一项关于替诺福韦相关范科尼综合征的药物遗传学候选基因研究。
A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome.
作者信息
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
机构信息
aDepartment of Bioengineering and Therapeutic Sciences bInstitute of Human Genetics, University of California cGenomics Core Facility, Institute for Human Genetics, San Francisco dGilead Sciences Inc., Foster City, California eDivision of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA.
出版信息
Pharmacogenet Genomics. 2015 Feb;25(2):82-92. doi: 10.1097/FPC.0000000000000110.
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 = -73.3 ml/min/1.73 m(2)) 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.
背景
富马酸替诺福韦二吡呋酯（TDF）是一种广泛使用的抗逆转录病毒药物，具有良好的疗效、安全性和耐受性。然而，在接受HIV感染治疗的一小部分患者中可能会发生肾脏不良事件，包括罕见的范科尼综合征（FS）。
目的
本研究的目的是确定可能与TDF相关的FS（TDF-FS）相关的基因变异。
方法
对从19例TDF-FS患者和36例匹配对照中收集的DNA样本进行测序，并对8个候选基因进行基因关联研究：ATP结合盒（ABC）转运蛋白ABCC2（MRP2）和ABCC4（MRP4）、溶质载体家族成员SLC22A6（OAT1）和SLC22A8（OAT3）、腺苷酸激酶2（AK2）和4（AK4）、氯转运蛋白CIC-5 CLCN5以及洛氏综合征蛋白OCRL。然后在表达已鉴定的ABCC4变异体的细胞中研究预测会改变替诺福韦转运的单核苷酸多态性（SNP）的功能效应。
结果
病例组显示罕见等位基因比例有升高趋势。ABCC2（3个SNP）、ABCC4（1个SNP）和OCRL（2个SNP）中的6个SNP与TDF-FS病例状态相关；然而，在进行多重检验校正后，这种关联不再显著。OCRL（4个SNP）和ABCC2（2个SNP）中存在的6个SNP与病例组血清肌酐水平升高显著相关，并且在多重检验校正后这种关联仍然显著（P < 2×10）。ABCC2中的一个同义SNP（rs8187707，P = 2.10×10，β = -73.3 ml/min/1.73 m(2)）也与病例组中肌酐估计肾小球滤过率降低显著相关。然而，这些结果是由少数严重受影响病例中存在的罕见SNP驱动的。最后，一个先前未鉴定的非同义SNP，rs11568694，预测会改变MRP4功能，但在体外对替诺福韦细胞内蓄积没有显著影响。
结论
虽然未鉴定出用于预测TDF-FS发生的单一遗传标志物，但我们的研究结果表明，参与替诺福韦肾脏处理和/或肾细胞内稳态的多个基因中的罕见变异可能与TDF-FS易感性增加有关。
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