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 language | English |
|---|---|
| Pages (from-to) | 82-92 |
| Number of pages | 11 |
| Journal | Pharmacogenetics and Genomics |
| Volume | 25 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 13 2015 |
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Keywords
- Anconi syndrome
- HIV
- pharmacogenetics
- tenofovir
- transporter
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Molecular Medicine
- Genetics(clinical)
Cite this
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 journal › Article
}
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
VL - 25
SP - 82
EP - 92
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 2
ER -