OCRL (four SNPs) and ABCC2 (two SNPs), were significantly associated with increased serum creatinine levels in the cases, and this association remained significant after multiple test correction (P<2×10). One synonymous SNP in ABCC2 (rs8187707, P=2.10×10, β=-73.3ml/min/1.73m) 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 in vitro. Conclusion: 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.

AB - Background: 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. OBJECTIVES: The aim of this study was to identify genetic variants that may be associated with TDF-associated FS (TDF-FS). METHODS: 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 ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. 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 ABCC4. Results: The case group showed a trend toward a higher proportion of rare alleles. Six SNPs in ABCC2 (three SNPs), ABCC4 (one SNP), and OCRL (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 OCRL (four SNPs) and ABCC2 (two SNPs), were significantly associated with increased serum creatinine levels in the cases, and this association remained significant after multiple test correction (P<2×10). One synonymous SNP in ABCC2 (rs8187707, P=2.10×10, β=-73.3ml/min/1.73m) 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 in vitro. Conclusion: 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.

KW - Anconi syndrome

KW - HIV

KW - pharmacogenetics

KW - tenofovir

KW - transporter

UR - http://www.scopus.com/inward/record.url?scp=84920884239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920884239&partnerID=8YFLogxK

U2 - 10.1097/FPC.0000000000000110

DO - 10.1097/FPC.0000000000000110

M3 - Article

C2 - 25485598

AN - SCOPUS:84920884239

VL - 25

SP - 82

EP - 92

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 2

ER -